The Usefulness of Indocyanine Green in Cytoreductive Ovarian Cancer Surgery

Indocyanine green may be highly sensitive in the identification of ovarian cancer metastases, though with low specificity. Introduction Ovarian cancer is the second most common malignancy of the female genital tract in the United States, according to the American College of Obstetricians and Gynecologists, 2017.

1 In terms of mortality, it ranked eighth worldwide in 2013 and fifth in Poland in 2019 among all cancers. 2,3 The high mortality rate associated with ovarian cancer is mainly due to its late diagnosis. At the time of diagnosis, two-thirds of patients present with intraperitoneal dissemination, corresponding to International Federation of Gynecology and Obstetrics (FIGO) stage III or IV.

4 The most important prognostic indicator in patients with advanced-stage ovarian cancer is the volume of residual disease after cytoreductive surgery. 4 The primary treatment approach remains debulking surgery. The goal of this procedure is to achieve complete cytoreduction.

Among patients with residual disease greater than 1 cm, those with residual disease smaller than 2 cm have better survival than patients with residual disease greater than 2 cm. 5 The significance of complete cytoreduction with no residual disease was analyzed in a study involving 3126 patients.

The most pronounced differences in progression-free survival (PFS) and overall survival (OS) were observed between patients who achieved complete resection and those with any macroscopic residual tumor. Comparing patients with residual tumors 1 mm to 10 mm in size with the group with residual disease greater than 1 cm showed that statistically significant progression-free survival and OS were achieved only in FIGO stage IIIC ovarian cancer.

6 In the latest study, a trial of radical up-front surgical therapy in advanced ovarian cancer (phase 3 TRUST trial [NCT02828618]), the most favorable outcome was observed among patients achieving complete gross resection; benefits of a primary debulking procedure over neoadjuvant chemotherapy with interval debulking procedure were shown to be significant, with a PFS benefit for primary cytoreduction.

7 It is therefore crucial to assess the likelihood of achieving complete cytoreduction and to identify metastatic lesions that can be completely excised. Despite comprehensive imaging studies during the preoperative evaluation, final tumor staging is verified intraoperatively. It indicates the need for careful evaluation of the abdominal organs, even in early-stage cases.

Despite advances in imaging, surgeons continue to rely on visual inspection during cytoreductive surgery to identify all disease sites in the peritoneal cavity. 8 Finally, the quality of surgery depends on training and the volume of ovarian cancer operated on. 9 One method used for intraoperative tissue imaging is indocyanine green (ICG).

According to European Society of Gynecological Oncology (ESGO) and National Comprehensive Cancer Network guidelines, ICG is used for sentinel lymph node mapping in endometrial and cervical cancer. 10-13 Only a limited number of studies have evaluated the use ofICG for the direct intraoperative detection of metastatic lesions in ovarian cancer.

14-16 We decided to assess the fluorescence with the use of ICG in the intraoperative imaging of ovarian cancer lesions in patients who qualified for primary debulking surgery. This is the first study assessing both the sensitivity and specificity of ICG in this indication. Materials and Methods The study is based on intravenous administration of ICG in patients with ovarian cancer and resection of infrared-stained lesions, according to the oncological protocol of cytoreductive surgery.

ICG-positive lesions were subsequently compared with histopathological findings and correlated with imaging studies. Objective This is an exploratory diagnostic accuracy study evaluatingICG in the intraoperative identification of ovarian cancer metastases in the peritoneal cavity, using a near-infrared imaging camera system.

Study End Points The end point of this study is the calculation of the sensitivity and specificity of ICG in the intraoperative identification of ovarian cancer metastases in patients qualified for primary debulking surgery. Inclusion Criteria We included in the study the patients with high suspicion of ovarian cancer (based on CT scan results indicating ovarian cancer; a score of the Risk of Ovarian Malignancy Algorithm and the overall clinical picture), qualified for primary debulking surgery, who did not meet the exclusion criteria.

A multidisciplinary team of gynecologic oncologists determined eligibility for primary debulking surgery. Exclusion Criteria The exclusion criteria for this study included patients older than 80 years and younger than 18 years, renal insufficiency (estimated glomerular filtration rate, < 55 mL/min/1.73m 2 ), allergy to iodine or ICG, hyperthyroidism, pregnancy or breastfeeding, and refusal to provide consent to participate in the study.

