Tackling a brain tumor deadly to pups and people
By Susan Steeves
Helen was a typical mom of the 50s and 60s with four kids who all had busy lives. By 1974, one son was married with two youngsters of his own. One daughter was just out of college and the two youngest children were in college. One fall day that year, they each received a call that their mother had been diagnosed with a brain tumor. Seven hours of surgery, months of radiation therapy, and nine months of worry ended in Helen's death at the age of 55.
Immediately after the operation, the surgeon had said that the kind of tumor they found was like "spilled milk." Today, that's still most often the story of what happens to people with the deadliest form of brain tumor, glioblastoma, also known as a stage IV glioma or stage IV astrocytoma. Sen. Ted Kennedy lived for 14-1/2 months with one, dying in 2009 even after receiving top-of-the-line medical care.
A team of scientists and surgeons at Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences have teamed up to use a new treatment technique on dogs, with the expectation that within a few years they may be performing clinical trials on humans with glial cell tumors.
Glioblastomas in canine patients are almost identical to those found in humans and, in fact, occur at least three times more often in dogs. And sadly, mortality patterns for dogs also are almost identical when corrected for normal longevity; dogs survive a few weeks to a few months and humans about nine months with surgery, chemotherapy, and radiation, and 15 months when a drug called temozolomide is added. It's these fatal facts that give researchers hope that they can learn from our four-legged pals how to beat this deadly demon for both people and pups.
"Dogs are the holy grail of a spontaneous model for glioblastomas because the tumors develop just like in people," says John Rossmeisl, the neurosurgeon in the Virginia-Maryland Regional College of Veterinary Medicine who is using the new procedure on dogs suffering from brain tumors and some other forms of cancer. "We don't know why these tumors develop. Some of it may be chemicals, cleaning products. Dogs are so similar in makeup to humans that they can be the environmental sentinels for people."
The brain is a mysterious place with an estimated 100 billion neurons, or nerve cells, that fire up to make your thoughts swirl, your senses work, and your body move. Researchers don't know exactly how the brain functions and they don't know why glioblastoma multiforme happens. But when the type of glial cells called astrocytes start multiplying uncontrollably inside a person or dog's skull, it's difficult to stop. One reason is that these types of tumors weave their tentacles into the surrounding tissue. Traditional radiation and chemotherapy can't pinpoint tumor cells precisely enough to prevent damage to other tissues.
Trying something new
A new treatment, non-thermal irreversible electroporation (N-TIRE), uses two electrodes about one millimeter in size, approximately the same as a needle used for thick thread, placed directly on the tumor cells. Very short pulses of electricity shoot through the device into the cancer cells. The electric pulse is so short that it raises the temperature of the wire by only about one-quarter of a degree.
One of the first patients treated with N-TIRE by the Neurology and Neurosurgery Service at the veterinary college in Blacksburg, Va., was a 12-year-old dog sent there because he was having vision problems, seizures, behavioral changes, and was unsteady on his legs.
These are some of the same symptoms that humans often exhibit. The tumor takes up space in the inelastic skull that the brain needs to function. So the brain is crowded and some of its normal work is blocked, preventing transmission of signals that control everything from your eyes to your feet. In Helen's case, she was having some vision, odor perception, and memory problems before the operation, and when the cancer cells not excised during surgery or killed by radiation grew into a tumor again, she lost her ability to speak, again had vision problems, and was unsteady on her feet until finally bedridden.
Rossmeisl's canine patient was diagnosed with a glioblastoma that was too large and rapidly growing to allow for standard surgery. This made the dog a candidate for N-TIRE.
Two days after the procedure, a magnetic resonance image (MRI) showed that the dog's tumor had shrunk to 75 percent its original size. He was put on a regimen of radiation, and by four months post-procedure, the family pet was in complete remission.
Non-thermal irreversible electroporation actually makes holes in the cancer cells that cause them to die. But because this treatment does not generate heat and because it can hone in on the tumor so accurately, it doesn't damage the normal cells, nerves, or normal vascular system around the tumor.
"What we're really doing is changing the cancer tissue's properties," says Rafael Davalos, co-inventor of the procedure. "Whatever area is treated, we can pinpoint it to half a millimeter. Also, it is super-fast, so there's no heating and no scarring."
The surgeon can see the placement and progress of the electrodes in real time by using an ultrasound or MRI, says Davalos, a biomedical engineer in the Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, who attends every procedure that Rossmeisl does using N-TIRE.
Currently, the standard follow-up protocol of radiation and chemotherapy is used on the canine patients after having a procedure using N-TIRE. Chemotherapy and radiation can be a two-edged sword because they can damage normal tissue and compromise the immune system. But the new treatment may have a two-fold benefit for the immune system.
"Irreversible electroporation seems to trigger an immune response, so we may not need any drugs as part of the treatment," Davalos says. "That means your immune system isn't weakened any further."
The veterinary college has successfully used N-TIRE on other types of cancers and other animals. Autumn, a chocolate Labrador retriever, was having trouble walking, so owner Sheryl Coutermarsh-Ott took her to the college for orthopedic surgery. They discovered that Autumn had an inoperable tumor on the inside of her thigh and groin.
"The tumor was wrapped around her femoral hip joint," says Coutermarsh-Ott. "The other options were not good. So, after talking to Dr. Rossmeisl, and reading some research papers about N-TIRE, we went ahead. Now she's doing absolutely fantastic and is clear of cancer."
Then there was the 11-year-old thoroughbred with an ulcerated, growing cancer of the lip. The treatment with N-TIRE almost completely obliterated the tumor and the rest was removed with a carbon dioxide laser. The horse is now back to horsing around.
