Page 159 - Fluorescence-guided cancer surgery

Clinical translation of OTL38 in ovarian cancer 157
INTRODUCTION
The completeness of surgical tumor removal is an important factor for determining the survival of patients with a solid tumor. Despite advances in preoperative imaging techniques, during surgery the surgical oncologist must rely primarily upon inspection and/or palpation to identify the tumor tissue; however, these methods are often inadequate1-3.
Ovarian cancer has the highest mortality rate of all gynecological cancers4. The surgical treatment of advanced-stage ovarian cancer (i.e., International Federation of Gynecology and Obstetrics stage IIb through stage IV) typically consists of cytoreductive surgery combined with systemic chemotherapy. Several studies have shown that the amount of residual tumor that remains following cytoreductive surgery is the most important prognostic indicator of survival5-9. Thus, because imaging modalities that improve tumor identi cation during surgery can increase the number and thoroughness of metastatic lesions resected during cytoreductive surgery, they can signi cantly improve patient outcome.
Near-infrared (NIR) uorescence imaging is an innovative technique that can be used to detect tumor lesions during surgery10. NIR uorescence is invisible to the human eye, but can be detected in the millisecond range using a dedicated imaging system. Because the imaging system can be toggled on and o rapidly, this approach allows the surgeon to identify malignant tissue in real time without altering the surgical eld. In addition, NIR light can penetrate tissue on the order of centimeters, allowing the surgeon to delineate targets underneath the tissue surface11;12. Despite its high potential in clinical applications, NIR uorescence in surgical oncology has been used primarily with nonspeci c agents previously available for clinical use. For example, indocyanine green is retained either in or around tumor tissue due to impaired secretion or increased vascular permeability and decreased lymphatic drainage; however, indocyanine green does not bind speci cally to cancer tissue13;14. This lack of speci city results in a high rate of intraoperative false positive images in patients with ovarian cancer15. Thus, uorescent agents that speci cally target cancer-speci c targets are highly desired.
Folate receptor alpha (FRα) is a promising target, as it is robustly expressed on a variety of cancers of epithelial origin, including >90% of epithelial ovarian cancers16-18. Moreover, FRα is expressed at relatively low levels in healthy tissue,