Fluorescence-guided Surgery: an overview and an institutional experience Emma De Ravin, BS Karthik Rajasekaran, MD Jason G Newman, MD Despite improvements in other surgical subspecialties, positive margin rates on final pathology in head and neck oncologic procedures remain high (up to 30%).1 Negative margin status is associated with improved survival and progression-free survival, and is the single most important prognosticator in head and neck cancer.2 As a result, head and neck oncologic surgeons are beginning to explore novel fluorescence-guided surgery (FGS) techniques to improve margin clearance rates and reduce iatrogenic neurovascular injury. FGS is the process of injecting patients with fluorescent contrast agents that target and highlight a tissue of interest, i.e., a tumor, blood vessel, or nerve bundle. When struck with a specific excitation wavelength, these probes emit near-infrared (NIR) light visible using specialized imaging systems, enabling realtime intraoperative nerve visualization, tumor localization, and tumor margin delineation. The last 10 years have seen remarkable progress in optical imaging techniques via novel fluorophore development, NIR camera advancement, and clinical trials. Currently, as far as we know, four NIR contrast agents are being studied in head and neck cancer: indocyanine green (ICG), Cyanine 5.5 (Cy5.5), IRDye800CW, and zw800-1.3 ICG is a non-targeted fluorophore that is widely used for multiple non margin-enhancing procedures and has been applied to intraoperative angiography, oncologic procedures, sentinel lymph node resection, and hepatic function testing.4 Unlike ICG, both IRDye800CW and zw800
10
SOUNDINGS | Fall 2021
are conjugated with other molecules to increase their specificity and improve tumor targeting: while IRDye800 is often conjugated with chemotherapeutic agents such as anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (panitumumab, cetuximab), zw800 has been conjugated to cyclo-[Arg-GlyAsp], a drug that binds to tumor surface antigens.3,5 There are multiple ongoing clinical trials at our institution working to advance intraoperative molecular imaging techniques across numerous specialties.6 However, these techniques are still in their infancy—as of yet, of the above fluorescent contrast agents, only ICG is FDA-approved for biomedical purposes and thus remains the most widely used fluorophore in head and neck surgery. Our group previously demonstrated that NIR imaging of high-dose ICG injected 24 hours preoperatively, a novel technique called Second Window ICG (SWIG), could be used for intraoperative identification of head and neck lesions and regional metastasis: ICG has an 86% and 100% sensitivity in primary head and neck cancers and metastatic lymph nodes, respectively.7 In a small proof of concept case series of six patients, we recently demonstrated the efficacy of ICG imaging during transoral robotic surgery. Furthermore, in two of the six cases, NIR imaging was able to identify occult neoplasm that was not otherwise visible under white light, indicating that intraoperative NIR imaging may be useful in the surgical management of head and neck carcinoma of an unknown primary (unpublished data, August 2021). We are currently performing immunohistochemistry studies on fixed surgical tissue specimens to further understand the localization of ICG on the tissue and cellular level. Though SWIG has demonstrated some promise in head and neck squamous cell
carcinoma (HNSCC), one limitation of ICG is that it has no molecular targeting abilities, and instead relies on the enhanced permeability and retention effect, which stipulates that ICG accumulates within neoplasms due to disrupted intratumoral vasculature and lymphatic drainage.8 We are currently also participating in a clinical trial for HNSCC investigating ONM-100 (OncoNano Medicine, Southlake, TX), a drug that applies ICG in a novel configuration, in which ICG is encased in a pH-sensitive micelle that dissociates within the acidic tumor microenvironment. This enables more targeted localization of the ICG fluorophore, as it is only released intratumorally. ONM-100 demonstrated clear demarcation of fluorescence at all doses tested in Phase 1a of the trial.9 Now in Phase 2a, we are currently evaluating ONM-100 administered 24 hours preoperatively in the imaging of Stage II-IV HNSCC Continued on page 11
