Rebecca W. Gao
AN OPTICAL CONTRAST agent composed of panitumumab (Vectibix), a humanized anti–epidermal growth factor receptor (EGFR) monoclonal antibody, conjugated to the near-infrared fluorescent dye IRDye800, may aid in the real-time detection and surgical resection of squamous cell carcinoma, according to data presented at the 2018 Multidisciplinary Head and Neck Cancer Symposium.1 Preliminary results from the first in-human trial using panitumumab-IRDye800, recently reported by Rebecca W. Gao, lead author and a medical student at Stanford University, showed the imaging agent to be both highly specific and sensitive in detection of EGFR-expressing tumors.
“Our lab has shown that panitumumab-IRDye800 has the potential to provide safe, real-time, highly sensitive, and specific information for intraoperative tumor discrimination to guide head and neck oncologic surgeries,” said Eben L. Rosenthal, MD, corresponding author of the study and the Cancer Service Line Director at Stanford University School of Medicine. “Additionally, we demonstrated a novel method of using fluorescence for tumor-mapping of surgical specimens, which may be able to assist in achieving complete resections and improving oncologic outcomes.”
Eben L. Rosenthal, MD
As reported, surgical resection remains a core treatment standard for squamous cell carcinomas arising from the head and neck, and tumor-free surgical margins are critical for disease management. Given the unforgiving nature of tumor resections in head and neck anatomy, patients may benefit from intraoperative tumor imaging.
“If resection is too conservative, the patient may suffer local recurrence from residual tumor,” said Dr. Rosenthal. “However, if resection is too aggressive, critical features of the aesthetic neck and face will be compromised. Conveniently, 90% of head and neck squamous cell carcinomas overexpress EGFR, which presents an attractive cancer-specific target for optical contrast agents.”
Phase I Trial Details
FOR THIS dose-escalation, phase I clinical trial, Dr. Rosenthal and colleagues first conjugated the therapeutic anti-EGFR antibody panitumumab to a near-infrared fluorescent dye. Panitumumab was chosen, said Dr. Rosenthal, because it was approved by the U.S. Food and Drug Administration and has already demonstrated safety, regulatory efficiency, cost savings, and promising in-human results.
Investigators enrolled 21 patients with biopsy-confirmed or recurrent squamous cell carcinoma arising from the head and neck who were scheduled to undergo standard-of-care surgery with curative intent. Patients with QT prolongation on a pretreatment electrocardiogram, previous infusion reactions to monoclonal antibodies, or significant liver or cardiovascular disease were excluded.
Patients on study were intravenously infused with panitumumab-IRDye800 1 to 5 days prior to surgery. Real-time, in vivo imaging was performed intraoperatively with a handheld and bedside wheeled device. Ex vivo imaging was performed with a close-field fluorescence imaging device during pathologic evaluation. Fluorescence locations and intensities were then histologically correlated with tumor location to determine the sensitivity and specificity of panitumumab-IRDye800 targeting.
Sensitivity and Specificity
THE ROSENTHAL lab reports that validation of EGFR targeting showed a positive correlation between fluorescent signal and EGFR expression, with a sensitivity and specificity for detection of tumor tissue at 91% and 88%, respectively. Panitumumab-IRDye800 also demonstrated the potential to improve the assessment of surgical margins.
“One method of assessing surgical margins is by sampling areas of the wound bed and sending specimens for intraoperative frozen analysis, but this is a resource-intensive method,” revealed Dr. Rosenthal. “We demonstrated that fluorescence can be used to screen and prioritize which specimens are more suspicious for tumor involvement, leading to savings of time and labor.”
Fluorescence showed a 100% sensitivity and a 100% negative predictive value with high specificity and a positive predictive value for tumor-involved margin samples. When the resecting surgeon was asked to predict which margin samples he or she thought would be tumor involved, the tumors had poorer sensitivity, the authors reported.
Nynke van den Berg, PhD
Nynke van den Berg, PhD, a postdoctoral student at Stanford University, used fluorescence for creating a tumor depth map in surgical specimens. The near-infrared fluorescent dye had a penetration depth of about 5 mm to 7 mm, said Dr van den Berg, who noted that 5 mm is the common distance for determining negative surgical margins. Although fluorescence was able to predict the presence of tumor tissue up to 7 mm, it was highly sensitive for tumors within 1 mm to 2 mm, allowing clinical teams to prioritize those areas for further examination.
“Our data suggest that panitumumab-IRDye800 can distinguish between areas of the primary specimen harboring tumor close to the margin edges and areas in which tumor is farther away,” said Dr. van den Berg. “This creates a fluorescent map that predicts tumor depth across the entire surface of the specimen.”
According to the authors, this mapping capability can also be used to reduce the sampling error inherent in the current standard of sampling areas of the primary tumor specimen or the wound bed to determine the presence of tumor-involved margins. The imaging agent was also shown to be safe, with no infusion reactions and only one grade 1 adverse event, the authors noted.
Improving Positive Predictive Value
Francis P. Worden, MD
THE MODERATOR of the session, Francis P. Worden, MD, a medical oncologist at the University of Michigan Health System Comprehensive Cancer Center in Ann Arbor, Michigan, noted the panitumumab-IRDye800’s relatively high positive predictive value for 1 mm and 2 mm margins but asked whether investigators are exploring ways to further enhance testing performance.
“Our positive predictive value for the wound bed margin samples is 100%, and our positive predictive value for 1 mm and 2 mm was in the 90th percentile; I think these are pretty high values,” said Ms. Gao. “For 5 mm, we have a better specificity and a negative predictive value, and that is probably due to the nature of our methods. Even though we decided to use a more conservative measurement, we still saw good results, but in reality, our numbers are probably a little bit better.”
DISCLOSURE: Ms. Gao, Drs. Rosenthal, van den Berg, and Worden reported no conflicts of interest.
1. Gao RW, Teraphongphom N, van den Berg NS, et al: Panitumumab-IRDye800 as an optical agent for image-guided surgery in patients with squamous cell carcinoma. 2018 Multidisciplinary Head and Neck Cancer Symposium. Abstract 11. Presented February 16, 2018.