Indocyanine Green Injection (ICG). Tumor Detection Potential of ICG-navigated Imaging in Liver Surgery for Metastatic Lesions

Table of Contents

Foreword:

1. ABSTRACT

2. SAMENVATTING

3. INTRODUCTION
3.1. Liver: Functional Anatomy and Surgical Management
3.1.1. Epidemiology
3.1.2. Surgical Management of Liver Metastases
3.1.3. Functional Surgical Anatomy
3.2. Diagnosis of Hepatic Metastases
3.2.1. Preoperative Imaging Methods
3.2.2. Intraoperative Imaging Methods
3.3. Indocyanine Green (ICG): a Promising tool for Intraoperative Liver Metastasis Detection
3.3.1. Indocyanine Green: Chemical and Optical Properties
3.3.2. Pharmacological Properties and Pharmacokinetics of ICG
3.3.3. ICG as a fluorescent dye: Historical Development
3.3.4. Indocyanine in Clinical Use

4. METHODOLOGY
4.1. Selection Criteria
4.2. Literature Search and Screening

5. RESULTS
5.1. Literature Search Results
5.2. Study Characteristics
5.3. Malignancy Detection Rate with intraoperative ICG use
5.4. Diagnostic improvement rate with ICG use
5.5. Does ICG have advantages over preoperative imaging techniques?
5.6. ICG versus other intraoperative diagnostic methods in hepatic metastases detection
5.7. Margin-free resection rate

6. DISCUSSION

7. CONCLUSION

8. APPENDIX

9. REFERENCES

Foreword:

This thesis is written in the context of the Master's degree in Medicine under the supervision of Prof. Dr. Frederik Berrevoet. In this thesis, I explored the advantages and limitations of indocyanine green use in the surgical diagnosis of liver metastases. Initially, this topic was new and challenging to me. However, as the project progressed, I enjoyed being introduced to the well-explored yet debatable area of cancer surgery. It was a great pleasure to analyze the literature and summarize the evidence highlighting the advantages and limitations of ICG-guided surgery.

I would like to thank my promoter Prof. Dr. Frederik Berrevoet, for his great support and encouragement, teachable feedback, and endless patience. His guidance was invaluable in shaping the project, and his feedback was a great source of learning.

I also thank Dr. Nigar Sofiyeva for her moral support, time, and feedback during this process.

Last but not least, I thank my family, my parents, and my sisters, Dr. Nooshin Bagheri and Nazanin Bagheri, for their continuous support. I am also grateful to my wife, Nataliia, for her love and care, without whom the writing period would be much more stressful.

1. ABSTRACT

Objective: Fluorescence imaging is an intraoperative guidance method used for malignancy detection with increasing potential. Indocyanine-green (ICG) is a fluorescent dye with FDA approval and is commonly used in various medical procedures, including segmental hepatectomy and liver metastasectomies. This review aims to evaluate the tumor detection potential of ICG-navigated imaging in liver surgery for metastatic lesions.

Materials and Methods: Medical databases, including PubMed, Embase, Web of Science, and Cochrane Library, were searched in July 2022. Articles analyzing the performance of ICG-guided surgeries in patients with liver metastases were eligible for inclusion. Tumor detection, diagnostic improvement, and margin-free tumor resection rates of ICG-guided imaging were evaluated and compared with preoperative and other intraoperative diagnostic methods.

Results: Screening of available literature has yielded 24 eligible studies for evidence synthesis. Colorectal cancers, with 335 patients in 19 studies, were the most commonly reported primary tumor site, followed by pancreatic (two studies with 54 patients) and neuroendocrine (four studies with 18 patients) malignancies.

The tumor detection rate using ICG ranged from 61.4% to 100% in colorectal cancer patients and 18.2% to 86% in neuroendocrine tumor malignancies. ICG was advantageous in detecting new, otherwise undiagnosed, small, and superficial metastatic lesions. The main factor affecting the ICG-guided visualization rate was the depth of the lesion from the liver capsule. The combined use of intraoperative ultrasound and ICG fluorescence significantly increased the efficiency of intraoperative tumor detection in most studies. Most authors reported that ICG-guided imaging is a helpful guidance tool aiding R0 resection.

Conclusions: ICG-navigated imaging is a promising tool for intraoperative tumor visualization. The method shows high sensitivity in detecting otherwise undiagnosed and unknown lesions and guides in visualizing the tumor demarcation line during liver resection.

2. SAMENVATTING

Inleiding: Fluorescentiebeeldvorming is een intraoperatieve geleidingsmethode voor het opsporen van maligniteiten die steeds meer mogelijkheden biedt. Indocyanine-groen (ICG) is een fluorescerende kleurstof met FDA-goedkeuring en wordt algemeen gebruikt bij diverse medische procedures, waaronder segmentale hepatectomie en resectie van levermetastasen.

Doel: Deze review heeft tot doel het tumordetectiepotentieel van ICG-gestuurde beeldvorming bij leverchirurgie van metastatische letsels te evalueren.

Methodologie: Medische databanken, waaronder PubMed, Embase, Web of Science en Cochrane Library, werden doorzocht in juli 2022. Artikelen die de prestaties van ICG-geleide operaties bij patiënten met levermetastasen analyseerden kwamen in aanmerking voor inclusie. Tumordetectie, diagnostische verbetering en margevrije tumorresectiepercentages van ICG-geleide beeldvorming werden geëvalueerd en vergeleken met preoperatieve en andere intraoperatieve diagnostische methoden.

Resultaten: Screening van de beschikbare literatuur leverde 24 in aanmerking komende studies op voor verdere analyse. Colorectaal carcinoom met 335 patineten in 19 studies was de meest gerapporteerde primaire tumorlocatie, gevolgd door pancreas- (twee studies met 54 patienten) en neuro-endocriene (vier studies met 18 patienten) maligniteiten.

De tumordetectie varieerde van 61,4% tot 100% bij colorectale kanker en 18,2% tot 100% bij neuro-endocriene tumormaligniteiten. ICG was voordelig bij het opsporen van nieuwe, anders niet gediagnosticeerde, kleine en oppervlakkige metastatische laesies. De belangrijkste factor die de visualisatiegraad van ICG beinvloedde, was de diepte van de laesie ten opzichte van het leverkapsel. Het gecombineerde gebruik van intra-operatieve echografie en ICG- fluorescentie verhoogde de efficiëntie van de intra-operatieve tumordetectie aanzienlijk. De meeste auteurs meldden de ICG-geleide beeldvorming als een nuttig begeleidingsinstrument voor R0-resectie.

Conclusie: ICG-gestuurde beeldvorming is een veelbelovend instrument voor intra- operatieve tumorvisualisatie. De methode vertoont een hoge gevoeligheid bij het opsporen van anders niet gediagnosticeerde en onbekende laesies en begeleidt bij het visualiseren van de tumor resectielijn.

3. INTRODUCTION

3.1. Liver: Functional Anatomy and Surgical Management

3.1.1. Epidemiology

Portal circulation makes hematogenously-disseminated colorectal malignancies the most common primary site to metastasize to the liver 1. In total, 30-50% of colorectal cancers develop liver metastasis (CRLM), and 15-20% are candidates for surgery. Surgery is the only treatment of choice and has a potential curative effect with a 5-year survival rate of 71% 2.

