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Clinical Trial
. 2015 Jun 25;10(6):e0129766.
doi: 10.1371/journal.pone.0129766. eCollection 2015.

The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer

Quirijn R J G Tummers  1 , Charlotte E S Hoogstins  1 , Alexander A W Peters  2 , Cor D de Kroon  2 , J Baptist M Z Trimbos  2 , Cornelis J H van de Velde  1 , John V Frangioni  3 , Alexander L Vahrmeijer  1 , Katja N Gaarenstroom  2
Affiliations
Clinical Trial

The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer

Quirijn R J G Tummers et al. PLoS One. .

Abstract

Objective: In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting.

Methods: Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions.

Results: 6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99).

Conclusions: This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false-positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains.

Trial registration: ISRCTN Registry ISRCTN16945066.

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Conflict of interest statement

Competing Interests: QRJG Tummers, CES Hoogstins, CD de Kroon, AAW Peters, JBMZ Trimbos, CJH van de Velde, AL Vahrmeijer and KN Gaarenstroom have no conflicts of interest or financial ties to disclose. JV Frangioni: FLARE technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. Dr. Frangioni has started three for-profit companies, Curadel, Curadel ResVet Imaging, and Curadel Surgical Innovations, which has optioned FLARE technology for potential licensing from Beth Israel Deaconess Medical Center. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. CONSORT flow diagram for patient enrollment.
Fig 2
Fig 2. Identification of ovarian cancer metastases using NIR fluorescence imaging.
A. Identification of ovarian cancer metastases located in a lymph node next to the right iliac vein (arrow) using NIR fluorescence imaging. The lesion was found histologically to be a metastasis of serous adenocarcinoma. B. Ex vivo imaging of the same ovarian cancer metastases located in a lymph node next to the right iliac vein (arrow).
Fig 3
Fig 3. Identification of ovarian cancer omental metastases using NIR fluorescence imaging.
A. Identification of 2 ovarian cancer metastases located in the greater omentum (arrow and dashed arrow) using NIR fluorescence imaging. B. Imaging of the same two NIR fluorescent lesions removed from the omentum (arrow and dashed arrow). Both lesions were found histologically to be metastases of serous adenocarcinoma.
Fig 4
Fig 4. Identification of ovarian cancer omental metastases using NIR fluorescence imaging.
A. Identification of a NIR fluorescent lesion located in the mesentery of the intestine. The lesion was classified clinically as a metastasis but was found histologically to be a calcified lymph node.
See this image and copyright information in PMC

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