Tracer Preparation ICG solution was prepared by dissolving ICG powder (25-mg vials; Verdye) in 10 mL of sterile water for injection. Before intravenous administration, the solution was examined to ensure clarity. Statistical Analysis Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false-positive rate were calculated, as introduced in work by Monaghan et al.

17 CIs were calculated as Clopper-Pearson, exact binomial CIs. The predictive values are the standard logit CIs reported by Mercaldo et al. 18 The analysis was performed at the lesion level.

Only patients with histologically confirmed ovarian cancer were included in the analysis. Study Protocol The study protocol was approved by the Local Bioethics Committee at the Center of Postgraduate Medical Education in Warsaw, Poland, on October 16, 2024 (Resolution No. 81/2024).

The study was conducted in accordance with the ethical principles of the 1975 Declaration of Helsinki. Patients with a high suspicion of ovarian cancer based on clinical examination, imaging, and laboratory tests were included in the study. All patients provided written informed consent before participation.

The first patient included in the study presented to the Department of Gynecology and Gynecologic Oncology at the Center of Postgraduate Medical Education in December 2024. The patients were qualified for laparoscopy or laparotomy. ICG solution, prepared by dissolving 25 mg ICG powder in 10 mL of sterile water for injection, was administered intravenously at a dose of 0.25 mg/kg based on the patient’s weight.

The time for ICG intravenous administration was 1 hour before skin incision. Intraoperative bias control was implemented using a standardized checklist, applied uniformly across all procedures. That checklist included opening the abdominal cavity; identification of the ICG-positive lesions in the pelvic and abdominal cavity, starting from the peritoneum of the diaphragm and upper abdomen; reidentification of the lesion immediately before excision during the surgical procedure; confirmation of ICG-positive staining by all operating surgeons; and excision of the lesions, sending excised lesions for histopathologic evaluation.

In the operating theater, after laparotomy and opening the abdominal cavity, lesions were identified using Stryker’s SPY Portable Handheld Imager. In the case of laparoscopy, the lesions were identified using Stryker’s laparoscopy system with near-infrared visualization (NIV) mode.

The interval between ICG administration and lesion imaging ranged from 70 to 120 minutes. No additional lesions were detected on imaging at later time points; this did not prolong the operation.Fluorescent lesions were subsequently resected unless their removal could jeopardize patient safety or compromise surgical outcome and were sent for histopathologic examination.

In addition, morphologically abnormal lesions suspected of malignancy but showing no fluorescence were also resected according to the cytoreductive surgery protocol. These lesions were labeled as ICG negative and submitted for histopathological evaluation. All surgical procedures were performed according to ESGO ovarian cancer surgery guidelines.

9 The resected specimens were subsequently subjected to routine histopathological examination to determine the presence of malignant cells. ICG status (positive or negative) was blinded for the pathologist. The final histopathology reports were then compared with the surgically removed specimens; sensitivity, specificity, PPV, NPV, and false-positive rate were calculated.

For each patient, the location and number of metastatic lesions on CT images were compared with intraoperative ICG staining. Results We obtained 107 lesions from 18 patients. Two patients were diagnosed with endometriosis, 3 patients with serous cystadenoma, 1 patient with retroperitoneal uterine leiomyoma in the final histopathologic confirmation, and 1 patient with metastatic breast cancer, previously confirmed as triple-negative breast cancer.

Finally, 11 patients were diagnosed with ovarian cancer; 89 lesions for histopathologic examination were obtained from these patients. All patients with ovarian cancer underwent primary debulking surgery, with laparoscopic biopsy and frozen section performed beforehand in 2 cases.

Of the patients with ovarian cancer, 3 patients were diagnosed with endometrioid type of ovarian cancer, and 8 patients with serous type of ovarian cancer. The characteristics of the patients are presentedin Table 1 . After a laparoscopic or open laparotomy approach to the abdomen and pelvis, using NIV mode, fluorescence was clearly visible and marked.

White-light image with integrated fluorescence (overlay mode) and high-contrast fluorescence visualization in grayscale (contrast mode) were primarily used. The ICG pooling around the suspected malignant lesions was labeled ( Figure 1 ). The size and locations of the lesions vary significantly among patients.