3.1.2. Surgical Management of Liver Metastases

A staging system based on the European Colorectal Metastasis Treatment Group classifies the disease according to the dissemination level; M0: with no metastasis, M1a: metastasis confined to one organ, in this case to the liver, M1b: metastasis in more than one organ, M1c: metastasis to the peritoneum with or without the organ involvement 5. Subsequently, the level of dissemination determines the resectability of the metastatic lesion; M1a: resectable, M1b: potentially resectable, and M1c: unlikely to ever be resectable 5 (Table 1).

The aim of hepatic metastasis surgery is the detection and complete removal of all suspicious and malignant lesions without residual tumor burden. Based on the OncoSurgery Approach recommendation, the primary aim of the CRLM treatment is to achieve a prolonged disease-free survival following the excision of the resectable metastasis 6. The definition of resectability was proposed by Clavien et al. 7 as a potential for a complete resection with a tumor-free or with a negative margin of more than 1 cm (R0). However, R0 excision should be limited to at least two disease-free liver segment preservation. These segments should be in continuity; the remnant liver must be supplied by a hepatic artery and portal vein, a bile duct with a continuation to the gut, and contain one of the three main hepatic veins 8. Moreover, the residual liver volume should be greater than 20% or 30% in the healthy or post-chemotherapeutic liver, respectively 9.

Table 1. Surgical management of colorectal cancer metastasis based on the ECMTG staging system according to the metastasis status 3

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NA: not applicable

3.1.3. Functional Surgical Anatomy

One of the main determinants of successful metastasis surgery is the tumor's location. The segmental anatomy of the liver, described by Couinaud et al. 4 in 1957, is being used as a guide in modern liver surgery. The functional anatomy of the liver is based on the liver architecture, in which the liver is divided into four sectors and eight segments. Each of these segments has an individual hepatic artery, hepatic vein, portal vein, and bile duct. Liver segments based on the description of Couinaud et al. are presented in Figure 1.

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Figure 1. Liver segments based on the description of Couinaud et al. (1957) 4 (Retrieved from the Primrose, J. N. (2010). "Surgery for colorectal liver metastases." Br J Cancer 102(9): 1313-1318.)

3.2. Diagnosis of Hepatic Metastases

3.2.1. Preoperative Imaging Methods

Preoperative imaging is essential for successful metastasis surgery. The aim of preoperative imaging is to evaluate the number of metastases, localize metastatic lesions and assess the volume of the liver.

Multidetector helical computer tomography (CT or MDCT) scan is the most commonly used diagnostic imaging method with a 70-95% detection sensitivity 5. It is easy to perform and more accessible. CT imaging is recommended as the first-choice method in the initial assessment and follow-up of metastatic liver lesions 6. Furthermore, CT, in combination with 3-D image analysis, can be helpful in calculating the resected and residual liver volume 7. However, the use of CT is limited in identifying lesions smaller than 1 cm 6.

Magnetic resonance imaging (MRI) is a safer technique without radiation. The use of MRI is associated with better tissue characterization. Moreover, MRI is superior to CT in detecting subcentimetric metastatic lesions 6. Combination with liver-specific contrast agents increases the efficiency of the method. Gadobenate dimeglumine (Gd-BOPTA)- and gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) - guided MRI provide information about the vascularization of the lesions 8. According to Granata et al. 9, gadoxetic acid-enhanced MRI has a higher metastatic detection rate than multidetector computer tomography, especially in cases that underwent neo-adjuvant chemotherapy and with subcapsular lesions. With the increasing need to assess the segmental anatomy of the liver, the use of computer-aided diagnosis, i.e., CT combined with an MRI, has been increased 10.

F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning is a widely used and informative diagnostic tool in cancer management. The sensitivity of the method to detect liver metastasis is around 75%, while this number increases up to 89% if combined with CT imaging. FGD-PET, in combination with CT, is considered a gold standard in the detection of liver metastasis 11.

3.2.2. Intraoperative Imaging Methods

An intraoperative evaluation of the liver is crucial for tumor detection, especially in cases with altered liver parenchyma, such as fatty liver, cirrhosis, or blue livers occurring after multiple chemotherapy regimens. Moreover, patients undergoing neo-adjuvant chemotherapy may present with small, nearly regressed lesions, which further challenges intraoperative management.

Inspection of the liver surface and palpation are important tools for detecting liver metastasis during surgery. However, this approach is highly limiting during laparoscopic and robotic surgeries.

Intraoperative Ultrasonography (IOUS) is the primary approach for intraoperative guidance in liver metastasis surgery. IOUS has been utilized in hepatobiliary surgery since the 1980s, and since the 1990s, it has become a routine in hepatic surgery.

IOUS provides information about the tumor location, size, and tumoral margins relative to healthy liver tissue. Direct contact of the ultrasound probe with the liver surface eliminates the skin and subcutaneous tissue barriers, which brings additional advantages to the IOUS compared to the preoperative imaging methods. The sensitivity of IOUS is 95-100%, which surpasses preoperative CT and the percutaneous US with sensitivities of 80% and 70%, respectively.

On the other hand, IOUS provides two-dimensional (2D) imaging. Most hepatic metastatic tumors are subcentimetric and isoechoic relative to the healthy liver tissue, which limits the use of IOUS. Moreover, it may have difficulty detecting tumors in the fatty liver 12.

The application of intraoperative MRI is a new promising approach with limited data available in the literature. Given the high success rate of preoperative MRI assessment, for the first time intraoperatively, it was applied in 2020 13. Based on the report, the method was fast, safe, and feasible. Moreover, it was successfully used to eliminate remaining metastases in the liver.

3.2.2.1. Perfusion Imaging Techniques

Microcirculation of the liver might be distorted by varying factors, one of them being malignant conditions of the organ. Based on this factor, perfusion imaging techniques (PITs) became a promising direction in liver cancer surgery.

PITs deliver real-time qualitative and quantitated measurements of hepatic microcirculation 14. The main domains of this method are described below.

3.2.2.1.1. Dynamic contrast-enhanced US (DCE-US)

Dynamic contrast-enhanced intraoperative ultrasonography (DCE-IOUS or CE-IOUS) is a combination of microbubble agent use with the conventional US. In this method, 1-10 pm diameter gas-filled microbubbles are injected intravenously. Due to the higher degree of echogenicity, microbubbles enhance the contrast of the tissue with an increased perfusion rate relative to the neighboring tissue—this aids with increasing the detection rate of small and additional lesions and guides with resection margin. With minimal cardio-, hepato-, and nephrotoxicity risks, this method is more suitable for use in pediatric and critically ill patients 14.

For the first time, the use of DCE-US in hepatic surgery practice was reported by Leen et al. 15, where authors reported higher sensitivity of the method over CT or MRI in the detection of liver metastasis. According to a recent meta-analysis including eleven studies, CE-IOUS shows significantly higher sensitivity and accuracy than MDCT, MRI, and IOUS 16.

