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Biomedicine

Electrifying Brain Tumors

Combined with chemotherapy, electric fields help prevent the growth of deadly brain tumors.

The particularly lethal brain cancer known as glioblastoma multiforme is fast-growing, difficult to treat, and nearly always fatal; even with aggressive therapy, patients have a median survival time of less than two years. But scientists are pursuing new ways to attack this type of brain tumor, and one company may just be succeeding. NovoCure, a small startup founded in Israel in 2000, has developed a device that uses an electric field to disrupt the growth of cancer cells, and early results are promising. Out of ten patients who started using the device in combination with chemotherapy shortly after their initial diagnosis, seven are still alive more than four years later, and five of them show no signs of cancer progression.

Electrifying division: These images show skin melanoma cells at various stages of disrupted division. The process was fatally interrupted through the use of electrical fields.

NovoCure’s device consists of insulated electrode pairs placed on a patient’s body near the tumors, attached by leads to a three-kilogram battery that the patient carries everywhere. The electrodes emit low-intensity electric fields that rapidly alternate to create a current that has no effect on any tissue in the body except dividing cells. Just before a dividing cell splits in two, it briefly forms an hourglass shape before the two daughter cells pinch off, and this shape is particularly vulnerable to electricity. The current gets concentrated at the cell’s narrow waist, and at the very moment of division, the cell membrane is destroyed, and the cells disintegrate.

Previous trials showed promising early results, first in patients with recurrent glioblastoma who had exhausted their treatment options, and then in patients newly diagnosed with the disease. The new results are so promising that the company is now recruiting 283 newly diagnosed glioblastoma patients across the United States and in Europe to participate in a two-year pivotal clinical trial. (The U.S. Food and Drug Administration approval process for medical devices requires only two clinical trial phases, pilot and pivotal, as opposed to the three required for medications.) Recent results from a pilot lung-cancer trial show that the combination of electric fields plus traditional chemotherapy may also increase survival and decrease disease progression in patients with late-stage non-small cell lung cancer.

While chemotherapy and the electric field generated by the device both have an effect when used in isolation, when they’re put together their properties are more than additive–the electric fields appear to make the cancer cells far more susceptible to chemotherapy without any additional increase in side effects and toxicity.

“Practically all chemotherapies are designed to hit specific receptors on cancer cells, and they are usually targeted to very specific types or even subtypes of cancer,” says physiologist Yoram Palti, the founder and director of NovoCure, who developed the therapy. In contrast, he says, radiation hits all types of cancers, but its ability to target cancer cells over other tissues is relatively low. “I was looking for a single modality that would be effective against most, if not all, types of cancer, without the negative effects of radiation,” Palti says. The electric field appears to do just that. “In the lab, it’s effective against all types of cancer cells we tested.”

Typical glioblastoma treatment consists of surgery followed by simultaneous chemotherapy and radiation. After about four weeks, radiation stops and chemotherapy continues. But the reason glioblastoma is so deadly is that cancerous cells spread throughout the brain long before they can be picked up by MRI scans. “The horses are already out of the barn, so to speak,” says Herbert Engelhard, chief of neuro-oncology in the neurosurgery division at the University of Illinois, Chicago. “NovoCure therapy has the potential of tracking down or affecting those cancer cells that are deep within the brain, because the [electric field] goes beyond what is seen on the MRI imaging of the brain tumor.”

Engelhard, who is a primary investigator on the study and has a number of patients in the NovoCure trials, became interested in the technology because it was something totally different and less toxic than traditional methods. “Surgery removes the malignant cells, radiation therapy exploits a difference in susceptibility to radiation between normal and cancer cells, chemotherapy exploits the fact that the cells are dividing, and this is a fourth way to exploit a difference between normal cells and cancer cells, namely the fact that the cancer cells have to physically split into two cells,” Engelhard says. “It’s using a completely different biological property of cancer cells as their Achilles heel.”

Such a novel perspective came from Palti’s background in biophysics. “I looked at electrical fields rather than chemical reactions,” Palti says. “I suddenly realized that dividing cells should behave very differently under electrical fields of specific frequencies. So I sat down and did some modeling and ended up doing experiments in my basement.”

“What he’s doing is rather new,” says David Cohen, an associate professor in radiology at Harvard Medical School. “Usually, electricity is passed through the skin to talk to the nerves and muscles. But this electricity alternates so quickly that it can’t affect nerves and muscles–it goes back and forth so many times that the nerves see zero effect. But the dividing cells, they know about it.” Cohen has closely examined the biophysics behind the phenomenon and notes that “the physical explanation for how the system works is sound. It’s not a shot in the dark; it’s carefully planned, carefully evolved work.”

Perhaps the largest drawback to the NovoCure device is the battery that patients must lug with them wherever they go. In order for it to work, patients have to carry the battery around until the cancer has disappeared–as long as 24 months. (One patient, whose tumor has stopped growing but has not disappeared, has been using the device continuously for more than three years.) “Anybody would like to have a cure for brain tumors, that’s for sure,” says Mary Lovely, a medical information specialist at the National Brain Tumor Society. “When it starts to decrease quality of life because you’re carrying it around, that’s when it might not work anymore.”

Engelhard says the current device is more a prototype than a final design. “First, we have to prove that it increases patient survival,” Engelhard says. “Then modifications of the device might be made to make it easier for patients to participate in the treatment.”

Novocure has high hopes. Because the electric-field effects appear to work across all cancers, at least in vitro, the company is interested in applying it to as many different disease types as it can. Although they also have “outstanding data” from a pilot trial in women with breast cancer, Novocure Board Chairman Bill Doyle notes, “We’ve focused our initial efforts on cancer where there is very poor long-term survival.” Glioblastomas and lung cancer fit the bill, and Doyle says that pancreatic cancer could be next. “Our hope is that we will take on another cancer, and then another, and then another over the years.”

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