Determination of Tumor Margins with Surgical Specimen Mapping Using Near-Infrared Fluorescence

Abstract

For many solid tumors, surgical resection remains the gold standard and tumor-involved margins are associated with poor clinical outcomes. Near-infrared (NIR) fluorescence imaging using molecular agents has shown promise for imaging during resection. However, for cancers with difficult imaging conditions, surgical value may lie in tumor mapping of surgical specimens. We thus evaluated a novel approach for real-time, intraoperative tumor margin assessment. Twenty-one adult patients with biopsy-confirmed squamous cell carcinoma arising from the head and neck (HNSCC) scheduled for standard-of-care surgery were enrolled. Cohort 1 ( = 3) received panitumumab-IRDye800CW at an intravenous microdose of 0.06 mg/kg, cohort 2A ( = 5) received 0.5 mg/kg, cohort 2B ( = 7) received 1 mg/kg, and cohort 3 ( = 6) received 50 mg. Patients were followed 30 days postinfusion and adverse events were recorded. Imaging was performed using several closed- and wide-field devices. Fluorescence was histologically correlated to determine sensitivity and specificity. imaging demonstrated tumor-to-background ratio (TBR) of 2 to 3, compared with specimen imaging TBR of 5 to 6. We obtained clear differentiation between tumor and normal tissue, with a 3-fold signal difference between positive and negative specimens ( < 0.05). We achieved high correlation of fluorescence intensity with tumor location with sensitivities and specificities >89%; fluorescence predicted distance of tumor tissue to the cut surface of the specimen. This novel method of detecting tumor-involved margins in surgical specimens using a cancer-specific agent provides highly sensitive and specific, real-time, intraoperative surgical navigation in resections with complex anatomy, which are otherwise less amenable to image guidance. This study demonstrates that fluorescence can be used as a sensitive and specific method of guiding surgeries for head and neck cancers and potentially other cancers with challenging imaging conditions, increasing the probability of complete resections and improving oncologic outcomes. .

Specific Targeting of Somatostatin Receptor Subtype-2 for Fluorescence-Guided Surgery

“…Given the use of numerous drug-device combinations in preclinical and clinical studies, a definitive TBR threshold that indicates a positive fluorescent signal is difficult to define. However, successful intraoperative visualization of tumors has been demonstrated with several targeted agents that produce TBRs > 2 (30,38,39) and suggests that contrast ratios for Ga-MMC(IR800)-TOC may be sufficient for tumor identification in a clinical setting.…”

Probe‐based fluorescence dosimetry of an antibody‐dye conjugate to identify head and neck cancer as a first step to fluorescence‐guided tissue preselection for pathological assessment

“…Due to the complicated surgical anatomy in the head and neck region and the presence of the crucial structures, such as carotid arteries and cranial nerves, 15%-30% of patients will have a positive margin upon final histopathology; a rate that has not changed over the last 30 years despite many novel surgical techniques. [9][10][11][12][13][14][15] In head and neck squamous cell carcinoma (HNSCC), the epidermal growth factor receptor (EGFR) is overexpressed in >90% of tumor cells, making it ideal for optical targeted imaging. [4][5][6][7] Accurate sampling of tissue samples to confirm adequate resection is crucial for this technique to be effective.…”

“…[4][5][6][7] Accurate sampling of tissue samples to confirm adequate resection is crucial for this technique to be effective. 9,[17][18][19] However, despite the rapid growth of fluorescence imaging, quantifiable fluorescence measurements using an open-field imaging system remain challenging because fluorescence imaging is a noncontact imaging technique and consequently is highly sensitive to lighting variations, due to irregular and nonflat tissue surfaces, and the operating room environment. 8 To improve surgical outcome and margin assessment accuracy, tumor-specific antibody-based fluorescence imaging has been proposed to achieve demarcation and differentiation of cancerous from healthy adjacent tissue.…”

“…8 To improve surgical outcome and margin assessment accuracy, tumor-specific antibody-based fluorescence imaging has been proposed to achieve demarcation and differentiation of cancerous from healthy adjacent tissue. [9][10][11][12][13][14][15] In head and neck squamous cell carcinoma (HNSCC), the epidermal growth factor receptor (EGFR) is overexpressed in >90% of tumor cells, making it ideal for optical targeted imaging. 16 We have previously demonstrated that our near-infrared fluorescently labeled anti-EGFR antibody, panitumumab-IRDye800CW, is highly sensitive and specific for HNSCC.…”

“…16 We have previously demonstrated that our near-infrared fluorescently labeled anti-EGFR antibody, panitumumab-IRDye800CW, is highly sensitive and specific for HNSCC. 9,[17][18][19] However, despite the rapid growth of fluorescence imaging, quantifiable fluorescence measurements using an open-field imaging system remain challenging because fluorescence imaging is a noncontact imaging technique and consequently is highly sensitive to lighting variations, due to irregular and nonflat tissue surfaces, and the operating room environment. Dosimetry has proven itself valuable for monitoring drug delivery in photodynamic therapy (PDT), where it provides a quantitative measurement of photoactivatable drug dose within the targeted region.…”