A tumor-specific fluorescent dye and an ultra-sensitive camera system used during surgery can help surgeons identify difficult-to-spot cancers. Surgeons at the University Medical Center, Groningen, the Netherlands, have used this technique for the first time on women with ovarian cancer. This type of cancer is typically difficult to detect early on, and is usually diagnosed at a late stage when prognosis is poor.

When a surgeon is operating on a cancer, he/she should ideally get it right during the first operation. However, tumors may be extremely small and hard to detect. With this new technology, which was created by a Purdue University researcher, the cancer cells literally glow, revealing themselves, so the surgeon can see what needs to be removed.

The surgery, reported in the journal Nature Medicine, was the first of 10 performed during the first phase of a clinical trial which is assessing the technology. The technology aids surgeons when removing malignant tissue from ovarian cancer patients. Smaller tumors that could easily be missed are lit up, making it easier for the surgeon to spot them and remove them.

Philip Low, from Purdue University, who invented the technology, said surgeons are now able to clearly see clusters of cancer cells just one-tenth of a millimeter wide, compared to the previous 3 millimeters without the technology.

Low said:

“Ovarian cancer is notoriously difficult to see, and this technique allowed surgeons to spot a tumor 30 times smaller than the smallest they could detect using standard techniques. By dramatically improving the detection of the cancer – by literally lighting it up – cancer removal is dramatically improved.”

A surgeon’s view of ovarian cancer cells with and without the tumor-targeted fluorescent imaging agent. (Image courtesy of Gooitzen van Dam)

In this technology, a fluorescent imaging agent is attached to a modified type of folic acid; this acts as a homing device that searches for ovarian cancer cells and attaches itself to them.

The patient receives an injection two hours before surgery. A multispectral fluorescent camera illuminates the cancer cells, revealing exactly where they are on a monitor which is placed next to the patient during the surgical procedure.

A surgeon would usually expect to find about seven tumor deposits using visual and tactile observations. With this technique 34 tumor deposits were found.

This technology fits in well with current surgical practice, Gooitzen van Dam, a surgeon who was involved in the trial said.

Gooitzen van Dam said:

“This system is very easy to use and fits seamlessly in the way surgeons do open and laparoscopic surgery, which is the direction most surgeries are headed in the future. I think this technology will revolutionize surgical vision. I foresee it becoming a new standard in cancer surgery in a very short time.”

Low added that chemotherapy or immunotherapy is much more effective when less cancerous tissue remains behind after surgery.

Low said:

“With ovarian cancer it is clear that the more cancer you can remove, the better the prognosis for the patient,” he said. “This is why we chose to begin with ovarian cancer. It seemed like the best place to start to make a difference in people’s lives.”

By concentrating on the removal of cancerous tissue, instead of evaluating patient outcome, the researchers were able to considerably reduce how long the clinical trial would take to complete.

Low said:

“What we are really after is a better outcome for patients, but if we had instead designed the clinical trial to evaluate the impact of fluorescence-guided surgery on life expectancy, we would have had to follow patients for years and years. By instead evaluating if we can identify and remove more malignant tissue with the aid of fluorescence imaging, we are able to quantify the impact of this novel approach within two hours after surgery. We hope this will allow the technology to be approved for general use in a much shorter time.”

Arrangements are underway with the Mayo Clinic for the next phase of the clinical studies.

Low had found that folate can be used like a Trojan horse to surreptitiously introduce an imaging agent or medication into a cancer cell. For ovarian cancer cells to grow and divide, they need large amounts of the vitamin (folic acid). Special receptors on the surface of the cancer cells seize the vitamin, and whatever is attached to it, and pull it inside.

As not all cancer cells express the folate receptor, a test is required to find out whether a patient’s cancer expresses enough of the receptors for the technique to be effective.

At about 85%, ovarian cancer has a very high rate of folate receptor expression. Expression rates for endometrial, kidney and lung cancers are at about 80%, and breast and colon cancers 50%.

Low and team are also looking into how they can target molecules that may be used to carry attached drugs or imaging agents to types of cancer that have no folate receptors.

He plans to develop a red fluorescent dye that can show up through the skin and deep inside the body. He now uses a green dye that has already been approved for patient usage. However, this green dye is not ideal for seeking out cancer cells deep in tissue. Green light has a short wavelength that does not pass through tissue very well, while red has longer a wavelength and does.

Low said:

“We want to be able to see deeper into the tissue, beyond the surface. Different cancers have tumors with different characteristics, and some branch and wind their way deeper into tissue. We will continue to evolve this technology and make improvements that help cancer patients.”

Written by Christian Nordqvist