The smallest excised lesion was 6 mm in diameter. The largest excised lesion was 260 mm in diameter and represented a tumor deposit in the greater omentum, high-grade serous ovarian cancer. The excised lesions were the tumor deposits from the peritoneum of the pelvis, peritoneum of the abdomen, the greater omentum, the lesions from the intestines, and the lesions from the diaphragmatic peritoneum.

Among patients with ovarian cancer, 42 lesions were confirmed to be malignant. Of these, 41 lesions were ICG positive, whereas 1 malignant lesion was ICG negative, representing a false-negative result. A total of 47 lesions were negative for malignant cells.

Among these, 23 lesions were ICG positive (false positive), while 24 were ICG negative. Overall, the ICG assessment had a sensitivity of 97.6% (95% CI, 87.4%-99.9%) and a specificity of 51.0% (95% CI, 36.0%-65.9%). The PPV was 64.0% (95% CI, 57.0%-70.5%), the NPV was 96.0% (95% CI, 77.2%-99.4%), and the false-positive rate was 48.9%.

In the patient with breast cancer, all confirmed metastatic lesions were also labeled ICG positive; these lesions were excluded from the diagnostic accuracy calculations, as the study concerns the use of ICG in patients with ovarian cancer. In 2 patients, 2 metastatic lesions that were not visible to the naked eye intraoperatively were identified due to positive ICG labeling.

Eight lesions from 5 patients, histologically confirmed as ovarian cancer metastases and marked as ICG positive, were not detected in preoperative visualization on CT images. These lesions include involvement of the diaphragmatic peritoneum (3 lesions), an appendix lesion, gallbladder infiltration, metastatic involvement of the round ligament of the liver and the right iliac lymph node, and a metastatic lesion on the anterior rectal wall.

ICG was especially concentrated in the liver and within the small bowel serosa. Due to the liver’s brightness in near-infrared fluorescence mode, lesions localized in the diaphragm could not be effectively labeled ( Figure 2 ). A false-negative result (ICG negative) was observed in a metastatic lesion located in the right diaphragmatic peritoneum.

The lesion was identified by palpation and excised due to suspicion of metastatic involvement. ICG was labeled in 1 patient clinically suspected of malignancy lesions in the mesentery ( Figure 3 ). These lesions were also excised and sent for histopathological confirmation.

On final histopathological examination, the lesions were confirmed to be nonmalignant calcified nodules. In several cases, due to the advanced stage of the disease, not all ICG-marked lesions were removed ( Figure 4 ). Discussion In this study, we aimed to prove the usefulness of ICG in cytoreductive surgery in patients with ovarian cancer.

We included patients with high suspicion of ovarian cancer who qualified for primary debulking surgery. During surgery, ICG-labeled lesions were excised, and after histopathological confirmation, the sensitivity and specificity of ICG in labeling ovarian cancer metastases were calculated.

Of the 11 patients, 42 malignant lesions were found, of which 41 were ICG labeled; the sensitivity was 97.6%. Forty-seven lesions were nonmalignant; however, 23 of them were ICG positive. The specificity of ICG labeling was 51.0%.

This study represents the second investigation evaluating fluorescence for intraoperative, real-time visualization of ovarian cancer metastases during primary debulking surgery. In the literature, we identified the first study conducted by Tummers et al. 15 In that study, 8 metastatic lesions were detected in a group of 6 patients, all of which were ICG positive (sensitivity, 100%);13 lesions from 21 ICG-labeled lesions were benign, and the false-positive ratio was 62%.

15 In our study, the sensitivity was 97.6%, while the false-positive rate was 48.9%. In 2 other studies, we found data on the use of fluorescence to visualize peritoneal metastases during real-time surgery after neoadjuvant chemotherapy. The literature data are summarized in Table 2 .

Currently, CT, MRI, and ultrasound are routinely used for preoperative assessment. However, CT has limited sensitivity for detecting small peritoneal metastases. 19 In addition, both CT and MRI are unable to reliably detect malignancy in normal-sized lymph nodes or distinguish between hyperplastic lymph nodes and metastatic involvement.