However, this technique requires extensive training. Moreover, even with minimal deviations from the liver surface, ultrasound may introduce an artifact in blood flow measurement. In cases with chronic right-sided heart failure or fatty liver, the sensitivity of the method decreases.

3.2.2.I.2. Indocyanine Green Fluorescence (ICG-F) imaging

During the last decades, indocyanine green fluorescence became an emerging method in liver metastasis surgery. This method is based on the intravenous injection of the contrast dye, indocyanine green, and real-time fluorescence visualization with near-infrared imaging.

3.3. Indocyanine Green (ICG): a Promising tool for Intraoperative Liver Metastasis Detection

3.3.1. Indocyanine Green: Chemical and Optical Properties

Indocyanine green is an odorless, water-soluble, tricarboncyanine dye with a molecular weight of 751.4 Da. ICG is produced as a powder for medical use due to its limited stability in aqueous solutions, especially under light exposure. Thus, the diluted drug should be used within 6-10 hours 17.

The color of the dye changes under different conditions; it has a brown appearance with sodium iodide addition, which is used to increase the solubility of the dye, and turns green or emerald green in water or phosphate-buffered saline (PBS) solutions, respectively (Figure 2).

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Figure 2. Indocyanine green with the sodium iodide has a brown appearance (left); Phosphate buffered saline (PBS)-diluted solutions display an emerald green color (right)

Retrieved from: Lu, C. H. and J. K. Hsiao (2021). "Indocyanine green: An old drug with novel applications." Tzu Chi Med J 33(4): 317-322.

ICG binding to the proteins in tissues and cells increases its spectral stability. Protein binding also changes the dye's optical properties, moving it to the longer 810 nm wavelengths 18. Thus, the fluorescence is invisible to the human eye.

ICG excites at 600-900 nm with a maximum of 875 nm and emits light at 750-950 nm with a peak at 830 nm in human blood 19 (Figure 3), which are located in the near-infrared (NIR) diapason. Therefore, NIR cameras are required to visualize the ICG intraoperatively within the tissues.

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https://api.intechopen.com/media/chapter/43481/media/image2.jpeg

This figure has been removed by GRIN for copyright reasons.

Figure 3. Optical Properties of ICG: ICG is invisible to the human eye. It has a peak spectral absorption at near-infrared rays of 760-780 nm and emits light at 790-850 (peak at 806 nm).

Retrieved from: Yamamoto, M. , Orihashi, K. , Sato, T. . Intraoperative Indocyanine Green Imaging Technique in Cardiovascular Surgery. In: Aronow, W. S. , editor. Artery Bypass [Internet]. London: IntechOpen; 2013 [cited 2022 Aug 13]. Available from: https://www.intechopen.com/chapters/43481 DOI: 10.5772/55311

3.3.2. Pharmacological Properties and Pharmacokinetics of ICG

ICG is nontoxic in humans in standard doses up to 5 mg/kg of body weight 20. However, due to the singlet oxygen molecule binding to the breakdown products, the dye has lethal effects (LD50- lethal dose) of 50-80 mg/kg. Moreover, dye aggregates are formed at higher, above 15 mg/L, concentrations 21.

ICG is not absorbable from the gastrointestinal tract and is being implemented intravenously. Upon intravenous injection, 98% of ICG conjugates with plasma proteins, almost exclusively with albumin, to a lesser extent a- and ß- lipoproteins, decreasing the extravasation of the dye 22. This binding doesn't change the protein structure proving the nontoxic property of the dye. 2% of ICG remains free in the serum, which later excretes into the bile 17.

ICG is selectively taken by hepatocytes with the use of glutathione S-transferase without modification [22, 23]. The only elimination way of the drug is strictly through biliary secretion in the unconjugated form after 8 min of injection, making ICG a great tool for hepatobiliary assessment.

Despite limited toxicity and adverse effects, the iodine content of the ICG should be considered in patients with iodine allergy and in cases who underwent the radioactive iodine uptake test within one week.

3.3.3. ICG as a fluorescent dye: Historical Development

Due to the fluorescing properties, ICG was initially developed for photography purposes by Kodak during World War 2.

Clinical and research use of ICG in humans started after the United States Food and Drug Administration 24 approval in 1956, although tissue injections of the drug are still off-label. Initial use was focused on functional assessments, including liver and renal blood flow, cardiac murmur, and brain perfusion evaluations by quantifying the ICG levels in blood [1, 27]. From the 1970s, ICG was used for its fluorescent properties in ophthalmology. With further advancements in digital imaging, ICG angiography has been expanded to tissue perfusion assessments in neurosurgery and cardiology. Although off-label, ICG fluorescence real-time imaging is widely used in abdominal, plastic, and oncological surgeries 1.

3.3.4. Indocyanine in Clinical Use

3.3.4.1. Quantification Methods

Hepatic Function Assessment

Given the exclusive excretion of the dye by hepatocytes and the affinity of ICG for the intravascular space, blood ICG levels directly correspond with hepatic function. Since 1959, ICG has been used to assess liver function with the liver clearance test. This method is considered the best discriminating test for preoperative hepatic function assessment to predict postoperative hepatic failure and estimate the reserve of residual liver tissue. Moreover, the intraoperative ICG clearance test is used to determine the preservation of sufficient liver parenchyma17.

For the liver clearance test, the patient is administered ICG intravenously and quantified following the injection levels of the dye. Measurements could be performed by serial blood sampling or non-invasively. In the noninvasive method, an optical sensor is placed on the fingertip of the patient, and ICG levels are quantified through pulse dye densitometry 25. Plasma disappearance rate (normal value: PDR <19.5%) and fractional retention at 15 min (normal value: R15>5.6%) compared to the preoperative values are used for the ICG clearance.

3.3.4.2. Fluorescence Methods

ICG is invisible to the human eye as a fluorescent and requires additional tools equipped with near-infrared (NIR) cameras. With the advancement of digital imaging, NIR camera systems also improved. Near-infrared fluorescence (NIRF) shows 70-100% sensitivity in detecting superficial tumors. As the penetration ability of the light is limited in deep tissues, its sensitivity decreases in evaluating deeper tumors. PINPOINT NIR imaging system is being used in laparoscopic surgeries. This method overlays NIR and visible-by-light images making the intersegmental boundaries visible with the color difference.

High-Risk Anastomoses

In high-risk anastomosis surgeries, including esophagectomy, small bowel and gastric resections, and low anterior resection of the rectum, indocyanine green angiography are used to visualize blood supply and anastomotic perfusion. Literature results evaluating the effectiveness of the method are limited, and further randomized trials are required to assess ICGA in anastomosis surgery 17.

Binary Surgery

Due to the exclusive biliary elimination of ICG, this method is used to visualize the biliary anatomy, including aberrant localization of biliary ducts, to prevent bile injuries in cholecystectomy and pancreaticoduodenectomy. It may provide additional biliary anatomy information if the intraoperative cholangiogram is insufficient 26. The biliary anatomy detection rate of ICGA is 95.1%-99% [26, 27]. As a limitation, biliary visualization with ICG might be affected by the fluorescence from the liver, which could be improved by the timing of ICG injection. Applying ICG fluorescence with NIR imaging also aids in detecting biliary leakage after hepatectomy.

