Comparison of narrow band and fluorescence molecular imaging to improve intraoperative tumour margin assessment in oral cancer surgery

Objective: New techniques have emerged to aid in preventing inadequate margins in oral squamous cell carcinoma (OSCC) surgery, but studies comparing different techniques are lacking. Here, we compared narrow band imaging (NBI) with fluorescence molecular imaging (FMI), to study which intraoperative technique best assesses the mucosal tumour margins.Materials and Methods: NBI was performed in vivo and borders were marked with three sutures. For FMI, patients received 75 mg of unlabelled cetuximab followed by 15 mg cetuximab-800CW intravenously-two days prior to surgery. The FMI borders were defined on the excised specimen. The NBI borders were correlated with the FMI outline and histopathology.Results: Sixteen patients were included, resulting in 31 NBI and 30 FMI measurements. The mucosal border was delineated within 1 mm of the tumour border in 4/31 (13 %) of NBI and in 16/30 (53 %) FMI cases (p = 0.0008), and within 5 mm in 23/31 (74 %) of NBI and in 29/30 (97 %) of FMI cases (p = 0.0048). The median distance between the tumour border and the imaging border was significantly greater for NBI (3.2 mm, range −6.1 to 12.8 mm) than for FMI (0.9 mm, range −3.0 to 7.4 mm; p = 0.028). Submucosal extension and previous irradiation reduced NBI accuracy.Conclusion: Ex vivo FMI performed more accurately than in vivo NBI in mucosal margin assessment, mainly because NBI cannot detect submucosal extension. NBI adequately identified the mucosal margin especially in early-stage and not previously irradiated tumours, and may therefore be preferable in these tumours for practical and cost-related reasons.</p

Improved intraoperative identification of close margins in oral squamous cell carcinoma resections using a dual aperture fluorescence ratio approach:first in-human results

Significance: Surgical excision is the main treatment for solid tumors in oral squamous cell carcinomas, where wide local excision (achieving a healthy tissue margin of &gt;5 mm around the excised tumor) is the goal as it results in reduced local recurrence rates and improved overall survival. Aim: No clinical methods are available to assess the complete surgical margin intraoperatively while the patient is still on the operating table; and while recent intraoperative back-bench fluorescence-guided surgery approaches have shown promise for detecting “positive” inadequate margins (&lt;1 mm), they have had limited success in the detection of “close” inadequate margins (1 to 5 mm). Here, a dual aperture fluorescence ratio (dAFR) approach was evaluated as a means of improving detection of close margins. Approach: The approach was evaluated on surgical specimens from patients who were administered a tumor-specific fluorescent imaging agent (cetuximab-800CW) prior to surgery. The dAFR approach was compared directly against standard widefield fluorescence imaging and pathology measurements of margin thickness in specimens from three patients and a total of 12 margin locations (1 positive, 5 close, and 6 clear margins). Results: The area under the receiver operating characteristic curve, representing the ability to detect close compared to clear margins (&gt;5 mm) was found to be 1.0 and 0.57 for dAFR and sAF, respectively. Improvements in dAFR were found to be statistically significant (p &lt; 0.02). Conclusions: These results provide evidence that the dAFR approach potentially improves detection of close surgical margins.</p

Improved intraoperative identification of close margins in oral squamous cell carcinoma resections using a dual aperture fluorescence ratio approach:first in-human results

Significance: Surgical excision is the main treatment for solid tumors in oral squamous cell carcinomas, where wide local excision (achieving a healthy tissue margin of &gt;5 mm around the excised tumor) is the goal as it results in reduced local recurrence rates and improved overall survival. Aim: No clinical methods are available to assess the complete surgical margin intraoperatively while the patient is still on the operating table; and while recent intraoperative back-bench fluorescence-guided surgery approaches have shown promise for detecting “positive” inadequate margins (&lt;1 mm), they have had limited success in the detection of “close” inadequate margins (1 to 5 mm). Here, a dual aperture fluorescence ratio (dAFR) approach was evaluated as a means of improving detection of close margins. Approach: The approach was evaluated on surgical specimens from patients who were administered a tumor-specific fluorescent imaging agent (cetuximab-800CW) prior to surgery. The dAFR approach was compared directly against standard widefield fluorescence imaging and pathology measurements of margin thickness in specimens from three patients and a total of 12 margin locations (1 positive, 5 close, and 6 clear margins). Results: The area under the receiver operating characteristic curve, representing the ability to detect close compared to clear margins (&gt;5 mm) was found to be 1.0 and 0.57 for dAFR and sAF, respectively. Improvements in dAFR were found to be statistically significant (p &lt; 0.02). Conclusions: These results provide evidence that the dAFR approach potentially improves detection of close surgical margins.</p

