Senator McCain, cancer and clinical frustration: The long road to better treatments

On Wednesday, July 19, Senator John McCain's office announced that he has brain cancer. The announcement came five days after surgeons removed a blood clot from his brain, located above and behind his left eye. McCain's tumor was diagnosed based on examination of tissue removed along with the blood clot as a glioblastoma multiforme, an aggressive tumor type.

Glioblastoma multiforme (GBM) develops in the connective tissue of the brain. Although it is the most common form of primary brain cancer, it is still a relatively rare disease, striking three people per 100,000, usually people older than 60. Glioblastoma does not spread to other organs in the body. It stays in the brain, but it grows quickly and unpredictably, invading surrounding tissues.

Science Life spoke with three University of Chicago physicians about this disease.

 

Prognosis:

"The thing to keep in mind is that this is difficult to treat, but not hopeless," explained Steven Chmura, MD, PhD, associate professor of radiation and cellular oncology at the University of Chicago.

"In, say, 2004, it was hopeless," he added. Surgery plus radiation helped, a little, allowing patients to live two or three times as long, but that's measured in months. Now, "some people do really well," he added. By combining radiation with the oral medication, temozolomide, "we have about one out of ten people, including many over age 65, alive at least three years later."

"There are rare reports of patients who had a resection of a glioblastoma and further treatment who survived for five or ten years," said neurosurgeon Peleg M. Horowitz, MD, PhD, assistant professor of surgery, "but they are very much the exception."

This remains a challenging disease to treat. "The tumor cells infiltrate," Horowitz said. "They extend beyond the tumor. Even when we remove everything that looks like tumor tissue, we know there are microscopic cells that have migrated outside of that area. These often recur, nearby or at a distance, a month or even years later.

"Location matters," Horowitz said. In some parts of the brain, the tumor could grow for a long time without causing problems. McCain's tumor, in the left frontal lobe, is in a place that is "usually amenable to surgery," Horowitz said. Some brain tissues "are not eloquent," he added. "They have room for more aggressive surgery." Some parts of the left frontal lobe control speech production, as well as motor activity, but much of the remaining lobe can be removed if needed. Other parts of the brain can often compensate.

"You're never really out of the woods with GBM," he added. "Most of these patients will have some progression or recurrence outside the resected area."

Treatment:

Surgery may be the first step, but it's just the beginning. Most patients also receive radiation and chemotherapy, usually temozolomide, which is reasonably effective with limited side effects. One typical treatment plan involves a six-week regime of daily chemotherapy and radiotherapy treatments pause for a month then six more months of chemotherapy.

An ongoing multi-center study, including the University of Chicago, compares standard radiation treatment with proton therapy. Another promising approach focuses on genetic analysis of specific diagnostic markers. This can help predict which patients could benefit from specific forms of chemotherapy.

"One study at UCM involves sequencing the tumor to see if it is over-expressing an epidermal growth factor," Chmura said. "About one out of five GBMs seem to be driven by this. We are looking at a small targeted investigational molecule, created by AbbVie, to attack that."

A different approach relies on electrical currents, delivered via skull cap. The FDA-approved Optune^TM system works by sending alternating electrical fields through the brain. The goal is to disrupt the mitotic spindles, tiny fibers that pull chromosomes apart when a cell is preparing to split in two-which cancer cells do relentlessly. If the spindles fail at their job, the cancer cells self-destruct. A recent study found that he five-year survival rate increased from five percent to 13 percent for patients treated with Optune and temozolomide. But even those who respond to treatment face challenges. "These tumors are very good at adapting and resisting whatever modality of therapy you give them," Horowitz said. "At the first sign of progression, we switch to another type of chemotherapy, perhaps a trial agent. Sometimes, patients can benefit from a second surgery."

"It's a difficult situation," said Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor of Radiation and Cellular Oncology and Chair of the Department of Radiation and Cellular Oncology at the University. "These tumors are, or quickly become, resistant to radiation and resistant to chemo. We treat the tumor with a margin, which is successful to a point. It improves survival, but the cure rate is low. Current treatments are not optimal."

The median survival for all patients with glioblastoma is about 16 months, but that can vary widely.

On the flip side, a market research company recently found 87 experimental therapies in clinical trials for glioblastoma. "Most of those won't be approved for years, if ever," according to an article in STAT, but more and more drugs are "making their way toward the clinic."