Liver Transplant Surgery

ICG fluorescence provides information about bile duct vascularization and aids with biliary, arterial, and portal anastomosis evaluation 25. Furthermore, ICG is useful for identifying portal territory with the transhepatic portal vein and systemic ICG injections.

Liver Cancer Surgery

ICG is used for intraoperative diagnosis of primary and metastatic liver tumors; in HCC, the dye is retained inside the tumor, while fluorescence is observed in the transition region between parenchyma and tumor in metastatic lesions 28. Nonetheless, this method cannot be used for the differential diagnosis of benign and malign tumors 14.

ICG aids in detecting superficial nodules, establishing resection margins, and identifying segmental boundaries. Moreover, ICG aids with visualizing segmental boundaries providing information for anatomical resection planning. The combination of ICG with IOUS improves diagnostic accuracy.

The method's shortcomings are the lack of quantifiable data with absolute values; the surgeon should interpret information visually, which may lead to subjective differences in results. Furthermore, NIR light does not penetrate deep tissues. Thus, the detection of lesions is limited to superficial lesions 14.

Given the survival benefits of liver metastasis surgery and difficulties in detecting all hepatic metastatic lesions during the surgery, ICG has been a promising intraoperative diagnostic tool in the last decades. In this thesis, we aimed to evaluate the effectiveness of indocyanine green for intraoperative metastasis detection, diagnostic improvement, and residual-free resection in liver metastases surgeries.

4. METHODOLOGY

4.1. Selection Criteria

Studies considered for this review were screened based on the PICO.

4.1.1. Inclusion Criteria

Patients: Patients diagnosed with liver metastasis regardless of the primary tumor origin and undergoing metastasis resection surgery;

Intervention: ICG administration prior to the surgery for metastasis (tumor) detection purposes;

Comparison: Other methods used for preoperative and intraoperative metastasis detection.

Outcome:

(1) Primary Outcome: Detection rate of histopathologically-confirmed malignancies;

(a) Tumor detection rate : detection of tumors diagnosed with preoperative (CT, MRI, PET, US) and intraoperative (IOUS, palpation, inspection) methods;
(b) Diagnostic improvement rate : identification of unknown or otherwise undetected metastatic lesions; 26 Secondary Outcome:

Margin-free resection rate : Success rate in achieving the residual-free (R0) tumor resection Studies investigating human participants published in English from 2000 to July 2022 were included in this review.

4.1.2. Exclusion Criteria

(1) Patients diagnosed with a primary liver tumor, biliary system malignancies, and extrahepatic metastases;
(2) Use of ICG for preoperative and postoperative liver function assessment in hepatic resection and liver transplant patients;
(3) Studies reporting animal model and in vitro and in vivo results;
(4) Studies published in a language other than English;
(5) Previously published case reports, reviews, meta-analyses, editorial letters, and expert opinions;
(6) Unpublished data, including conference abstracts.

4.2. Literature Search and Screening

4.2.1. Search Strategy

Medical databases, including PubMed, EMBASE, and Web of Science, were searched from 2000 to July 2022 using search keywords including (((((indocyanine) OR (indocyanine green)) OR (ICG)) AND (liver)) OR (hepat*)) AND (metastas*). The search was filtered using the parameters "Human" and "English." A detailed description of search keywords is presented in the Appendix.

4.2.2. Screening of Selected Studies

Search results were exported to the EndNote 20 Library Software (Clarivate, Philadelphia, USA). The initial search was performed based on the title and abstract information. Later, eligible studies were screened based on full-text information.

4.2.3. Data Extraction

Data including the publication identifier (first author's last name and the publication year), study design, cohort information (age, sample size, primary tumor site), investigation methodology (preoperative imaging, surgery type, ICG administration, and NIR imaging) and outcomes (tumor detection rate, diagnostic improvement rate, and margin-free resection rate, when available) were collected in a predesigned template.

5. RESULTS

5.1. Literature Search Results

Our literature search yielded 19 288 records. After removing the duplicated entries, 12 786 studies were included in the screening process. Following the title and abstract screening, 51 studies were evaluated based on full-text information. During the full-text screening, the main reasons for exclusion were the absence of the outcome of interest or the presentation of data in a mixed manner with primary liver tumors. Of 51 studies, 24 studies were used for the qualitative evidence synthesis. The steps of the study selection and screening process is presented in the PRISMA flow diagram (Figure 1).

5.2. Study Characteristics

More than half of the included studies were conducted prospectively in a non-randomized setting (n=17, 70.8%), while four articles (16.7%) were reported from the retrospective assessment. Despite the low evidentiary value, studies reporting rare cases with uncommon primary tumor sites also were included in the summary; data from three case series (12.5%) were also synthesized in this review. No randomized-controlled studies investigating the ICG properties in metastatic liver patients were found at the time of the literature search.

Studies were mainly reported from Asia (41.7%), Japan being among the first reporting centers (7/10 studies), and Europe (54.2%), the Netherlands being one of the leading centers (7/13 studies).

Depending on the primary tumor site and the study type, the sample size of participants varied significantly from report to report. Colorectal malignancies were the most common primary tumor site (n=335 patients; 19 studies), followed by pancreatic cancer (n=54 patients; 2 studies). Other sources of liver metastases were neuroendocrine tumors (n=18 patients; 4 studies), uveal melanoma (n=5; 2 studies), gastrointestinal tumor (GIST), meningioma, leiomyosarcoma, hemangioendothelioma, lung carcinoid tumor, uterine, breast, and thyroid cancers.

Studies concurred regarding the intravenous ICG administration route with different doses and timing. In most reports, the administration dose was 0.5 mg/kg or 2.5-5mg/mL. The timing of administration varied from 24 hours to 14 days prior to surgery. In some cases, intraoperative management was used [29, 30].

Upon intravenous administration, the fluorescence of indocyanine green was visualized using various near-infrared light (NIR or NIRF) sources. Depending on the surgical approach, the authors used different NIRF tools, photodynamic eye (PDE) and Karl Storz imaging systems being the most common ones in the open and minimally invasive settings, respectively.

The characteristics of the included studies are summarized in Table 3.

Figure 1. PRISMA Flow Diagram illustrating the screening process of the current systematic review.

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Table 3. Summary of included studies in the current review.

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5.3. Malignancy Detection Rate with intraoperative ICG use

Indocyanine green use was associated with differing success rates from report to report. The main factors affecting the success rate were the location and size of the lesions.

5.3.1. Colorectal cancer (CRC) Metastases

Ishizawa et al. 31 were among the first authors to report findings of ICG use in liver metastasis surgery. According to the report, ICG-fluorescence imaging positively identified 28 metastatic lesions showing 100% sensitivity and positive predictive value in colorectal cancer samples. Other studies with 100% ICG sensitivity were reported by Lim et al. 48 and Picollo et al. 49, analyzing 12 and 13 CRC metastases, respectively.

