Discussion
OSCC, tumor, tumors
TUMOR, TUMORS, PREMALIGNANT, ORAL SQUAMOUS CELL CARCINOMA
Our ex vivo fluorescence molecular imaging approach using cetuximab-800CW during oral squamous cell carcinoma surgery not only detected tumor-positive margins with 100% sensitivity but also the majority of close margins. Intrinsic cetuximab-800CW fluorescence showed increased signal in all tumors compared to normal mucosa, with a median tumor to normal mucosa ratio of 3.1. FMI detected three malignant and premalignant satellite lesions that were missed by standard of care. In 10 out of 13 patients with tumor-positive margins, adjuvant chemoradiotherapy was solely based on margin status and intraoperative detection, and subsequent correction of the margins could have prevented this, had these margins been detected. In 20 (77%) patients with close margins, adjuvant radiotherapy could have been avoided through intraoperative correction of the margin. Consequently, the approach presented here—including the tracer-dose combination, interval and specimen-driven imaging performed directly after tumor excision—could be used immediately in intraoperative decision-making.Dose-escalation studies have suggested that FMI has the potential to improve clinical outcomes in OSCC surgeryVan Keulen et al.An important aspect of using FMI for intraoperative margin assessment with an SBR approach is that it requires an experienced clinician or technician to execute the procedure and therefore requires training for assessors. Ultimately, standardized image interpretation protocols and training of assessors are advisable for easy implementation of this techniqueFrom the data of this study, we suggest using SBR cut-off values based on Youden’s index that can be used for intraoperative margin assessment (i.e., SBR ≥ 2 and SBR ≥ 1.5). Although an SBR of ≥2 identifies all tumor-positive margins with high specificity, to improve close margin detection with FMI, we advocate using an SBR of ≥1.5 as cut-off. Since we found a limited PPV with an SBR of >1.5, we propose to perform fluorescence-guided fresh frozen sectioning from the excised specimen specifically aimed at the identified spot, which was not done in the current study to allow for an exact correlation of the margin width with the identified spots. This approach would enable the detection of all tumor-positive margins and the majority of close margins, potentially saving 10/13 patients from adjuvant chemoradiotherapy and 20/26 patients from adjuvant radiotherapy.In conclusion, we have shown that EGFR-targeted fluorescence molecular imaging with cetuximab-800CW accurately identifies tumor-positive surgical margins of oral squamous cell carcinoma. This phase II FMI diagnostic accuracy study confirms the safety and potential of this technique and justifies a phase III multicentre study using the suggested strategy of the SBRs to determine the clinical impact in the treatment of OSCC.