Molecular-specific optical guided surgery in head and neck squamous cell cancer, a systematic review of animal models and clinical trials.

Aim: Because of its important role in oncological curation, surgical oncology has radically advanced over the last decades with new techniques and technological improvements resulting in better outcome and survival in cancer patients. However, one prominent risk factor remains the complete removal of the solid tumor with acceptable margins. In head and neck cancer, when tumor cells remain present in the patient postoperatively, a significantly lower chance of curation is described and these patients are hence referred for further adjuvant therapies [1]. This has led to the recent development of intra-operative optical guidance to visualize the tumor margins by use of fluorescence. The field of optical guided surgery has evolved tremendously over the last couple of years, resulting in an explosion of different tracers [2]. This sudden growth of optical guided surgery has led to an unclear overview of the tracers used in the field. The current systematic review aimed at systematically collecting all different molecular specific probes studied in animal models and clinical trials for their application in the optical visualization of head and neck squamous cell cancer specifically. Material and Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [3]. The Medline, Embase and Web of Science databases were systematically searched for eligible articles using a specifically designed search string. Only studies were included which investigated molecular specific probes for the macroscopic identification of mucosal squamous cell cancers of the head and neck in animal models or in clinical trials. Studies considering non-specific targets or non-animal studies were excluded, and only articles in English, French or Dutch were selected. There were no restrictions on publication date of publication. Results: After removal of duplicates a total of 1137 records were described. Title and abstract revealed a total of 128 eligible records, of which 47 manuscripts were included in the systematic review after full text screening and application of in- and exclusion criteria. All molecular specific imaging agents were grouped into groups based on their responding proteins. These imaging agents make use of the tumor-upregulated proteins CD44v6 (n=2), COX-2 (n=1), EGFR (n=21), EpCAM (n=1), Fr (n=1), GGT (n=2), Integrins (n=6), Cathepsin and MMP (n=7), PARP (n=2), PDPN (n=1), Tf (n=1), uPAR (n=2) and VEGF (n=1). Because of the heterogenous presentation of the results, a primary narrative systematic review was conducted. The main differences between the groups will be discussed, and the possible research implications will be presented. Conclusion: This study systematically reviews all studies published on the topic of molecular specific optical visualization of squamous cell cancers of the head and neck in clinical or animal studies. These results could help researchers determine which probes are useful for their implementation in further studies and hence advance FDA- and EMA-approval for these molecular specific optical imaging agents.