Uchiyama et al. 32 evaluated thirty-two patients with colorectal liver metastasis. ICG was positive in 55 out of 56 lesions; the missed lesion was 3 mm in diameter and was discovered in the resected tissue. In addition, ICG fluorescence showed false positivity in four lesions, thus resulting in 91.1% sensitivity in detecting metastatic lesions.

In another study analyzing CRC patients, van der Vorst et al. 35 reported 73% sensitivity with ICG-guided NIR imaging. While ICG detected occult lesions in five patients, it was unsuccessful in identifying lesions deeper than 8 mm from the surface. Thus, ICG missed the detection of 26 lesions in three patients. Boogerd et al. 41 shared experiences from the same center, with new CRC cases analyzed. According to the updated results, ICG was 94.4% successful in detecting colorectal metastatic lesions (17 out of 18 lesions in twelve patients); the missed CRC lesion was also located >8 mm below the liver capsule 41. Again from Leiden, Netherlands, Handgraaf et al. 42 reported results from a large cohort of 67 CRC patients. In this study, ICG was associated with 83% sensitivity in detecting all metastatic lesions, while this number reached 100% when superficial lesions only were taken into consideration.

Successful detection of metastatic lesions, located not deeper than 8 mm from the liver capsule, was later shown in the study by Kudo et al. 36, analyzing five CRC cancer cases along with a uterine cancer patient. Results suggested 69% sensitivity in detecting 11 out of 16 lesions within 0-5 mm depth from the surface. The distance from the surface was a determining factor in another study by Takahashi et al. 38. Authors showed the poor performance of ICG/NIRF imaging in all deeply located tumors; in eight colorectal cancer patients, ICG assisted in identifying 27 out of 44 lesions (61.4% sensitivity), which all were superficially located. Similar to the abovementioned studies, Patel et al. 62 also indicated limited ICG performance with deeply located lesions; ICG could detect 27 out of 30 lesions (90%) missing the lesion located 20 mm below the capsule.

Abo et al. 37 analyzed hepatocellular cancer (HCC) cases along with metastatic patients. Per the report, in metastatic patients, ICG fluorescence was detected in a rim-like pattern, thus facilitating the detection of liver metastasis in 31 out of 36 patients. Similar results were followed in the study by Shimada et al. 47; seven out of 19 liver malignancy cases were CRC metastases. Unlike HCC lesions, rim fluorescence was observed in metastatic lesions leading to the detection of nine tumors in total. In like manner, the study by Lieto et al. 44 analyzed CRC metastatic cases along with HCC patients. They also reported a rim-like fluorescence pattern in metastatic lesions, which led to the detection of all previously indicated tumors and one new metastasis. Not different from previous reports, Marino et al. 46 also described the rim-type fluorescence differentiating metastatic lesions from primary liver tumors. In total, 27 metastatic lesions were excised from 22 CRC cases.

5.3.2. Pancreatic Cancer Metastases

In a prospective analysis of forty-nine pancreatic cancer patients, Yokoyama et al. 33 assessed ICG in the capacity of micrometastases detection. Preoperative clinical imaging reported metastasis-free views in all cases. Lesions with at least 1.5 mm abnormal hepatic fluorescence were examined by frozen section. Out of 49, only in eight patients (16%), histology confirmed micrometastasis. In a six-month follow-up, the positive and negative predictive values of abnormal fluorescence for the hepatic relapse were 77% and 97%, respectively.

In another study, Handgraaf et al. 43 tested ICG-guided imaging in pancreatic and periampullary cancer patients as a tool in staging laparoscopy. In 2 out of 25 patients, laparoscopic near-infrared fluorescence imaging detected liver metastases, preventing patients from futile laparotomies. It must be noted that these lesions also were identifiable by inspection and laparoscopic ultrasound.

5.3.3. Neuroendocrine tumors

Despite the mixed presentation of results with colorectal cancer cases, Abo et al. 37 reported 86% sensitivity in detecting neuroendocrine tumor-originated metastasis with ICG-navigated imaging.

Takahashi et al. 30 presented two cases of neuroendocrine tumor metastasis. In this cohort, ICG performed markedly poorly by missing 9 out of 11 lesions in two patients (18.2%). All missed lesions by ICG were located deeply in the liver parenchyma. The authors acknowledged the practical side of ICG in guidance for detecting the real-time demarcation line 30.

5.3.4. Uveal Melanoma

Tummers et al. 48 reported results from three uveal melanoma cases. ICG diagnosed histopathologically-confirmed metastases with 100% sensitivity showing superiority to other diagnostic methods. Following this study, Boogerd et al. 41 presented two more uveal melanoma cases from the same study center. This once, ICG performed lower than preoperative and intraoperative imaging methods; one lesion located deeper than 8mm was missed by ICG/NIRF imaging.

5.3.5. Metastases originated from other organs

Gastrointestinal Stromal Tumor (GIST)

Bijlstra et al., 47 reported two rare cases with GIST metastases to liver. In the first case, ICG successfully detected one preoperatively diagnosed lesion in segment VIII. In addition, the second, previously unidentified lesion was also ICG positive in segment V. However, the third metastasis at segment VI was not visualized by NIR imaging due to the deeper localization.

The second case also showed similar results; ICG detected one previously diagnosed tumor but failed to identify the second lesion located 24 mm subcapsularly. No additional lesion was found by ICG in this case.

Thyroid cancer

Minimal information is available on thyroid cancer metastasis. Piccolo et al. 49 evaluated one patient with this diagnosis and found one liver metastasis as a result of preoperative and postoperative investigations. The lesion was ICG-positive and aided intraoperative visualization.

Uterine cancer

Data from one uterine cancer patient was presented by Kudo et al. 36. Although results were reported together with other tumors, i.e., hepatocellular cancer and CRC metastasis, the study finds 69% sensitivity in metastasis detection with the aid of ICG/NIRF imaging during the resection surgery.

Leiomyosarcoma

One leiomyosarcoma case underwent ICG-guided metastasis resection was reported by Takahashi et al. 30. The patient was diagnosed with two deeply located liver metastasis by preoperative MRI imaging. ICG/NIRF imaging was not successful in identifying either lesion (0%).

Hemangioendothelioma

A 61-old female patient diagnosed with hemangioendothelioma was presented by Takahashi et al. 30. The patient was diagnosed with three metastatic lesions with the guidance of ICG/NIRF imaging, making ICG the most successful method among other preoperative and intraoperative diagnostic approaches.

Breast cancer

A single case of breast cancer-originated liver metastasis was reported by Boogerd et al. 41. The authors reported successful imaging of a single 11 mm metastatic lesion using ICG/NIRF visualization.

Table 4. Summary of malignancy detection rate using ICG-guided imaging

Abbildung in dieser Leseprobe nicht enthalten

5.4. Diagnostic improvement rate with ICG use

One of the main advantages of ICG use in hepatic metastasis surgery is the discovery of new, previously unidentified lesions using preoperative assessment methods. As such, we analyzed the diagnostic improvement ability of the intraoperative ICG navigation method.

