Pilot Study Is the First to Show that Fluorescent Imaging Technique with the Antibody Cetuximab Can Be Used Safely in Patients with Glioblastoma

News from the American College of Surgeons
2017 Clinical Congress

The imaging technique may allow surgeons to find and remove cancer more extensively during brain surgery.

In its first test in humans, the antibody cetuximab proved to be safe and feasible for infrared fluorescent imaging of tumors during brain surgery. The study is the first to show that the antibody-based infrared fluorescent imaging can specifically distinguish cancer from normal tissue in patients with glioblastoma. Findings from this pilot study of several patients were presented at the American College of Surgeons Clinical Congress 2017.

Infrared fluorescent imaging is often used to map lymphatic and blood flow in patients during surgery. In this setting, use of the fluorescent molecule attached to an antibody can specifically target cancer cells and makes them visible when illuminated by a camera during an operation.

Cetuximab is a monoclonal antibody that binds to epidermal growth factor receptor (EGFR), a protein that appears on the surfaces of cancer cells at abnormally high levels. Because of its ability to inhibit EGFR, the antibody has been approved by the U.S. Food and Drug Administration for the treatment of head and neck primary cancer and colorectal metastases.

For the current study, investigators from Stanford University School of Medicine, Stanford, Calif., tested the ability of infrared fluorescent imaging using fluorescently labeled cetuximab to identify cancerous tissue in three patients undergoing an operation to remove a glioblastoma tumor, the most common malignant brain tumor in adults. It is an aggressive and often fatal brain tumor. Maximal surgical resection of glioblastoma is complicated by the diffuse, invasive nature of the tumors.*

“The tumor strays into normal brain tissue, and its edges are incredibly difficult to see. If surgeons can specifically identify the extent of the tumors, they may be able to remove more cancerous tissue, and this more complete resection of tumors tends to correlate with better progression-free survival,” said Eben L. Rosenthal, MD, FACS, principal author of the study and medical director of the Stanford Cancer Center.

In the study, three patients with glioblastoma were injected with either a high dose (100 mg) or low dose (50 mg) of cetuximab-IRDye800 two to five days before surgery. Intra-operative imaging using novel near-infrared cameras could clearly identify tumor relative to the normal brain tissue. Resected tumor and normal tissue was also imaged prior to pathological processing – so that fluorescence intensity could be correlated directly with histology. Tumor-to-background ratios were calculated based on the difference in intensity of fluorescence between tumor and normal tissue. (See figure 1: Glioblastoma imaging.)

Image credit: Stanford Cancer Center

The technique was highly specific for detecting tumor tissue in patients; normal tissue produced minimal fluorescence. Tumor-to-background ratios were nearly three times higher in tumor tissue than in a normal brain. The 100 mg dose of cetuximab dye produced significantly higher tumor-to-background fluorescence than the lower dose, and it allowed detection of as small as 10 mg of tumor tissue in the closed setting (see figure 2).

Image credit: Stanford Cancer Center

“The study is interesting for two reasons. First, we show that the antibodies can be used for imaging the brain. It remains controversial whether antibodies can penetrate the brain because of the blood brain barrier. Our study shows that this antibody not only passes through tumor and -disrupts blood brain barrier, it also highly specifically binds to brain tumor. Secondly, it represents an opportunity for surgeons to visualize brain tumors more clearly while they are operating,” Dr. Rosenthal explained.

The study also makes use of an antibody and an operative imaging technique that are already being used widely in patients. The antibody cetuximab has been approved for treating patients with cancer. The imaging devices in the study are standard equipment in operating rooms.

“In this study, we are taking something that has been used in thousands of patients safely and effectively, rather than creating a new probe that has potential unknown toxicity and is more expensive to bring through toxicity studies. We also repurpose imaging devices that are common in the operating room. The imaging technique we describe is therefore highly cost effective, and it’s safer than introducing a new agent for imaging,” Dr. Rosenthal said.

Dr. Rosenthal’s research colleagues are Gordon H. Li, MD; Gerald A. Grant, MD, FACS; Edward D. Plowey, MD; Griffith R. Harsh, IV, MD, FACS; Sarah E. Miller; Willemieke S.Tummers, MD; Nutte Teraphongphom, PhD; Alifa J. Hasan, MBA, Robert D. Ertsey and Christina Kong, MD.

“FACS” designates that a surgeon is a Fellow of the American College of Surgeons. 

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* Brown TJ, et al: Extent of resection associated with likelihood of survival in glioblastoma. JAMA Oncology, 2016; DOI:10.1001/jamaoncol.2016.1373.