Additionally, CT and MRI do not provide real-time intraoperative guidance. 20 In our study, 8 lesions histologically confirmed as ovarian cancer metastases, marked as ICG positive, were not detected in preoperative visualization on CT images.Intraoperative visualization may represent a valuable tool for identifying lesions requiring excision and facilitating complete cytoreduction.

Particularly in patients with cancer with small metastatic lesions, preoperative imaging assessment often does not correlate with intraoperative findings. Various receptors have been investigated as targets for the intraoperative visualization of metastases. One promising target is folate receptor (FR)-α, which is overexpressed in approximately 72% to 89% of patients with epithelial ovarian cancer.

21,22 Van Dam et al used folate-conjugated fluorescein isothiocyanate to target FR-α with a real-time multispectral intraoperative fluorescence imaging system. In patients with malignancy and overexpression of FR-α, all malignant lesions were fluorescent positive. No fluorescent signal was detected in patients with malignancy characterized by the lack of FR-α expression, or in patients with benign lesions.

23 Although tumor cells lacking FR-α were not detected during the study, these results are promising in the usefulness of this type of fluorescence in the intraoperative visualization. Similar findings were reported in a study conducted by Tummers et al. 24 In this study, 57 fluorescent lesions from patients with ovarian cancer have been obtained; among these lesions, 77% were confirmed to be malignant on final histopathological examination, whereas 23% were benign.

In comparison, 3 metastatic lesions showed no fluorescent signal, representing false-negative results. 24 Other tracers that have been tested for intraoperative visualization include an FRα-targeted ligand bound to a cyanine dye, OTL-38, or 5-aminolevulinic acid (ALA). 25,26 5-ALA functions as a prodrug that induces the accumulation of protoporphyrin IX in the mitochondria of tumor cells, where the accumulated compound acts as a photosensitizer.

25 In detection of peritoneal metastases during surgery, the sensitivity, specificity, and PPV for OTL-38 and ALA were 92.2% vs 79.8%, 67.3% vs 94.8%, and 55.8% vs 95.8%, respectively. 27 One of these substances, OTL-38 (known as pafolacianine), has been the subject of numerous clinical trials.

28 Data from a phase 3 study demonstrated that pafolacianine-guided near-infrared imaging in patients with ovarian cancer enables the detection of additional lesions not identified by white-light imaging and palpation, with additional cancer lesions detected in approximately 33% of patients.

29 Pafolacianine (Cytalux; On Target Laboratories) was approved by the US Food and Drug Administration (FDA) on November 29, 2021, as an adjunct to improve intraoperative tumor detection when used with an FDA-approved near-infrared fluorescence imaging system. 30 Study Limitations In this study, we assessed the sensitivity and specificity of ICG fluorescence imaging during real-time surgery in patients with ovarian cancer.

The low specificity and high false-positive rate associated with ICG limit its utility in staging procedures and may lead to the resection of nonmalignant lesions. As a result, its application for tumor deposit identification in patients with ovarian cancer remains limited. In our study, analysis was performed at the lesion level.

Multiple lesions were obtained from 11 patients. This introduces within-patient clustering, which may influence the precision of the reported CIs. From a technical perspective, the portable handheld imager does not allow simultaneous visualization of fluorescence and white-light images.

The need to switch among white-light, monochromatic fluorescence imaging, green fluorescence overlay, and color-segmented fluorescence modes may interrupt the surgical workflow. 31 In cases of extensive peritoneal disease and the presence of unresectable lesions, it was not possible to obtain histological confirmation for all ICG-positive lesions.

The same limitation was met by other authors assessing fluorescence in the visualization of peritoneal metastases. 32 Another technical limitation was the reduced visualization of lesions on the diaphragmatic peritoneum, likely due to the strong fluorescence signal from the liver in fluorescence mode.

Physical shielding of the liver with a swab was attempted; this did not significantly affect the visualization of fluorescent changes on the diaphragm. In future protocols, some technical issues to mitigate fluorescence signal from the liver are necessary to obtain better visualization of the diaphragmatic peritoneum.