Uchiyama et al. 32 used an ICG/PDE imaging tool to identify colorectal cancer metastases during hepatic resection surgery. With the use of ICG, the authors found four additional lesions missed by preoperative MRI imaging and IOUS use; only two of these lesions were confirmed malignant.

The study by van der Vorst et al. 35, investigating colorectal liver metastases, reported diagnostic improvement in 12.5% of patients; in five out of 40 patients, NIR-guided resection was associated with the detection of small and superficial lesions which were missed by preoperative CT, IOUS, visual inspection, and palpation. Updated data analyzing new CRC cases were published from the same center. In this assessment, two otherwise missed metastases (out of 18) were detected by ICG/NIR visualization 41 . Another large CRC cohort from Leiden, Netherlands, compared intraoperative assessments with and without ICG/NIRF imaging 42. According to findings, ICG guidance increased the new lesion detection rate up to 12%.

ICG-guided metastasis resection was also advantageous in the study presented by Lieto et al. 44, analyzing six colorectal cancer patients; ICG increased the total number of metastases by identifying one more lesion in addition to seven previously diagnosed tumors. In like manner, the report by Marino et al. 46 detected two superficial CRC metastases missed by IOUS.

The study by Barabino et al. 40 using ICG fluorescence in the "ex-vivo" (postoperative) setting has benefited from the method in detecting one previously unidentified colorectal cancer metastasis in the resected specimen.

In the study by Takahashi et al. 30, ICG was successful in the detection of eleven new CRC metastases missed by preoperative imaging. In this study, analyzing tumors originating from multiple sources, ICG improved the diagnostic rate only in one case with hemangioendothelioma by detecting one additional lesion missed by all other assessment methods.

The study analyzing uveal melanoma cases showed the superiority of ICG-guided metastasis resection; NIR visualization revealed multiple small lesions on the liver surface in two out of three cases. Moreover, ICG identified one more lesion in the third patient, undiagnosed otherwise 39. Another report from the same center evaluated two more uveal melanoma patients. In this case, no additional melanoma metastases were identified 41 .

Table 5. Summary of diagnostic improvement rate using ICG-guided imaging

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5.5. Does ICG have advantages over preoperative imaging techniques?

Preoperative imaging methods are the primary tools in decision-making for metastasis surgeries. However, despite continuous improvement in imaging methodologies, major imaging methods may miss to locate or suggest the existence of all metastatic lesions in the liver. We also compared preoperative and intraoperative assessment results to find the possible advantageous effects of ICG-navigated imaging methods.

Van der Vorst et al. 35 presented a study analyzing colorectal cancer metastasis patients. According to the report, preoperative imaging predicted only 66 of 71 lesions that were ICG-positive during the surgery. Thus, preoperative CT imaging had a slightly higher sensitivity than the ICG-NIRF method (75% vs. 73%). Later, a study group from the same center reported comparatively lower performance of CT and MRI imaging compared to ICG/NIRF-guided resection; in this cohort, CT and MRI respectively missed four and seven CRC metastasis lesions during preoperative assessment, while ICG missed only one out of 18 lesions. This resulted in a 94.4% detection rate by ICG/NIRF, surpassing the 77.8% and 61.1% sensitivity of preoperative scanning methods 41.

Uchiyama et al. 32 analyzed colorectal cancer patients with liver metastasis. Based on the study results, preoperative MRI imaging was less sensitive than the ICG-IOUS combination (88.5% vs. 98.1%). Similarly, in the study by Peloso et al. 34, preoperative CT imaging was associated with a lower tumor detection rate than the ICG-IOUS combination (58.4% vs. 98.6%). Results from Takahashi et al. 30 also were associated with a worse performance with preoperative imaging than ICG by detecting 19 out of 44 lesions in eight patients (43.2 vs. 61.4%) 30.

On the other hand, in CRC cases analyzed by Patel et al. 50, MRI was successful in imaging all 30 lesions, which was higher than the ICG and IOUS detection. Another cohort with five CRC patients reported an equal success rate of preoperative imaging and ICG use; both methods identified 13 metastatic lesions 49.

Case series evaluating uveal melanoma metastasis found preoperative CT and MRI imaging insufficient to diagnose multiple superficial lesions in two patients. Moreover, these methods failed to specify one additional lesion in the third case 48. On the other hand, two more uveal melanoma cases, presented later by the same center, were successfully diagnosed by preoperative CT and MRI imaging, while ICG missed detecting one out of two lesions 41.

Detection of deeply located neuroendocrine tumors and leiomyosarcoma metastases was more successful with preoperative imaging than ICG in the report by Takahashi et al. 30. However, the same report also presented a hemangioendothelioma case in which preoperative CT scanning missed one out of three ICG-positive metastases (66.7% vs. 100%). A case series with GIST metastases reported by Bijlstra et al. 47 highlighted the limited capacity of ICG-guided imaging in deeply located lesions compared to the scanning imaging methods. A single case of thyroid cancer presented by Picollo et al. 49 showed equally successful detection with preoperative and ICG/NIR imaging.

Table 6. Comparison of ICG-guided imaging with preoperative imaging methods

Abbildung in dieser Leseprobe nicht enthalten

5.6. ICG versus other intraoperative diagnostic methods in hepatic metastases detection

Literature results reported various comparative assessments of ICG versus other intraoperative tumor detection methods. While some studies aimed to compare ICG with IOUS or inspection, others utilized IOUS in combination with ICG-navigated imaging.

IOUS was used as an intraoperative comparison method in the study by Marino et al. 46, analyzing 22 colorectal cancer cases. According to the report, IOUS has failed to identify two out of 27 ICG-positive lesions with 92.6% sensitivity. In another study by Patel et al. 50, IOUS was the lowest-performed method and detected only 23 lesions (77%), mainly missing small and superficial lesions. In their study conducted with 40 CRC patients, Van der Vorst et al. found 95% sensitivity of IOUS use in combination with palpation and inspection. However, these methods missed 14 occult ICG-positive lesions in five patients. One of the missed lesions was labeled as a complicated cyst in IOUS, while it showed apparent rim-like ICG fluorescence. In another report by the same group, inspection (57.1%) and IOUS (85.7%) were less efficient than ICG/NIR imaging (94.4%) in the detection of colorectal cancer metastases 41. In this evaluation, IOUS missed superficially located tumors. Notably, the highest detection rate was associated with a combination of IOUS and NIRF imaging 41.

The study with eight CRC patients found IOUS the most beneficial diagnostic tool in their cohort; ICG was successful only in detecting superficial lesions and subsequently missed 17 lesions identified by IOUS (61.4% vs. 100%). IOUS also was superior to preoperative imaging by diagnosing 25 more metastases (43.2% vs. 100%) 30.

Uchiyama et al. 32 evaluated the concomitant use of contrast-enhanced intraoperative ultrasound (CE-IOUS) with an ICG navigation system in colorectal cancer patients. Based on the authors' findings, the combination of CE-IOUS with ICG fluorescence identified 51 malign lesions out of 52, increasing the overall sensitivity of the method to 98.1%. Another study reported by Peloso et al. 34 compared IOUS results with the combined use of IOUS with ICG. The study found that IOUS alone increased the tumor detection rate by 13% compared to preoperative CT imaging. The number of detected lesions increased significantly (from 55 to 77) when IOUS was combined with ICG.

