A Novel Tumor-Specific Agent for Intraoperative Near-Infrared Fluorescence Imaging: A Translational Study in Healthy Volunteers and Patients with Ovarian Cancer

Abstract

Purpose: Completeness of cytoreductive surgery is a key prognostic factor for survival in patients with ovarian cancer. The ability to differentiate clearly between malignant and healthy tissue is essential for achieving complete cytoreduction. Using current approaches, this differentiation is often difficult and can lead to incomplete tumor removal. Near-infrared fluorescence imaging has the potential to improve the detection of malignant tissue during surgery, significantly improving outcome. Here, we report the use of OTL38, a near-infrared (796 nm) fluorescent agent, that binds folate receptor alpha, which is expressed in >90% of epithelial ovarian cancers.Experimental Design: We first performed a randomized, placebo-controlled study in 30 healthy volunteers. Four single increasing doses of OTL38 were delivered intravenously. At fixed times following drug delivery, tolerability and blood/skin pharmacokinetics were assessed. Next, using the results of the first study, three doses were selected and administered to 12 patients who had epithelial ovarian cancer and were scheduled for cytoreductive surgery. We measured tolerability and blood pharmacokinetics, as well as the ability to detect the tumor using intraoperative fluorescence imaging.Results: Intravenous infusion of OTL38 in 30 healthy volunteers yielded an optimal dosage range and time window for intraoperative imaging. In 12 patients with ovarian cancer, OTL38 accumulated in folate receptor alpha-positive tumors and metastases, enabling the surgeon to resect an additional 29% of malignant lesions that were not identified previously using inspection and/or palpation.Conclusions: This study demonstrates that performing realtime intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial.

Setting Standards for Reporting and Quantification in Fluorescence-Guided Surgery

“…The disk can hold eight clear polypropylene tubes of 0.65 ml (Catalog # 15160, Sorenson, [3]) were used to make dilution series in Intralipid 2 %. All dilution series consisted of 21 concentrations, starting at 10,000 nM and, following one on one dilution with Intralipid 2 %, ending at 10 pM.…”

“…Fluorescence imaging (FI) is ideal for intraoperative applications due to fast acquisition times (milliseconds), flexibility in application, and portability [2]. Various tumor-targeted near-infrared (NIR) fluorescence agents have been successfully studied in clinical trials [3][4][5][6]. Moreover, there is great potential for a broad range of clinical applications besides oncology, such as infectious and inflammatory diseases [7].…”

“…Therefore, we conducted a systematic, controlled in vitro comparison between two commercially available, state-of-the-art clinical imaging systems using a novel designed calibration device for FI systems and various fluorescent agents to evaluate important performance characteristics of fluorescence imaging. In addition, we evaluated the effect of ROI selection and background noise on SBR calculation by analyzing 271 fluorescence images from previous studies [3,[15][16][17][18][19][20]. Based on these results, we propose an easily applicable, standardized approach to quantify and report imaging device performance and fluorescence image analysis.…”

Data-Driven Prioritization and Review of Targets for Molecular-Based Theranostic Approaches in Pancreatic Cancer

“…In PDA, molecular imaging might enhance disease staging by enabling visualization of small PDA lesions, possibly leading to optimized selection of patients who will benefit from curative surgery. Clinical trials already demonstrated the feasibility of molecular fluorescence imaging in identifying micrometastases in peritoneal metastasized ovarian and colon cancer patients by targeting the folate a-receptor and vascular endothelial growth factor A (24)(25)(26). Besides, molecular imaging can be used to better assess the extent of the primary tumor during PDA surgery and evaluate essential resection planes.…”

Folate receptor-targeted molecular imaging improves identification of malignancy during pulmonary resection: a case report

“…OTL38 exploits highly specific FRα-targeted binding which has similarly observed with the visual contrast agent, EC17 (folate-FITC) [5]. Unlike EC17, folate is linked to a NIR fluorophore in OTL38 and emits in the NIR range (λ ex 774 and λ em 795) [6]. NIR imaging probes have several advantages over visual range probes; most notably, less autofluorescence and superior depth of penetration.…”