The relatively low PPV (64.0%) may have adverse clinical implications, as it could lead to unnecessary excision or biopsy of ICG-positive lesions. Consequently, this may increase the risk of intraoperative bleeding, injury to adjacent organs, and prolongation of operative time. The decision to resect a lesion always rests with the surgeon, who considers intraoperative conditions and risks.

ICG is a fluorophore approved for clinical use by the FDA and the European Medicines Agency. However, it is a nontargeted dye, and its chemical structure does not allow specific conjugation with tumor ligands. Because ICG can follow lymphatic drainage pathways but does not bind specifically to tumor cells, it is commonly used for sentinel lymph node mapping in cervical, endometrial, and vulvar cancers.

11,12,33,34 Nonspecificity to cancer tissue does not interfere with the application of ICG as a tracer in ureteral visualization or bile duct visualization. 35,36 One of the main mechanisms of ovarian cancer metastatic growth is neoangiogenesis. 37 Due to neoangiogenesis and increased vascular permeability, macromolecules formed by ICG and lipids tend to accumulate in cancer tissue.

38 It is known as the enhanced permeability and retention (EPR) effect, which is observed in most solid tumors. 39 Consequently, structures containing ICG can be visualized using near-infrared fluorescence imaging. 40 The EPR effect could be influenced by factors such as the size of the lesion, presence of necrosis, prostaglandins, and bradykinins.

It was also shown that the EPR effect could be caused by inflammation. 41,42 This correlates with a high percentage of false-positive results (such as ICG-positive calcified nodules) in our study. False-positive fluorescence could also have resulted from neoangiogenesis in the patient’s mesentery with malignant disease.

In addition to fluorescence-based techniques, other tracers are commonly used for sentinel lymph node mapping. Among these, technetium-99m–based radiopharmaceuticals are the most widely used agents in lymphoscintigraphy. Although technetium tracers have the highest specificity in sentinel lymph node mapping, ICG itself allows some of the benefits of technetium (signal penetration through tissue) to be achieved without the need for nuclear medicine techniques.

43,44 Additionally, the use of radiotracers requires the involvement of a nuclear medicine specialist; other disadvantages are high costs and a lack of visual information. 45 Some studies could be found about using ICG in similar settings (intravenous route of administration) in the visualization of peritoneal metastases from nonovarian malignancies: colorectal cancer (CRC) and hepatocellular carcinoma (HCC).

32,46-48 The sensitivity varies from 72.4% to 96.9%, and the specificity varies from 60.0% to 75.0% for CRC (ICG dose, 0.25 mg/kg). For HCC (ICG dose of 0.5 mg/kg), sensitivity was 100% and specificity was 100%. 49 To establish the usefulness of fluorescence in routinely performed debulking surgery, prospective randomized studies are needed to demonstrate its benefits.

Positive results of such studies would help implement the use of ICG in ovarian cancer surgery. A generally accepted protocol with recommendations on how to report changes in intraoperative decision-making that result from fluorescence imaging would help establish the role of near-infrared imaging in routinely performed cancer surgery.

50 Conclusions The study was conducted to assess the usefulness of ICG in the intraoperative visualization of ovarian cancer metastases during primary debulking surgery. Preliminary results suggest that ICG fluorescence enables highly sensitive staining of cancerous lesions. Limited specificity of ICG labeling of the metastatic lesions in our study and in a few previous studies mentioned in the discussion indicates a cautious approach to the intraoperative use of near-infrared imaging.

In some cases, ICG fluorescence could reveal metastatic changes invisible to the naked eye. The localization and excision of metastatic lesions that are not visible to the naked eye are key components of cytoreductive surgery. Additional studies are required to determine the specificity of near-infrared imaging for intraoperative lesion detection and to investigate the effect of fluorescence-guided surgery on OS and time to disease progression in patients with ovarian cancer eligible for surgical treatment.

Institutional Review Board Statement The study was conducted in accordance with the Declaration of Helsinki and approved by the Local Bioethics Ethics Committee of the Center of Postgraduate Medical Education on October 16, 2024, under resolution number 81/2024. Funding The work was funded by Center of Postgraduate Medical Education, research program number: 501-1-106-44-24 Informed Consent Statement Informed consent was obtained from all patients involved in the study.

Data Availability Statement The original contributions presented in this study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author(s). Conflicts of Interest The authors declare no conflicts of interest.

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