Analysis of uveal melanoma and neuroendocrine tumor cases showed the limited capacity of IOUS in the detection of superficial lesions 4830, while its superiority to detect deeply located tumors was demonstrated in a leiomyosarcoma case and GIST metastases [30, 47]. Moreover, Barabino et al. 40 found IOUS insufficient in determining the tumor borders of neuroendocrine and meningioma metastases.

Table 7. Comparison of ICG-guided imaging with intraoperative imaging

Abbildung in dieser Leseprobe nicht enthalten

5.7. Margin-free resection rate

ICG fluorescence-navigated resection might also be advantageous in determining the demarcation line and estimating resection margins. The success rate of ICG in achieving margin- free tumor resection was evaluated as a secondary outcome in this review.

Studies by Zhang et al. 29, Picollo et al. 49, Lieto et al. 44, and Marino et al. 46 conducted with two, five, six, and 22 colorectal cancer patients, respectively, reported 100% margin-free resection with ICG-guided resection . The largest to date study analyzing neuroendocrine tumor malignancies by Wang et al. 52 has revealed a 100% margin-free resection rate under ICG guidance in 102 lesions from 25 neuroendocrine tumor patients, while the comparison group without ICG implementation harbored five R1 lesions. A case series presenting gastrointestinal tumor metastases also showed a 100% margin-free resection rate with ICG-navigated management 47.

However, some studies presented cases in which ICG showed slightly lower performance. According to Patel et al. 50, only 71% of patients (10 out of 14) had negative margins. Another study presented by Handgraaf et al. 42 evaluating a slightly larger CRC cohort (n=67) reported the ICG guidance to be beneficial in achieving margin-free resection in 83% of cases, which was not significantly different from the group without ICG guidance (79%). In the study by Peloso et al. 34 using IOUS in combination with ICG fluorescence with 25 CRC patients, only one out of 77 malign lesions was margin-positive, leading to a 98.7% margin-free resection rate.

Achterberg et al. 45 evaluated tumor margins with ICG fluorescence intraoperatively and validated results with ex-vivo (postoperative) NIR fluorescent microscopy and histopathology. According to findings, out of eight tumors that indicated negative margins during the surgery, only one was positive postoperatively. Moreover, out of eight intraoperatively positive lesions, two were negative for tumor margin. Barabino et al. 40 evaluated three cases with CRC, neuroendocrine tumor, and meningioma in the study comparing the efficiency of IOUS to the ex-vivo (postoperatively) ICG analysis under a fluorescent microscope. According to the findings, IOUS has failed to guide the R0 in neuroendocrine and meningioma metastases cases.

Tashiro et al. 51 retrospectively investigated patients with four colorectal and one lung­carcinoid liver metastases who underwent salvage hepatectomy following radiofrequency ablation therapy. Metastatic lesions were resected under fluorescence guidance and postoperatively evaluated under fluorescence microscopy. Analysis has revealed that all seven lesions resected under ICG guidance had negative tumor margins showing the successful use of the method in patients after radiofrequency ablation.

Table 8. Margin-free resection with ICG-guided imaging

Abbildung in dieser Leseprobe nicht enthalten

6. DISCUSSION

Liver cancer is the third most common cause of cancer death worldwide 53. Furthermore, due to its unique anatomical and histological properties, the liver is a common site for metastatic spread from multiple organs 54. Among young men, colorectal cancers are the most common primary tumors metastasizing to the liver. The 1-year survival of all patients with liver metastasis is considerably lower than those without extrahepatic metastases 54.

Surgery is a very effective treatment for colorectal liver metastases, with a 30-50% postoperative 5-year-survival rate 55. Liver metastases may present as multifocal or solitary lesions or may differ in vascularity depending on the primary tumor site. Moreover, fatty liver or hepatic changes following chemotherapy may increase diagnostic difficulties of metastatic lesions. Although preoperative imaging methods suggest a complete response following the chemotherapy, 34% of patients are diagnosed with a residual disease during intraoperative assessment 56. These facts increase the importance of detecting all metastatic lesions to achieve tumor-free status.

ICG fluorescence imaging is another promising intraoperative diagnostic tool. Despite being approved for human use since the 1960s, it's still not a routine intraoperative imaging method. This study summarized the literature reporting the diagnostic capacities and shortcomings of ICG-guided metastasis detection and margin-free excision.

Fourteen studies investigated the tumor detection capacity of 287 colorectal cancer patients, and the tumor detection rate ranged from 61.4% to 100% (average 89.1%). The majority of studies reported 100% tumor detection with ICG fluorescence [31, 38, 44, 46, 48, 49]. The lowest success rate was presented by Takahashi et al. 30, reporting data from nine CRC patients. Similar to other reports observed with significant ICG fluorescence failure, the main factor affecting the method's success was the depth of lesions. Lesions missed by ICG were located from 8 mm to 21 mm deeper from the liver capsule [30, 35, 36, 41, 42].

Preoperative imaging methods are the initial step for staging surgery. Despite the inexpensive and safe nature, the performance of preoperative US might be affected by the patient's body habitus, performers' skills, etc. More importantly, due to the limited spatial resolution, the US is limited in detecting subdiaphragmatic, post-chemotherapeutic, and less than 3-5 mm metastatic lesions. These factors result in approximately 69% sensitivity of ultrasound use in a preoperative setting 57. Contrast-enhanced and three-dimensional ultrasounds are associated with significantly improved diagnostic results compared to the conventional US [58, 59].

Multidetector CT is a great tool for hepatic volume calculations, preoperative staging, and tumor localization. Despite the method's 72-73% sensitivity, CT may miss identifying subcapsular and small liver metastases 60. The sensitivity of computed tomography significantly decreases to 16% in lesions smaller than 10 mm 61. Moreover, prior chemotherapy may increase the missed lesion frequency by up to 83% 62.

Several studies have shown superior performance of preoperative MRI compared to CT, especially in detecting small lesions. Diffusion-weighted imaging is associated with a significantly increased sensitivity (95%) compared to conventional protocols (87%) [63, 64]. However, metastases from some organs, such as neuroendocrine tumors, melanoma, sarcoma, and ovarian cancers, may present with a moderately high signal intensity 65.

According to the review results, the literature comparing preoperative imaging methods with ICG-guided imaging shows a significant discrepancy in their findings. In some reports, preoperative imaging was superior to ICG fluorescence in detecting metastatic lesions. The study analyzing 40 CRC patients showed that ICG failed to detect 23.4% of lesions 35. Similarly, data with rare cases such as a neuroendocrine tumor, leiomyosarcoma, and GIST have revealed 81.8%, 100%, and 40% failure rates with ICG guidance [30, 47]. The main reason for ICG failure, generally, was the depth of the lesion.

