Page 118 - Fluorescence-guided cancer surgery

116
Chapter 8
signal. NIR uorescence is relatively easy and provides su cient contrast due to high tissue penetration and low auto- uorescence13.
For tumor identi cation, it is essential that contrast agents accumulate in tumor tissue either actively or passively. Active accumulation can be achieved by targeting ligands that are over-expressed on tumor tissue. Van Dam et al. were the rst to show tumor identi cation using a folate receptor alpha (FR- a) targeting agent14. In their series they were able to identify tumor tissue in 3 patients with FR-a positive ovarian cancer intraoperatively. However, these results have not yet been reproduced in other studies using a FR-a or di erent targeting agents. A possible cause for this may be the expensive and time-consuming nature of the development of these tumor-speci c agents. Therefore, it is of great importance to exploit clinically available contrast agents, such as indocyanine green (ICG)15.
In vivo ICG binds to serum proteins and therefore behaves as a macromolecule in the circulation. It is known that macromolecules accumulate in tumor tissue due to increased vascular permeability and reduced drainage. This phenomenon is called the “enhanced permeability and retention” (EPR) e ect and has been observed in most solid tumors16;17.
Clinical feasibility trials using this e ect with ICG in breast cancer patients in a pre-operative diagnostic setting and in gastric cancer patients during endoscopic surgery showed that it was possible to distinguish tumor from surrounding tissue18-23. In addition, Kosaka et al.24 detected small ovarian (1-2 mm in size) cancer implants using NIR uorescent imaging after intravenous (IV) administration of ICG in a mouse model. Pathophysiological heterogeneity of solid tumors, for examples in size, presence of necrosis, or presence of vascular mediators may in uence accumulation of macromolecules in tumor tissue25;26. It is therefore not clear if all preclinical results can be translated to the clinic.
The primairy aim of the current study was to determine the feasibility of ovarian cancer metastases detection using ICG and NIR uorescence imaging in a clinical setting. Secondary aim was to assess concordance between uorescence signal and tumor status on histopathology. In addition, we sought to determine if a su cient tumor-to-background ratio (TBR), based on the EPR e ect, could be obtained to discriminate between malignant and non- malignant tissue.