*2.5.2 Indocyanine green*

Since the inclusion of fluorescence, the authors such as Holloway et al. [31] have replaced the radiocolloid and achieved equally good results. ICG is a tricarbocyanine dye with a short half-life of 3–4 min and hepatic excretion. ICG was developed by Kodak in the 1950s for use in photography and was approved by the US Food and Drug Administration in 1956 for IV administration [36]. The dye emits an intense blue colour detectable in real time when excited by laser in the near-infrared wavelength (range 750–900 nm, with an absorption peak at 800 nm) [6]. The high avidity by lymphatic tissue enables a high detection rate and accuracy compared with common tracers [4, 56, 57].

ICG has been used for years in laparoscopic and open surgery and in numerous other specialties (cardiology, general surgery, ophthalmology, vascular surgery, urology, etc.). The dye has recently been included in gynaecology. Lymph node mapping by fluorescence with ICG was first described by Furukawa et al. in 2010 in patients with cervical cancer. In 2012, Rossi et al. [58] applied ICG to 20 patients with cervical cancer or EC who underwent robot-assisted laparoscopic detection, achieving a detection rate of 85% and bilaterality of 60%.

The supposed benefits of this technology include high tissue penetration with low autofluorescence [59]. ICG has been shown to be superior to blue dyes, particularly in patients with obesity [30]. Following an interstitial injection, ICG is absorbed to the lymphatic system and travels quickly to the lymph nodes. ICG binds to plasma proteins and is excreted by the liver [36]. The dye lacks significant adverse effects. A single case of a severe allergic reaction after IV injection has been reported (incidence rate of 0.05%) [60]. However, the dye is contraindicated for use in patients with allergies to iodine [23, 56]. Nevertheless, given that iodine is a chemical element and an essential component of the human body, a number of authors have suggested the safety of using ICG in patients with iodine allergies, given that a type I allergic reaction (antibody-mediated and responsible for anaphylactic shock) will not occur [36]. The use of ICG in pregnant patients has been reported as safe [61].

To date, there has been no standard in the concentration and volume to be injected. Rossi et al. [58], Jewell et al. [62] and Holloway et al. [63] established the optimal ICG dose for detecting SLN at 1, 1.25 or 2.5 mg/mL in 4 mL [23]. Unlike 99mTc, ICG does not remain confined to a lymph node but rather diffuses rapidly through the lymphatic tissue towards the second step lymph nodes without losing intensity. It is therefore crucial to quickly start the search for the SLNs after the administration of ICG, without delaying the start of detection by more than 10 min [23], thereby reducing the risk of sampling too many lymph nodes [36], which limits the technique beyond 25–30 min of the injection [64].

Erikson et al. [65] compared the isolated use of ICG and MB in 472 patients, obtaining a higher detection rate (95 vs. 81%; p < 0.001) and bilaterality (85 vs. 54%; p < 0.001) with ICG. In 2015, How et al. [66] compared ICG, MB and 99mTcnanocolloid, obtaining a higher detection rate (86 vs. 71%; p = 0.005) and bilaterality (65 vs. 43%; p = 0.002) with ICG than with MB and a similar rate (87 vs. 88%; p = 0.83) and bilaterality (65 vs. 71%; p = 0.36) to 99mTc. In 2016, Papadia et al. [67] published the results of a retrospective, multicentre comparative study between detection with the combined technique using radiocolloid and blue dye versus radiocolloid and ICG. The overall detection rate was 97.3% for 99mTc-blue and 96.9% for ICG (p = 0.547). The bilaterality was 84.1% with ICG and 73.5% with the blue dye; ICG was significantly superior (p = 0.007). In a series by Martinelli et al. [19] of 202 cases using ICG plus 99mTc as tracer, there were no differences in the detection rate (93.2%), and the bilateral detection was superior with ICG (72.8 vs. 53.3%; p = 0.0012). All of the authors (and many not mentioned here) agree that ICG offers the highest detection rates comparable to those of the standard 99mTcblue technique but with superior bilaterality [11, 26].

*2.6.3 Blue dye and ICG*

*Role of Sentinel Node Biopsy in Endometrial Cancer DOI: http://dx.doi.org/10.5772/intechopen.89949*

risk of adverse effects [54].

