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ORIGINAL ARTICLE
Ahead of print publication  

Standardized comparison of radioguided surgery with indocyanine green detection of the sentinel lymph node in early stage breast cancer patients: Personal experience and literature review


1 Department Surgical Sciences and Integrated Diagnostic (DISC), School of Medicine, University of Genoa; Breast Surgery Clinic, Department Surgical Sciences and Integrated Diagnostic (DISC), San Martino Policlinic Hospital, Genoa, Italy
2 Department Surgical Sciences and Integrated Diagnostic (DISC), San Martino Policlinic Hospital, Genoa, Italy
3 Breast Unit, ASL3, Genoa, Italy
4 Plastic and Recostructive Unit, San Martino Policlinic Hospital, Department Surgical Sciences and Integrated Diagnostic (DISC), School of Medicine, University of Genoa, Genoa, Italy
5 Department of Internal Medicine (Di.M.I.), University of Genoa, San Martino Policlinic Hospital, Genoa, Italy

Date of Submission19-Sep-2019
Date of Decision10-Apr-2020
Date of Acceptance06-May-2020
Date of Web Publication15-May-2021

Correspondence Address:
Marco Gipponi,
Breast Surgery Unit, San Martino Policlinic Hospital, Genoa
Italy
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_772_19

 > Abstract 


Keywords: Breast cancer, indocyanine green, node biopsy, sentinel lymph



How to cite this URL:
Fregatti P, Gipponi M, Sparavigna M, Diaz R, Murelli F, Depaoli F, Baldelli I, Gallo M, Friedman D. Standardized comparison of radioguided surgery with indocyanine green detection of the sentinel lymph node in early stage breast cancer patients: Personal experience and literature review. J Can Res Ther [Epub ahead of print] [cited 2021 Jun 22]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=316089




 > Introduction Top


The pathologic staging of regional lymph-nodes is essential for establishing the therapeutic decision-making in breast cancer patients. In fact, axillary lymph node staging by means of minimally invasive sentinel lymph node biopsy (SLNB) is regarded as the standard of care in patients without clinical evidence of axillary lymph node metastasis.[1] From the methodological standpoint, SLNB usually requires a preoperative lymphoscintigraphy by means of subdermal injection of a Technetium-99m (99mTc)-labeled nanocolloid into the tumor site with subsequent intraoperative detection of the sentinel lymph node/s (SLN) thanks to the use of a radio-guided gamma-detection probe (radio-guided surgery [RGS]).

Although this procedure is well established, some drawbacks still exist as regards the availability of a nuclear medicine unit and of the nuclear medicine physicians intraoperatively and, last but not the least, radiation exposure-related risks.[2],[3] An alternative approach might be represented by lymphatic mapping with vital dye, although previous clinical experiences with a vital blue dye, such as Patent-blue-V, showed a rather low detection rate (80%–87%) as well as some complications, such as local persistent tattoo and anaphylaxis.[4],[5]

Notably, new methods and markers have been introduced into the clinical practice, such as the use of super-paramagnetic iron oxide particles detected by means of a magneto-metric probe (SentiMag®) or indocyanine green (ICG) as a vital dye.[6],[7],[8],[9],[10] ICG appears green, and it is a fluoride that emits fluorescence; after its subcutaneous injection, ICG bonds to proteins and other macromolecules that changes the intensity of fluorescence and the emission spectrum to near infrared (NIR). This radiation is invisible to the human eye, but can be effectively identified using a special camera (HyperEye Medical System [HEMS]) (Mizuno Corp., Tokio, Japan) that captures color and NIR fluorescence for visualizing ICG-enhanced structures, such as lymphatic vessels and SLNs, thus helping the surgeon to detect the SLN into the axilla.[11] Pivotal experiences included only a few number of patients with the aim of improving the visualization and detection rate of SLN (i.e., improved performance of detection systems, associations of vital dyes, combinations of different ICG isotopes, and associations with protein vectors), and to compare ICG with RGS.[8],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30]

On these grounds, a prospective clinical study was undertaken in patients with early-stage breast cancer in order to compare into the same patient the efficacy and effectiveness of the standard procedure (RGS) with ICG and HyperEye so as to assess its feasibility in those clinical settings where a nuclear medicine unit cannot be available.


 > Patients and Methods Top


Between November 2016 and January 2017, 54 consecutive patients with early-stage breast cancer (<2 cm) and clinically negative lymph node underwent combined SLNB by means of ICG with HyperEye as well as the standard RGS procedure at the Breast Unit of “Ospedale Policlinico San Martino” in Genoa-Italy. Patients with tumor larger than 2 cm, distant metastatic spread, previous axillary surgery, or hypersensitivity to ICG were not included. Written informed consent was obtained from all patients, and the study was submitted to Regional Ethic Committee.

