Page 138 - Fluorescence-guided cancer surgery

136
Chapter 9
Biological characteristics of uorescent contrast agents are essential to achieve target-speci c uorescence imaging. Ideally, a contrast agent binds exclusively to a cancer speci c ligand, while being excreted rapidly from the rest of the body. Over the past years, extensive preclinical validation of tumor- speci c contrast agents targeting a variety of ligands was reported, however only very few were clinically introduced15;16. For this reason, several clinical studies have been performed to explore feasibility of clinically available uorescent contrast agents like methylene blue (MB) and indocyanine green (ICG) for intraoperative tumor imaging of breast cancer tissue and ovarian cancer tissue17;18. These agents do not speci cally bind to the tumor, but make use of other mechanisms such as the Enhanced Permeability and Retention (EPR)19;20 e ect and disturbed excretion pro les causing accumulation in or around tumor tissue. Although promising results were described, resection of non-malignant lesions due to false positive uorescence proved an insurmountable problem in the road to clinical application. Consequently, the need for newly developed contrast agents with highly speci c binding to tumor-speci c targets remains.
A promising target for image-guided surgery is the folate receptor alpha (FRα). Normally the FRα is expressed only at low levels and due to its location on the apical membrane of epithelial cells it is not accessible for molecules transported by blood21;22. In contrast, in many types of epithelial cancers, the FRα is highly expressed. As a result of the loss of cell polarity in cancer, the FRα is easily accessible by blood making it an ideal tumor target. Over 90% of all epithelial ovarian cancers over-express FRα, and in ovarian cancers of serous morphology this percentage is even higher (90-100%)23-25. Moreover, expression is not altered by chemotherapy26;27, allowing use of this target in both primary and interval cytoreductive surgical procedures. In breast cancer, FRα overexpression is reported in 30% of tumors, this percentage is even higher (67%) in tumors with a “triple-negative” receptor pro le28. In almost all breast cancer patients, preoperative biopsies are available, allowing characterization of FRα status before surgery to select patients who will bene t from FRα targeted imaging agents.
While multiple preclinical studies have been performed on the imaging of FRα positive tumors29-31, clinical experience is very limited. Van Dam et al. showed feasibility of intraoperative imaging of ovarian cancer metastases using EC17, a FRα targeting contrast agent with uorescent properties in