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Novel fluorescent agent may identify ovarian lesions during surgery
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The use of a real-time intraoperative tumor-specific fluorescent agent and imaging system aided surgeons in identifying and removing tumors not visible to the naked eye in patients with ovarian cancer, according to the results of a translational study.
“Surgery is the most important treatment for ovarian cancer, and surgeons mainly have to rely on their naked eyes to identify tumor tissue, which is not optimal,” Alexander L. Vahrmeijer, MD, PhD, head of the image-guided surgery group at Leiden University Medical Center in the Netherlands, said in a press release. “Near-infrared fluorescence imaging is a novel technique that may assist the surgeons to improve visualization of tumors during surgery.”
Alexander L. Vahrmeijer
Vahrmeijer and colleagues sought to determine the efficacy of OTL38 (On Target Laboratories) — a newly developed fluorescent agent composed of near-infrared fluorescent dye and a folate analog binding to folate receptor alpha — to recognize malignant lesions during ovarian cancer surgery.
They first conducted a double blind, randomized controlled trial in 30 healthy adult volunteers (women, n = 18; men, n = 12), to judge the tolerability and pharmacokinetics of OTL38.
The volunteers received a single IV dose of OTL38 at one of four possible dose levels (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg or 0.2 mg/kg) or placebo. The researchers collected blood samples to observe the pharmacokinetic profile and perform routine tests.
OTL38 resulted in mild and transient adverse events when infused at the 0.025-mg/kg, 0.05-mg/kg and 0.1-mg/kg dose levels. These included abdominal discomfort, nausea and pruritus, all of which did not require intervention.
Dosing at the 0.2-mg/kg level led to moderately severe adverse events that required temporary infusion interruption. However, no dose levels caused clinically meaningful changes to baseline laboratory values or vital signs.
The pharmacokinetics analysis showed that volunteers achieved a maximum blood plasma concentration immediately at the end of the infusion of each dose, with a half-life extending between 2 hours and 3 hours.
The level of OTL38 excreted in urine increased with each dose, with the highest level (11%) seen at the 0.2-mg/kg dose.
The researchers then studied OTL38 in 12 women (age range, 44-79) undergoing surgery for ovarian cancer.
The first three patients received OTL38 at the 0.025-mg/kg dose. The researchers increased the dose to 0.05 mg/kg in the next three patients, which resulted in increased adverse events. Thus, the researchers decreased the dose to 0.0125 mg/kg, which they determined to be the optimal dose.
Researchers identified and resected 83 fluorescent legions during surgery, which included 62 malignant lesions.
Eighteen malignant lesions (29%) that were identified using the novel method had not been identified by surgeons through standard inspection or palpation methods.
The mean tumor-to-background ratio was 4.4 (standard deviation [SD] = 1.46; range, 1.7-9.8), and fluorescence remained detectable for at least 6 hours after infusion.
Of the 83 detected malignant lesions, 21 had no malignant disease, which corresponded to a false-positive rate of 23%. The mean tumor-to-background ratio of false-positive lesions was 5.4 (SD = 2; range, 1.8-9.3).
“A limitation of this study is that we cannot say yet what the impact of our findings is on cure or survival of the patients,” Vahrmeijer said. “It is reasonably plausible to assume that if more cancer is removed, the survival will be better. However, long-term follow-up studies need to be performed in large patient groups to prove such effects.” – by Cameron Kelsall
Disclosure: On Target Laboratories funded this study. Vahrmeijer reports no relevant financial disclosures. Other study researchers report consultant roles with OmniComm and employment and ownership interests, including patents, with On Target Laboratories.
Perspective
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Christina S. Chu, MD
For decades, one of the hallmarks of treatment for advanced ovarian cancer has been meticulous surgical debulking with the express goal of removing all visible disease, if possible. The extent of debulking is correlated with patient survival, so the importance of complete tumor removal cannot be underestimated. New technologies are emerging to allow identification of tumors that may be invisible to the naked eye. Hoogstins and colleagues have reported a study using near-infrared fluorescence imaging to help identify tumors that may otherwise be unidentified by routine examination at the time of surgical debulking.
The investigators studied OTL38, a drug that binds to folate receptor alpha, which is found on the surface of more than 90% of ovarian cancers. OTL38 then fluoresces, or glows this near-infrared fluorescence is invisible to the eye, but may be detected using a special camera system. The study administered different doses of OTL38 or a placebo to 30 healthy volunteers to help determine the optimum dose and time window for imaging. Then, 12 patients with ovarian cancer received OTL38 and underwent surgery.
The investigators noted that the surgeon was able to remove 29% more cancerous lesions when using the near-infrared fluorescence imaging system than when just using the normal methods of looking and feeling for tumors. They concluded that near-infrared fluorescence imaging used with a drug that binds specifically to the tumor is feasible and potentially helpful to maximize surgical debulking.
Although the technique is promising, it is still under investigation, and such imaging systems are not widely available. It still remains to be studied whether removing invisible tumor cells improves patient survival.
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