A Standardized Framework for Fluorescence-Guided Margin Assessment for Head and Neck Cancer Using a Tumor Acidosis Sensitive Optical Imaging Agent

PURPOSE: Intra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery. PROCEDURES: Thirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology. RESULTS: All six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion. CONCLUSION: Our specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity

Fluorescence-guided imaging for resection margin evaluation in head and neck cancer patients using cetuximab-800CW:A quantitative dose-escalation study

Tumor-positive resection margins are present in up to 23% of head and neck cancer (HNC) surgeries, as intraoperative techniques for real-time evaluation of the resection margins are lacking. In this study, we investigated the safety and potential clinical value of fluorescence-guided imaging (FGI) for resection margin evaluation in HNC patients. We determined the optimal cetuximab-800CW dose by quantification of intrinsic fluorescence values using multi-diameter single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy. Methods: Five cohorts of three HNC patients received cetuximab-800CW systemically: three single dose cohorts (10, 25, 50 mg) and two cohorts pre-dosed with 75 mg unlabeled cetuximab (15 or 25 mg). Fluorescence visualization and MDSFR/SFF spectroscopy quantification was performed and were correlated to histopathology. Results: There were no study-related adverse events higher than Common Terminology Criteria for Adverse Events grade-II. Quantification of intrinsic fluorescence values showed a dose-dependent increase in background fluorescence in the single dose cohorts (p<0.001, p<0.001), which remained consistently low in the pre-dosed cohorts (p=0.6808). Resection margin status was evaluated with a sensitivity of 100% (4/4 tumor-positive margins) and specificity of 91% (10/11 tumor-negative margins). Conclusion: A pre-dose of 75 mg unlabeled cetuximab followed by 15 mg cetuximab-800CW was considered the optimal dose based on safety, fluorescence visualization and quantification of intrinsic fluorescence values. We were able to use a lower dose cetuximab-800CW than previously described, while remaining a high sensitivity for tumor detection due to application of equipment optimized for IRDye800CW detection, which was validated by quantification of intrinsic fluorescence values

mTHPC mediated PDT of Head and Neck Cancer, Modifying pharmacokinetics using liposomal drug carriers

In dit proefschrift wordt beschreven dat fotodynamische therapie (PDT) met de fotosensitizer mTHPC opgelost in ethanol, Foscan, kan worden toegepast bij de behandeling van uitbehandelde patiënten met een plaveiselcelcarcinoom in het hoofd-halsgebied. De resultaten van curatieve behandeling van kleine T1 plaveiselcelcarcinomen na Foscan PDT is vergelijkbaar met chirurgische behandeling. Gerandomiseerde, prospectieve studies over de resultaten van fotodynamische therapie ontbreken echter. In tumor-modellen lieten liposomale dragers van mTHPC, in het bijzonder Fospeg, een hogere en eerder opname in tumorweefsel zien in vergelijking met Foscan. De betere eigenschappen van Fospeg vallen te verklaren door de polymeer coating van de liposomale drager van mTHPC. Door deze coating wordt de herkenning en het wegvangen uit het lichaam van mTHPC verminderd. De resultaten rechtvaardigen nader onderzoek naar de effectiviteit van Fospeg gemedieerde PDT in vergelijking met Foscan gemedieerde PDT. Hieruit moet blijken of een lagere dosis mTHPC en vroegere belichting de gewenste weefselschade veroorzaakt. Fluorescence Differential Pathlength Spectrsocopy (fDPS) bleek een betrouwbare, niet-invasieve methode om de mTHPC concentratie in-vivo en real-time in homogeen weefsel te meten. Door een verschil in het interrogatie volume tussen fDPS en de gouden standaard, chemische extractie, was de correlatie tussen beide meetmethodes echter laag. Waarschijnlijk berust dit op de grotere nauwkeurigheid van de fDPS metingen terwijl bij chemische extractie sprake is van middelende metingen. De fDPS meetmethode biedt door zijn real-time informatie over de mTHPC concentraties en de zuurstofoxygenatie, de mogelijkheid om de complexe PDT reactie te optimaliseren. This thesis shows that photodynamic therapy mediated by the photosensitizer mTHPC, dissolved in ethanol (Foscan), can be used in the palliative treatment of patients with end-stage squamous cell carcinoma of the head and neck area. The results after curative treatment of small squamous cell carcinomas (T1) by either Foscan mediated PDT or surgical treatment are similar. However, randomized, prospective studies on the results of photodynamic therapy compared to standard treatment are lacking. Liposomal carriers of mTHPC, in particular Fospeg, have shown in tumor models a higher and earlier uptake in tumor tissue compared to Foscan. The improved properties of Fospeg are due to the polymer coating of the liposomal carrier of mTHPC. Because of this coating, the recognition and the clearance of mTHPC from the circulation is reduced. The results warrant further research into the effectiveness of Fospeg mediated PDT compared to Foscan mediated PDT. This will show whether a lower dose of mTHPC and past exposure causes the desired tissue damage. Fluorescence Differential Path Length Spectrsocopy (fDPS) proved to be a reliable, non-invasive method to measure mTHPC concentration in homogeneous tissue. However, due to a different interrogation volume of fDPS and the gold standard, chemical extraction, the correlation between the two measurement methods was low. Probably this is based on the greater accuracy of the FDPS measurements compared to the averaging extraction measurements. FDPS provides by its real- time, non-invasive nature information on the mTHPC tissue concentration and the oxyugen saturation, the ability to optimize the complex PDT reaction.