**2.8 Paramagnetic tracer**

Detection rate/ bilaterality

Comfort for the patient

Need for specific equipment

*Reference source: Papadia et al. [36].*

*Characteristics of tracers.*

**Table 2.**

**183**

presacral areas to the hypogastric vessels.

nanoparticles, marketed under the name Sienna<sup>+</sup>

Adverse Reactions

**2.7 Triple tracer**

The prospective cohort study by Holloway et al. [31] combining blue dye with ICG achieved a significant increase in the detection rate (87.8% with blue-ICG vs. 76% for blue alone), bilaterality (83.9% with blue-ICG vs. 40% for blue alone; p < 0.001) and detection of lymphatic metastases (21.1% with blue-ICG vs. 13.5% for blue alone; p = 0.056) versus the isolated injection of blue dye. In the study by Jewell et al. [62], lymphatic mapping with ICG detected the SLN in 95% of cases, with bilaterality of 79% and no statistically significant differences versus the combined use with isosulfan blue (detection rate of 93%, p = 0.64; bilaterality of 77%, p = 0.8). Other authors have reached the same conclusion as Jewell: the high effectiveness in the identification with fluorescence is not increased by blue dye. The combination therefore appears unnecessary, which would avoid an increased

There are few published studies on this subject. How et al. [66] concluded that the triple injection (blue dye, 99mTc and ICG) in the cervix (submucosa and stroma) provided a detailed mapping of the lymphatic canals, from the parametrium and

New tracers are being applied. Recently, the Central-European SentiMAG multicentre clinical trial compared the use of the standard tracer (99mTcnanocolloid and MB) with superparamagnetic iron oxide (SPIO) labelled

cated comparable detection rates of 97.3 versus 98% with the same number of SLNs

**Characteristics 99mTc Blue ICG** Economic cost + + Technical complexity +

> ++ (Radiopharmaceutical/ lymphogammagraphy/SPECT–CT)

> > (1–6/100.000)

Lymphotropism ++ + +++

*The score was assigned according to the following gradation: () = absence of the characteristic or negative evaluation, (+) = meets the characteristic or positive evaluation, (++) = complies being better; (+++) = it fulfils being superior. 99mTc = 99mTc-nanocolloid albumin; ICG = indocyanine green; NIR = near-infrared electromagnetic spectrum.*

Duration marking 24 h/+++ 10–

®. The preliminary results indi-

+

(NIR detection hardware)

> (<0.05%)

20–30 min/++

++ + +++

+ +

++ (2%)

20 min/+

ICG achieves greater diffusion; better visualisation; greater bilateral detection, which translates into a lower risk of lymphadenectomy (61% with MB vs. 39% with ICG; p < 0.001 [63]); a shorter surgical time and long-term financial savings and can obviate the need for an injection of radiotracer [68]. It was initially stated that ICG represented an increase in the number of resected SLNs, a finding that became standard with experience in the technique [69]. Therefore, considering its good toxicity profile, its ease of use and high effectiveness, ICG is the current tracer of choice [70]. The main disadvantage of ICG is that the NIR detection equipment is expensive, because it requires specific optical systems [71].

Advances in the fluorescence technique are ongoing. New NIR detection systems, such as the PINPOINT® Endoscopic Fluorescence Imaging System, specifically identify the uptake intensity with colour codes, such that the primary lymph node is differentiated from the secondary nodes, preventing the excision of nonlymphatic or canalicular tissue [72].

#### **2.6 Combined method**

The objective of the double injection method is to optimise the detection rate and bilaterality, given that single dyes (mainly blue dyes) have lower detection rates and bilaterality [27]. The recent systematic review by Cormier et al. [27] achieved superior results with a combination of two tracers. Various combinations have been applied.

#### *2.6.1 Radiocolloid and blue dye*

Results vary significantly; however, the conclusion is that a better detection rate (81 vs. 57%; p = 0.01) and bilaterality (54 vs. 28%; p = 0.009) are achieved with the combination than with the isolated application of each tracer [45]. The multicentre prospective study by the AGO group with 590 patients obtained a better detection rate applying the combined method of radiocolloid and patent blue dye (88.6 vs. 93.5%; p < 0.001). Other authors have achieved similarly improved surgical detection results by applying this double method, which has become established as the most appropriate combination of tracers. The review by Ruscito et al. [70] compared the detection by the combined technique (of 99mTc and MB) with ICG and achieved superior bilaterality with ICG and a tendency to a higher overall detection rate, without differences compared with the combined method.

#### *2.6.2 Radiocolloid and ICG*

How et al. [66] compared ICG and isosulfan blue with radiocolloid in a cervical injection in 100 patients with EC. The detection rate (87 vs. 88%; p = 0.83) and bilaterality (71 vs. 65%; p = 0.36) achieved with ICG and the radiocolloid were comparable to the data obtained with only an injection of ICG. In the meta-analysis by Lin et al. [73], the combined technique with 99mTc and ICG achieved a detection rate of 92% and bilaterality of 86%, results comparable to those using only ICG (91% and 78%, respectively).