Patients had the standard technique of RGS detection of the SLN by means of Tc99m subdermal injection into the peri-tumoral area (37 MBq) and consequent lymphoscintigraphy about 18 h before surgery. In addition to the usual procedure, ICG was injected soon after induction of general anesthesia; a 25 mg vial with ICG powder was diluted in 20 mL of aqueous sterile water and then subdermally injected into the same peritumoral site of Tc99m. The volume administered of ICG was related to body mass index (BMI) status of each patient, according to the following indications: BMI <20: 0.3–0.4 ml ICG; BMI 20–25: 0.4–0.5 ml ICG; BMI 25–30: 0.5–0.6 ml ICG, and BMI >30: 0.6–0.7 ml ICG.

The progression of the dye tracer from the peritumoral region was promoted by a 5 min local massage. ICG fluorescence and the lymphatic drainage were detected and mapped by a fluorescence detector (HEMS) visualized on a monitor in real time. The fluorescent signal progressed from the injection site to the axilla in order to define the site of axillary incision. After having detected the SLN by means of ICG, its location was confirmed with radio-guided gamma-detection probe and each “hot” and ICG-positive lymph-node was sampled, checking as well any persistent area of radioactivity within the axilla in order to excise additional SLN. Hence, all excised lymph nodes were categorized as: ICG+/Tc99m+, ICG−/Tc99m+, or ICG+/Tc99m−; thereafter, all lymph nodes were sent for definitive histological examination: patients with one or more metastatic SLN underwent delayed axillary lymph nodes dissection (ALND).

As regards the evaluation of the efficiency of ICG detection, we analysed thereported in [Table 1] and [Table 2].
Table 1: Sentinel lymph-node biopsy with Tc99m

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Table 2: Sentinel lymph-node biopsy with indocyanine green

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The total costs included those for the required specific instrumentation, that is the hand-held gamma-detection probe and HEMS equal to 50,000.00 and 80,000.00 €, respectively.


 > Results Top


The clinicopathologic features of patients are reported in [Table 3]. Detection time, agreement as for lymph nodes detected by means of ICG and RGS, and the number of patients with correct SLNB by type of procedure are reported in [Table 4]. Overall, 87 and 90 SLN were detected by means of ICG and RGS, respectively; at least one SLN was identified by ICG in 52 out of 54 patients with a corresponding detection rate of 96.3% as compared to 100% with RGS. Notably, one of the patients with unsuccessful SLN detection by means of ICG had undergone previous breast surgery at the upper-outer breast quadrant, and this might have disrupted the lymphatic network. The mean (± standard deviation) detection times of SLN were rather similar with both procedures; 7.8 (±1.86) and 8 (±2.4) min with ICG and RGS, respectively; the mean biopsy time of both methods simultaneously performed was 12.8 min (±2.7). The mean number of sampled SLNs was 1.6 (±0.6) and 1.8 (±0.8) with RGS and ICG, respectively. In 9 out of 54 (16.7%) patients, a tumor-positive SLN was detected, and they all underwent delayed ALND.
Table 3: Clinical-pathologic features of patients

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Table 4: Parameters of efficacy of radio-guided surgery and indocyanine green sentinel lymph-node detection

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As regards the cost analysis [Table 5], ICG was cost-effective if the cost of the device was not included, given the rather low number of patients examined in the present series. It was estimated, however, that with the addition of the cost of the device, the breakeven point could have been reached when at least 118 patients undergo the ICG method of SLNB, with a net saving of about 254.00 € for each patient with ICG.
Table 5: Cost analysis of radio-guided surgery and indocyanine green sentinel lymph-node detection in 54 patients

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 > Discussion Top


Axillary lymph node staging by means of SLNB represents an established minimally invasive procedure for the pathological staging of the axillary status in breast cancer patients.[1] However, it implies the availability of a nuclear medicine unit as well as the nuclear medicine physicians intraoperatively and, last but not the least, some cautions regarding radiation exposure.[2],[3] New methods and markers have been introduced into clinical practice, such as the use of super-paramagnetic iron oxide particles detected by means of a magneto-metric probe (SentiMag®) or ICG as a vital dye in order to overcome the need of a nuclear medicine department with the related costs and logistic requirements.[3],[10]

