Tiny bubbles in the brain might offer some respite for Richard Miller.
The 62-year-old Chestertown man was diagnosed this year with a deadly brain cancer, and he recently became the first person in an experiment using those bubbles to help treatment drugs get to places normally out of reach.
The technique could give Miller and thousands of others with glioblastomas far longer lives. It could also offer a way to treat other devastating brain diseases such as Alzheimer’s and Parkinson’s.
With brain cancers, “normally chemotherapy gets in a little but not a lot,” said Dr. Graeme F. Woodworth, a neurosurgeon in the University of Maryland School of Medicine who is testing the method on Miller and 14 other people. "In the future, we’re hoping we can provide our drugs of choice a way to get in. We’re hoping we can use it for lots of things.”
Miller was vacationing in Florida when his wife, Diana, noticed his speech and even his laugh weren’t quite normal. He passed out for a few seconds three days in a row. A critical care nurse, she initially suspected heart problems, but doctors quickly found he had brain cancer.
A week after he was diagnosed, surgeons removed a large tumor in the right side of his brain. But fast-growing glioblastomas are virtually impossible to remove entirely, making them certain to return.
Glioblastomas are the most common form of brain cancer, with about 14,000 cases diagnosed each year in the United States, according to the National Cancer Institute. Sens. Edward M. Kennedy and John McCain are among those who have died from glioblastomas.
Radiation and chemotherapy are commonly used to slow new cancer growth, but usually aren’t effective for long with these brain cancers. Federal figures show the median survival is 15 to 18 months. About 15% of patients survive five years.
Woodworth removes three to four brain tumors of all kinds a week. He says he kept thinking: “Surgery isn’t going to be a fix for this.”
That’s when he latched onto work elsewhere with the bubble technique, known as targeted ultrasound. Woodworth started working with an Israeli medical device company, Insightec Ltd., that developed the tools for the procedure. It took him several years to gain federal approval for a study.
The idea is to bypass the protective layer on the brain that keeps out toxins — but also life-saving drugs. This layer, called the blood-brain barrier, is a tightly wound mess of cells that is covered with blood vessels. Pharmaceuticals don’t normally get past the blood vessels.
That’s where the bubbles come in.
For the study, nurses would inject a chemical into Miller’s arm that produces the bubbles and direct them with ultrasound, or sound waves, to the specific spot on his brain where his tumor had once lodged. The bubbles would cause such a commotion bouncing around that the protective layer would become leaky and, temporarily, allow treatment drugs to slip through.
The window would last several hours, enough time for Miller to return home and take his regular round of chemotherapy pills.
The method uses low-frequency sound waves and builds on an existing treatment that uses high-frequency sound waves. The high-frequency method creates heat and is used to burn portions of the brain that cause disorders such as tremors. That method also is being tested for maladies such as obsessive compulsive disorder.
Before his procedure in August, Miller charmed the nurses who were preparing him, cracking jokes as his scalp was shaved to reveal the large c-shaped scar from his earlier surgery. His head was immobilized in a metal brace to keep him still for the hourslong experiment.
His wife blew him a kiss and squeezed his hand before he was put in a magnetic resonance imaging, or MRI, machine that allowed doctors, radiology specialists, nurses and engineers from InSightec to monitor the procedure’s progress from a control room.
Nurses injected the bubbling agent into Miller’s arm several times.
Diana Miller and her sister waited for hours nearby in the University of Maryland Medical Center and said they were hopeful for Miller and others who would follow.
“This tumor was grade 4, and there is no grade 5. But he wants to live, and I think this will help him,” Diana Miller said. “If they can get through the blood-brain barrier, they will be able to help so many.”
Days later, Miller was recovering well and expected that more of the chemotherapy drugs would reach lingering cancer cells. A separate study at Maryland is investigating whether there is a more effective chemotherapy drug to pair with the treatment.
It’s still too soon to know whether the experiment will help him or anyone else with the devastating brain cancer. This was an early test designed only to ensure the technique was safe and that it worked.
While advocates suggest the bubble procedure eventually could help people with brain maladies other than cancer, not everyone is convinced there will be many more uses.
Dr. Jeffrey Rothstein, a professor of neurology and neuroscience at Johns Hopkins University and the Hopkins Brain Science Institute, said the technique seems most suited to treating tumors. There is a specific target on a specific part of the brain, he said.
Other brain diseases are chronic, requiring daily medication to stem increasingly widespread and irreversible brain damage. It would be unsafe and probably not effective to try to treat so much of the brain this way, Rothstein said.
Other researchers have been exploring means of opening the brain’s barrier, with chemicals and catheters, but no one has found a simple solution without significant risks, Rothstein said. An injection directly into the brain could cause a difficult-to-treat infection, for example.
Another problem is the sheer number of people to treat. Rothstein said there are a few thousand with brain tumors but millions with Alzheimer’s.
“I think it’s a great idea for cancer, when you need short-term exposure to a drug,” Rothstein said. “I’m not sure there is high utility for chronic disease.
"I would be glad to be proved wrong,” he added.
Rothstein did say technological advances eventually might streamline the procedure and allow treatment to resemble dialysis, the regular blood cleaning mechanism that replaces kidney function. But doctors would have to diagnose Alzheimer’s and other brain disease patients early, before symptoms arise, and that doesn’t normally happen.
That’s precisely the idea, said Dr. Nir Lipsman, a neurosurgeon and scientist at Sunnybrook Research Institute at the University of Toronto, who first opened the blood-brain barrier in an Alzheimer’s patient.
Lipsman said Alzheimer’s is a brain-wide disorder, but it starts somewhere, which eventually could serve as the target.
Researchers also are working on safely opening larger portions of the barrier for drug delivery. Another possibility is loading viruses with genes or antibodies that could attack disease inside the brain longer term, Lipsman said.
Early studies even suggest that just opening the barrier offers benefits to Alzheimer’s patients, perhaps by allowing in the body’s own natural defenses, Lipsman said.
The method using bubbles “delivers something that has not worked in the past or not worked well enough,” he said. “It’s early days, but those of us doing research have tremendous hope.”
Lipsman’s Toronto lab now plans studies in Parkinson’s and brain tumor patients.
Back at Maryland, a few hours into the procedure on Miller, the last image of his brain was taken. It showed faint white splotches on the right side where the tumor was removed.
The medical staff was thrilled. This proved that a contrast dye nurses also injected into Miller’s blood had gotten past the barrier into the brain — and the cancer drugs could, too. There was no sign of bleeding, swelling or other problems.
If tests continue to go well, Woodworth hopes to use the method widely on glioblastoma patients in three to five years.
Diana Miller wants Richard to be around to see that. He just had his second treatment at Maryland and will return for more in coming months.
“He really believes that this gives him a greater chance of survival," she said. "And he is very happy to be able to share this with others that are devastated by this cancer.”