On the other hand, much larger studies acknowledged the superiority of ICG-guided imaging over preoperative assessments. ICG/NIRF imaging (94.4%) surpassed the tumor detection performance of preoperative CT (77.8%) and MRI (61.1%) scanning in the cohort with 18 CRC cases 41. Similarly, ICG was superior to preoperative scanning methods by 18.2%-50% in colorectal cancer patients 30 . The same direction was observed in uveal melanoma and hemangioendothelioma cases [30, 39].

In addition to these results, some studies reported equal performance by both methods 49.

The limitations in identifying all metastatic lesions with preoperative imaging increase the importance of intraoperative diagnostic tools. Inspection, palpation, and IOUS are among the most commonly utilized methods. However, despite advancements in imaging techniques, detection and residual-free resection of all tumors may not be achieved in every case.

Despite its safe, cheap, and easy-to-use nature, IOUS performs poorly in detecting small, superficial, and isoechoic lesions. Contrast enhancement of IOUS imaging enables angiography of small vessels, thus allowing dynamic real-time imaging during the surgery. According to a recent meta-analysis, IOUS shows 84% sensitivity in detecting hepatic colorectal cancer metastases, which increases up to 98% with the addition of contrast enhancement 66.

Based on the review results, intraoperative imaging methods also showed varying performances. ICG showed superiority over IOUS assessment by 7.4%-80% in colorectal cancer patients [41,46]. In another study, IOUS failed to detect 19.7% of ICG-positive lesions in CRC patients when assessed alone. However, the sensitivity of the intraoperative assessment significantly increased to 95% when inspection, palpation, and IOUS results were combined 35.

On the other hand, IOUS was found to be superior to ICG imaging by 38.6%, 50%, 81.8%, and 100% of patients with colorectal cancer, uveal melanoma, neuroendocrine tumor, and leiomyosarcoma, respectively 41.

Interestingly, both intraoperative methods complement each other with their limitations in diagnosing intraoperative liver metastases. Thus, the combination of the two methods seems to be a plausible solution to their shortcomings. The results of this review showed that the superiority of ICG-guided imaging increases with the combined use of IOUS. Concomitant use of IOUS and ICG were superior to preoperative MRI by 9.6% and 38.9% [32, 41] and to CT imaging by 40.2% and 22.2% [34, 41], respectively.

ICG-guided metastasis detection is also advantageous for its ability to diagnose occult lesions. Studies, mainly presenting colorectal cancer cases, reported diagnostic improvement rates ranging from 3.5% to 50% 32. However, the majority of studies have improved the metastasis detection rate within the 10-20% range [30, 35, 41, 42, 44]. The majority of newly detected tumors were found on the liver surface or were located superficially. The size of otherwise occult lesions was smaller than previously detected tumors.

It's worth noting that, unlike the IOUS, ICG-navigated surgery determines the tumor demarcation line leading to margin-free tumor resection. In the great majority of studies, the margin-free resection rate was 100% [29, 44, 46] . Some studies reported failure rates ranging from 2.3% to 29% [34, 42, 50].

Study limitations

The current study has a few limitations, including the quality of the reporting studies and outcomes.

While there was an abundance of studies investigating colorectal cancer metastases, a very limited number of articles reported tumors originating from other sources. Due to these limitations, we used an "all-inclusive" approach and reported data from case series, along with prospective and retrospective cohort studies. The study design of included articles led to a low sample size; in some reports, only data from one or two patients were available. This factor may skew the main effect, such as tumor detection rate or diagnostic improvement rate, and may challenge the evidence synthesis in a statistically meaningful way. To the date of the literature search, no randomized-controlled studies have been published on this topic, reducing the evidence level of the overall analysis.

Another difficulty arose from the mixed presentation of studies, including primary and metastatic liver tumors in the same study. Some of the studies did not provide separate data on metastatic cases; thus, those studies were not suitable for evidence synthesis. Moreover, there were limitations in extracting uniform data in metastasis-only studies; some studies focused on the pathological assessment of data, and the primary outcome was the resection margin assessment. These studies lacked information on preoperative and other intraoperative assessment data. On the other hand, studies reporting tumor detection information were not uniform regarding the data presentation; some studies presented percentages of failed patients, while others focused on the number of metastatic lesions.

7. CONCLUSION

Indocyanine green fluorescence detected by near-infrared imaging is a promising intraoperative diagnostic tool for the surgical management of liver metastases. ICG-navigated imaging successfully identifies most metastatic lesions, including preoperatively and intraoperatively identified tumors. Moreover, in several cases, ICG-guided imaging has assisted in detecting several previously unknown tumors, improving the malignancy detection rate. These occult lesions are generally small and superficial lesions. As the previous statement indicates, ICG has limited penetrance for deep locations; tumors deeper than 8 mm from the liver capsule are generally missed by ICG imaging. Given the high success rate of intraoperative ultrasound imaging in visualizing deep lesions, the combination of IOUS and ICG-guided imaging might be considered for better success rates.

8. APPENDIX

Supplementary Information 1. Search Terms used for literature search

a. Source: PubMed (accessible at: https://pubmed.ncbi.nlm.nih.qov/)

Search: (((((indocyanine) OR (indocyanine qreen)) OR (ICG)) AND (liver)) OR (hepat*)) AND (metastas*) Filters: Humans, English, from 2000 - 2022 (((("indocyanin"[All Fields] OR "indocyanine"[All Fields] OR "indocyanines"[All Fields] OR ("indocyanine qreen"[MeSH Terms] OR ("indocyanine"[All Fields] AND "qreen"[All Fields]) OR "indocyanine qreen"[All Fields]) OR "ICG"[All Fields]) AND ("liver"[MeSH Terms] OR "liver"[All Fields] OR "livers"[All Fields] OR "liver s"[All Fields])) OR "hepat*"[All Fields]) AND "metastas*"[All Fields]) AND ((humans[Filter]) AND (enqlish[Filter]) AND (2000:2022[pdat]))

Translations indocyanine: "indocyanin" [All Fields] OR "indocyanine" [All Fields] OR "indocyanines" [All Fields] indocyanine qreen: "indocyanine qreen" [MeSH Terms] OR ("indocyanine" [All Fields] AND "qreen" [All Fields]) OR "indocyanine qreen" [All Fields] liver: "liver"[MeSH Terms] OR "liver"[All Fields] OR "livers"[All Fields] OR "liver’s"[All Fields]

b. Source: Web of Science (accessible at: https://webofknowledqe.com)

Search: indocyanine (All Fields) or ICG (All Fields) and hepat* (All Fields) or liver (All Fields) and metastas* (All Fields)

c. Source: EMBASE (accessible at: https://embase.com)

Sources Embase, MEDLINE, Preprints

Query('indocyanine qreen'/exp OR 'indocyanine qreen') AND ('liver metastasis'/exp OR 'liver metastasis') AND (2000:py OR 2002:py OR 2003:py OR 2004:py OR 2005:py OR 2006:py OR 2007:py OR 2008:py OR 2009:py OR 2010:py OR 2011:py OR 2012:py OR 2013:py OR 2014:py OR 2015:py OR 2016:py OR 2017:py OR 2018:py OR 2019:py OR 2020:py OR 2021:py OR 2022:py) AND ('article'/it OR 'article in press'/it)

Mapped termsn/a

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