As regards SLNB using ICG, pivotal clinical experiences including only a few number of patients suggested a detection rate with ICG of approximately 100%; as for the false-negative rate, that is the rate of patients with tumor-positive SLN detected using ICG out of all patients with axillary metastases as determined by RGS, the sensitivity of ICG was even better than RGS (92%–95% vs. 78%–91%).[15],[31] Our findings confirmed the efficacy of ICG with HEMS (96.3%) in agreement with the meta-analysis by Sugie et al.[12] with a reported detection rate ranging from 89% to 98%, although in our experience, the detection rate of RGS was more effective when coupled with ICG (100%), and higher than ICG alone.[12],[30] Notably, as reported by Sugie et al.,[12],[30] the number of SLNs was significantly higher with ICG than RGS (2.3 vs. 1.7: P < 0.001) coupled with a higher, although not significant, detection of SLN metastasis. This might be explained by the small volume of ICG molecule which quickly migrates from the “first” and, in fact, the “true” SLN to echelon SLNs. In this view, Ballardini et al.[27] observed that a lower number of SLNs can be recovered if the procedure starts immediately after ICG reaches the axilla. As a matter of fact, our detection time with ICG was rather short (<8 min), but this parameter was not reported in previous experiences, and it may well explain the lower number of ICG-positive SLNs that was sampled in each patient with a more selective approach to SLNB. In order to limit the mobility of ICG, thus reducing the number of SLNs, some authors used conjugated ICG with human serum albumin although no clear advantage was observed.[32]

A limitation of ICG may be represented by the rather difficult identification of the lymphatic pathway with HEMS in patients with BMI greater than 25, as opposed to Sugie et al.[12],[30] In such cases, ICG progression from the breast to the axilla followed more frequently deeper lymphatic pathways with disappearance of fluorescence on the monitor; this determined a less precise localization of the SLN as compared to RGS, with consequent need of wider surgical accesses, as confirmed by Grischke et al.[33]

Hence, the detection rate of ICG looks very similar to RGS, but it is clearly superior to the blue dye technique alone (65%–83%).[3],[7],[33],[34] As a matter of fact, most authors have questioned the added value of blue dye alone or associated with RGS as a marker for SLNB that is regarded, at most, minimal, or marginal.[35],[36],[37],[38] Moreover, the use of blue dye may present some drawbacks, such as skin tattooing, skin necrosis, and allergic reaction, the latter being reported in almost 2% of patients.[35]

As regards the other parameter of efficacy, that is the sensitivity of the procedure to detect a metastatic SLN, no false-negative case with ICG was reported in the present study so that both ICG with HEMS and RGS procedures were more than acceptable. Our findings are in agreement with the meta-analysis of Sugie et al.,[12] reporting a detection rate for tumor-positive SLNs for the fluorescence method and RGS ranging from 92.6%–100% to 76.9%–100%, respectively. Notably, the wider range of sensitivity for RGS can be well explained by the different methodological approaches such as the particle size of 99mTc-labelled colloids that have been employed in different clinical experiences; the site (peritumoral or subareolar region); and the depth of injection (subdermal or intra-parenchymal) of the radiocolloids.[39] Confirmatory evidence was reported in an initial experience by Aydoğan et al.[40]

Among the alternative options to the use of radiocolloids for SLNB, contrast-enhanced ultrasound (CEUS) using microbubbles to preoperatively identify and biopsy SLN and superparamagnetic iron oxide (SPIO) nanoparticles have more recently been assessed. The larger study on CEUS is a multicenter clinical study including 1906 patients by Cox et al,[41] reporting a successful core biopsy ranging from 79.6% to 88% coupled with a sensitivity to identify SLN metastases ranging from 45.5% to 52.5%. As for SPIO, the SentiMAG multicenter trial on 160 patients with invasive, in situ breast malignancy requiring SLNB reported a detection rate with the magnetic technique of 94.4%, a mean number of SLN excised equal to 1.86 per patient, with a sensitivity to detect a positive SLN of 92% (23 out of 25 patients with macrometastases).[42]

As for the effectiveness of the ICG procedure, the breakeven point for the amortization of the higher costs of HEMS will be faster, obviously, in high-volume centers; this corresponds to an average of about 60 operative days at a center that performs at least 500 SLNBs every year. Instead, in the breast units with the minimum number of cases allowed by EUSOMA (150 new cases/year), that is those breast units usually without the support of a nuclear medicine unit, the amortization of HEMS costs is estimated to be approximately 17 months. Especially at these centers, the SLNB with ICG would have an economic impact in decreasing collateral costs due to the absence of a nuclear medicine physician, saving in the transport of patients at the nearest nuclear medicine department, longer length of hospitalization days, and nuclear medicine physicians refund for his/her presence during surgery.


 > Conclusions Top


The use of the ICG method for the SLNB proved effective and with a more than satisfactory cost/effectiveness ratio as compared to RGS, although the latter method remains the gold standard. The absence of radioactive isotopes makes it safer physically, psychologically, and socially for patients. The efficiency of the ICG may prove as a source of considerable savings for both high-volume centers and those without a nuclear medicine unit.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
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