Despite those successes, the focus of the Virginia Tech-Wake Forest team is on brain tumors, especially glioblastomas, because no really good treatment exists unless the tumors are diagnosed early, which happens rarely.
Like humans, dogs that develop glioblastomas tend to be older — seven years and up; for people it's usually around age 65 or older. More men than women develop this type of tumor.
According to the American Cancer Society, about 13,000 Americans will die from brain tumors this year. More than 77 percent of those tumors are glioblastomas, which have a fatality rate of about 50 percent within 15 months and 75 percent in 24 months. That's actually a much better survival rate than in 1974.
This type of brain cancer is called a primary tumor because it develops in the brain. Tumors that grow elsewhere in the body and spread to the brain are called metastatic tumors.
Because it's often too late to save the life of someone with a glioblastoma, Rossmeisl is involved in a related project to investigate how to discover brain cancer early. Currently, by the time symptoms appear, the tumor is often too large and has infiltrated too much of the brain to be treated effectively.
"Early detection is something that we really need," Rossmeisl says. "We need something noninvasive that we can test for in blood or urine samples."
The human side
Dr. Thomas L. Ellis at Wake Forest is working with Rossmeisl, Davalos, and John Robertson to advance research on the use of N-TIRE. Robertson is a veterinary college professor of pathology, the director of the Center for Comparative Oncology in the veterinary college at Virginia Tech, and coordinator of the N-TIRE project. Ellis is a neurosurgeon and professor at the Wake Forest University Brain Tumor Center of Excellence.
It's Ellis who will take N-TIRE to clinical trials for people if given approval by the Wake Forest institutional review board and the FDA. If the procedure advances to human trials, it will first be used for patients who have recurrent glioblastomas. These are the patients who have run out of treatment options.
Every month, a couple of patients come to Ellis with a diagnosis of glioblastomas. Although the cases are all different in some ways, they're also all the same in other ways.
"The causes for these tumors aren't known; there are many factors but no known exposure pattern," Ellis says. "These tumors are only rarely inherited. They occur sporadically in humans and there are no known exposures to chemicals or other agents that predispose patients to develop them. We don't know of any brain tumor that is connected with a prior head injury."
Scientists, including Ellis, don't believe that primary brain tumors are inherited; however, he has had two cases that seem to defy the odds. He had two siblings as patients who had developed mirror-image glioblastomas, and a recent patient's father also had a glioblastoma.
In July 2009, a man from South Carolina who was having trouble with numbers and with spelling his sister's name came to Ellis. James Rollison thought he was having early onset Alzheimer's disease at the age of 58. He hadn't suspected a brain tumor, although his father died of a glioblastoma. But that was what he had.
"The thought never crossed my mind that it was a GBM (glioblastoma multiforme) because my father's doctor had said there was no way it was hereditary," Rollison says. But when Rollison started having problems, his family doctor ordered an MRI and then sent Rollison to a neurosurgeon.
Fortunately, Rollison's tumor was one of the rare ones that was diagnosed early. The retired attorney credits his work and being attuned to his body to sending him to the doctor at the first indication something was wrong. Rollison doesn't look like, sound like, or act like someone who has had the deadliest brain cancer possible.
Rollison was lucky because Ellis is a top-notch surgeon who got the tumor relatively early and was able to remove 100 percent of the visible mass. However, in order to treat the microscopic tumor cells that inevitably remain after surgery, Rollison underwent the standard chemotherapy and radiation regimen. Now he goes back to Wake Forest every three months for a checkup with Dr. Glenn Lesser, of the hematology and oncology department of the university's Comprehensive Cancer Center, and has a follow-up MRI to make sure the tumor hasn't returned.
The past, present, and future
But not all outcomes are like this and Ellis wants to have more assurance that when he treats a brain tumor patient he's giving them a chance at life. "In the last 40 years, we've made little progress in treating these tumors," he says. "Using radiation and chemotherapy the (survival) numbers are pretty dismal."
In 1975, when Helen died, chemotherapy wasn't common because most drugs couldn't pass through the blood-brain barrier — a layer of closely spaced cells over the brain that stops harmful substances from invading. According to the National Cancer Institute, the rate of brain, spinal cord, and other nervous system cancers then was 5.9 per 100,000 adults. Today the rate is 6.4 per 100,000.
Experts say the apparent increase in cases is mainly because of better diagnostic tools. Some of the treatments are also better, such as the MRI that can be used both for diagnostics and treatment. A functional MRI (fMRI) now exists that can monitor neurological blood flow in real time. In addition, more drugs can cross the blood-brain barrier and some better ways to deliver drugs are under development. Still, improved technologies usually buy patients only a few months more than they would have had 37 years ago.
"One of the more difficult parts of my job, that never gets any easier, is when a person comes in who was living a normal life the day before and I have to tell them that they have only one to two years to live," says Ellis.
N-TIRE could give Ellis the advantage of reaching deep tumors and giving uniform treatment, he says. So far the procedure on dogs has been "excellent. This is an amazing collaboration with the vet school, Virginia Tech's biomedical engineering group, and Wake Forest. I truly believe that N-TIRE can become an important new effective tool against glioblastomas."
In the meantime, Rossmeisl and his team continue to use N-TIRE to treat dogs that have no other hope. "So far, the outcomes with dogs have encompassed all the possible clinical outcomes," he says. He works with Robertson and other collaborators to identify the reasons certain dogs, most notably dogs with snubbed muzzles and broad heads, such as boxers and Boston terriers, are more prone to primary brain tumors. He also wants to make major strides in drug delivery to overcome the blood-brain barrier so the medications go directly where they are needed and stay there.
"We believe that glioblastomas have so many ways to evolve and to evade all the treatments we have now that if we can figure out a way to beat those cancers we can cure any tumor," Rossmeisl says.