Laird Harrison

October 26, 2017

SAN DIEGO — Paired with a fluorescent dye, the antibody cetuximab can safely image glioblastoma, researchers say.

The infrared imaging technique could make it easier for surgeons to find the tumors during brain surgery, said Sarah Miller, a researcher at Stanford University in California.

She presented the pilot study here at the American College of Surgeons (ACS) Clinical Congress 2017. "It's a promising first step," she told Medscape Medical News.

Better imaging techniques could save patients' lives, she said. Currently, patients with glioblastomas die a median of 15 months from their diagnosis. They live longer if surgeons leave less than 2 cm3 of cancer cells after surgery, but the cells are difficult to find.

Researchers at Stanford previously showed they could image head and neck cancers by infusing patients with a combination of cetuximab and fluorescent dye IRDye 800CW, then image the cancer in infrared light. Now, they decided to try the same approach in glioblastoma.

Cetuximab is an IgG1 monoclonal antibody against the cell membrane receptor epidermal growth factor receptor (EGFR). The US Food and Drug Administration has approved it under the brand name Erbitux (Lilly) as a treatment for head, neck, and colorectal cancer.

EGFR is overexpressed in 50% to 70% of glioblastomas but has low levels of expression in normal brain tissue.

To see whether the cetuximab/dye combination could reveal gliomas — the category of brain cancer to which glioblastomas belong — the researchers infused it into three patients 2 days before they were scheduled for surgery.

Patient 1 had glioblastoma and received 50 mg. Patient 2 had glioblastoma and received 100 mg. Patient 3 had grade II diffuse astrocytoma and received 50 mg.

The researchers then viewed the patients' brains using two widefield cameras, the SurgVision Explorer Air and the Novadaq Pinpoint. The researchers could not detect fluorescence in patient 3, probably because the blood-brain barrier was intact in that patient and prevented the cetuximab/dye combination from penetrating, Miller said. Glioblastoma, however, disrupts this barrier, she explained.

In the other two patients, the researchers divided the mean fluorescence intensity (MFI) of the tumors by the MFI of the normal brain tissue to derive tumor-to-background ratios. For patient 1, who received the low dose of cetuximab, the tumor-to-background ratio was 1.58. For patient 2, who received the high dose, the tumor-to-background ratio was 2.65.

Comparing the fluorescent tissue with formalin-fixed, paraffin-embedded tissue sections evaluated by a neuropathologist, they found a high correlation. The minimal detectable tumor volume was 0.07 cm3 with the low dose and 0.01 cm3 with the high dose — 200 times smaller than the maximal residual volume needed to achieve a benefit in median survival.

For the low dose, the researchers calculated that the sensitivity of detecting cancer cells was 78.3% and the specificity was 66.3%. For the high dose, they calculated a sensitivity of 98.2% and specificity of 69.8%.

There were no adverse reactions to the infusion of the cetuximab and dye.

Surgeons could use the technique to visualize tumors in real time as they operate on patients, Miller said. Cameras could show their instruments in relation to fluorescent tumors. In that way it would offer an advantage over other imaging modalities.

"It's infrared, so there is less autofluorescence and less photobleaching with ambient white light, and it takes into account brain shift, the shifting brain tissue in intraoperative MRI," she said.

The researchers hope to conduct larger trials and investigate in animal models which cancers sufficiently disrupt the blood-brain barrier for the cetuximab/dye combination to penetrate.

Antibodies for other receptors could also be paired with dyes, Miller said in response to a question from session moderator Edward Vates, MD, PhD, a neurosurgeon from the University of Rochester in New York. The researchers started with cetuximab because it has already been developed for clinical trials, she explained.

Other imaging techniques for glioblastoma already use fluorescence, including 5-aminolevulinic acid and intravenous fluorescein, Dr Vates told Medscape Medical News, and it remains to be seen whether cetuximab is superior.

"It's hard to know if that particular agent will make a difference," he said. "But it is an interesting proof of principle that novel imaging markers should be developed and deployed to help when we're trying to assess extent of resection."

To more fully assess the value of cetuximab, he'd want to see the pathology specimens and understand how the researchers correlated the fluorescence  to the tumor burden in specific regions of the brain, he continued. He would also want to know whether the absence of fluorescence was a true indicator of absence of cancer.

"Then the other thing you want to know is, if you use this fluorescence marker to guide your surgical procedure in a large number of patients, are you actually seeing the most important indicator of extent of resection, which is longer term survival," Dr Vates said.

The authors and Dr Vates have disclosed no relevant financial relationships.

American College of Surgeons (ACS) Clinical Congress 2017. Presented October 25, 2017.


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