Comparison of narrow band and fluorescence molecular imaging to improve intraoperative tumour margin assessment in oral cancer surgery

Objective: New techniques have emerged to aid in preventing inadequate margins in oral squamous cell carcinoma (OSCC) surgery, but studies comparing different techniques are lacking. Here, we compared narrow band imaging (NBI) with fluorescence molecular imaging (FMI), to study which intraoperative technique best assesses the mucosal tumour margins. Materials and Methods: NBI was performed in vivo and borders were marked with three sutures. For FMI, patients received 75 mg of unlabelled cetuximab followed by 15 mg cetuximab-800CW intravenously-two days prior to surgery. The FMI borders were defined on the excised specimen. The NBI borders were correlated with the FMI outline and histopathology. Results: Sixteen patients were included, resulting in 31 NBI and 30 FMI measurements. The mucosal border was delineated within 1 mm of the tumour border in 4/31 (13 %) of NBI and in 16/30 (53 %) FMI cases (p = 0.0008), and within 5 mm in 23/31 (74 %) of NBI and in 29/30 (97 %) of FMI cases (p = 0.0048). The median distance between the tumour border and the imaging border was significantly greater for NBI (3.2 mm, range −6.1 to 12.8 mm) than for FMI (0.9 mm, range −3.0 to 7.4 mm; p = 0.028). Submucosal extension and previous irradiation reduced NBI accuracy. Conclusion: Ex vivo FMI performed more accurately than in vivo NBI in mucosal margin assessment, mainly because NBI cannot detect submucosal extension. NBI adequately identified the mucosal margin especially in early-stage and not previously irradiated tumours, and may therefore be preferable in these tumours for practical and cost-related reasons

Epidermal Growth Factor Receptor-Targeted Fluorescence Molecular Imaging for Postoperative Lymph Node Assessment in Patients with Oral Cancer

Rationale: In most oral cancer patients, surgical treatment includes resection of the primary tumor combined with the excision of lymph nodes (LN), either for staging or treatment. All LNs harvested during surgery require tissue processing and subsequent microscopic histopathological assessment to determine the nodal stage. In this study, we investigated the use of the fluorescent tracer cetuximab-800CW to discriminate between tumor-positive and tumor-negative LNs before histopathological examination. Methods: Here, we report a retrospective ad hoc analysis of a clinical trial designed for resection margin evaluation of oral squamous cell carcinoma patients (NCT02415881). Two days prior to surgery, patients were intravenously administered with 75 mg cetuximab followed by 15 mg cetuximab-800CW, an Epidermal Growth Factor Receptor (EGFR)-targeting fluorescent tracer. Fluorescence images were obtained of excised, formalin-fixed LNs and correlated with histopathological assessment. Results: Fluorescence molecular imaging of 514 LNs (61 pathologically positive nodes) can detect tumor-positive LNs ex vivo with 100% sensitivity and 86.8% specificity (AUC 0.97). In this cohort, the number of LNs that require microscopic assessment was decreased by 77.4%, without missing any metastasis. Additionally, in 7.5% of the fluorescence false-positive LNs, we identified metastases missed by standard histopathological analysis. Conclusion: Our findings suggest that EGFR-targeted fluorescence molecular imaging can aid in the detection of LN metastases in the ex vivo setting in oral cancer patients. This image-guided concept can improve the efficacy of postoperative LN examination and identify additional metastases, which safeguards appropriate postoperative therapy and may improve patient prognosis

EGFR-targeted fluorescence molecular imaging for intraoperative margin assessment in oral cancer patients: a phase II trial

Abstract Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins