Researchers at the Leiden University Medical Center (Netherlands) and collaborators developed a tumor-specific fluorescent agent and imaging system that could guide surgeons in real time to remove additional tumors in ovarian cancer patients that were not visible without fluorescence or could not be felt during surgery.
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Surgeons mainly have to rely on their own sight to identify tumor tissue, explains Alexander L. Vahrmeijer MD, Ph.D., head of the Image-guided Surgery group in the Department of Surgery at Leiden University Medical Center. But near-infrared (NIR) fluorescence imaging, he says, is a novel technique that may allow surgeons to improve visualization of tumors during surgery.
"In our study, using a tumor-specific fluorescent agent and a dedicated imaging system, a fluorescent signal was detected in tumors in real time during a surgical procedure for ovarian cancer called cytoreduction. This allowed resection of additional tumor lesions that were not visible to the surgeons' naked eyes," Vahrmeijer explains. "Although more research is needed, this is hopefully the first step toward improving the surgical outcome of cancer patients."
Philip S. Low, Ph.D., from Purdue University (West Lafayette, IN) and colleagues developed a new fluorescent agent, OTL38, which is a conjugate of NIR fluorescent dye and a folate analog that binds to folate receptor-alpha (FRα). Vahrmeijer and Jacobus Burggraaf, MD, Ph.D., from the Centre for Human Drug Research (also in The Netherlands), studied OTL38 in humans. According to Vahrmeijer, FRα is expressed in more than 90% of ovarian cancers, but in relatively low levels in some normal tissues. "The main advantage of NIR light is that it can penetrate tissue in the order of centimeters, allowing the surgeon to visualize tumors underneath the tissue surface that can be detected using a dedicated imaging system," Low explains.
The researchers first conducted a randomized, double blind, placebo-controlled clinical trial to assess the tolerability and pharmacokinetics of OTL38 in 30 healthy volunteers. This allowed them to rapidly determine the optimum dose range and time window for intraoperative imaging in patients with ovarian cancer, Burggraaf says. Next, under the supervision of gynecologist Katja Gaarenstroom, the researchers tested OTL38 in 12 patients with ovarian cancer. In addition to measuring tolerability and pharmacokinetics, they studied whether OTL38-guided surgery resulted in the detection of more tumors that were not visible or palpable during surgery.
The researchers found that OTL38 accumulated in FRα-positive tumors and metastases, and enabled the surgeons to remove an additional 29% of malignant lesions (confirmed by pathological examination of the resected tumors) that could not be identified with naked eyes and/or palpation.
This was a small, exploratory study, and was not designed to estimate the sensitivity and specificity of the imaging method. A larger study to address this, as well as other fluorescent agents for other tumor types that do not express FRα, are being planned, Burggraaf adds.
Full details of the work appear in the journal Clinical Cancer Research; for more information, please visit http://dx.doi.org/10.1158/1078-0432.CCR-15-2640.