Abstract
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. 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. 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. This study demonstrates that performing real-time intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial. Clin Cancer Res; 22(12); 2929-38. ©2016 AACR.
Highlights
The completeness of surgical tumor removal is an important factor for determining the survival of patients with a solid tumor
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
This study demonstrates that performing realtime intraoperative near-infrared fluorescence imaging using a tumor-specific agent is feasible and potentially clinically beneficial
Summary
Clinical trial in healthy volunteers This study included a total of 30 subjects (18 females and 12 males) 18 to 64 years of age with a BMI of 18 to 30 kg/m2 (see Supplementary Fig. S3 for the CONSORT flow diagram). Tolerability OTL38 at 0.025 mg/kg diluted in 20 mL 0.9% NaCl infused for 10 or 60 minutes caused moderate hypersensitivity in two of the four subjects receiving this dose. These reactions were not classic allergic reactions, as they were not accompanied by an increase in tryptase or IgE, nor did they involve the complement system (see Supplementary Data File S1). The dose was decreased to 0.0125 mg/kg for the three patients (patients 7, 8, and 9), yielding fewer, less severe symptoms, and an increase in TBR Even at this lowest dose, mild, self-limiting adverse events were reported. The complete list of all adverse events recorded in the patients is provided www.aacrjournals.org
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