Deep into the night, even in her sleep, Melanie Perone was haunted, fearing that the most aggressive and deadly of brain tumors might be growing back. Day after day, she would run down the stairs to her basement, to the computer, to search for a way to save her life.
A few years ago, when brain tumors were the poor cousin of cancer research, the Mount Airy woman's prospects would essentially have been no different than the dismal options of the 1960s.
But an explosion of findings in molecular biology has transformed the study and treatment of brain cancer.
Suddenly, this stubborn, lethal cancer that few wanted to study because it is so rare, so complicated and so hard to reach, is now attracting top researchers.
The number of clinical trials has multiplied. And patients like Perone can choose from scores of experimental therapies.
"I thought if I found the perfect trial, it would save my life," she said.
The first hint of her brain tumor came in late March, while she was waiting in line at the library. She felt a tingling on the lower right side of her mouth.
"It was enough for me to go, 'Huh, what was that?' " she said.
Within a few weeks, she got her answer: a mass on her brain. But Perone, 36, an optimist with a big smile, wasn't worried. She felt confident her age would protect her, even after the operation on Good Friday when surgeons removed her walnut-sized tumor.
But then doctors told her the biopsy results. A nurse closed the door. Perone's husband, Jim, stood at her side. Two physicians looked at her from the foot of the bed. One of them used the word "malignant."
Perone screamed, not in fear, she said, but in grief. It was the wail of a woman who had just lost her baby. Doctors gave her six months to two years to live.
Unlike so many before her, though, she received the diagnosis at a pivotal period. For the first time in a generation, doctors can offer novel therapies, therapies that give Perone a chance to survive.
"We're kind of lucky now," said Perone, who finds herself reeling between despair and hope. "There's more magic bullets to look at. Maybe they'll find a cure tomorrow."
The turnaround in this largely neglected field started in 1994, when frustrated federal health officials decided to rethink their approach to brain tumors.
For years, researchers were mostly testing variations on radiation and chemotherapy by enrolling hundreds of patients in costly trials that often took years to complete. They also produced little new knowledge -- and saved few people.
So the National Cancer Institute decided to try lots of different strategies in much smaller studies, to get quicker results and find promising therapies.
Now, researchers can learn in a year to 18 months whether a treatment is safe and might work. Research dollars dedicated to brain tumors multiplied, growing from $12.6 million in 1982 to an estimated $59.6 million in 2000, according to NCI figures.
At the same time, discoveries in molecular biology -- such as deciphering some of the key genetic changes in brain tumors -- gave physicians fresh targets to pursue.
Tumors rare but varied
Brain tumors make up only 1 percent of all cancers, but there are more than 100 types of them. They behave unlike any other cancers. They don't spread to other parts of the body, and they have a gnarled network of leaky blood vessels.
Scientists discovered that those distinctive features make them perfect models for two of the most promising cancer treatments today -- gene therapy and a strategy that starves tumors by shrinking their blood supply.
Suddenly, dozens of scientists with no previous interest in brain tumors have been drawn into the field.
"We used to have these tiny little meetings in which we were kind of voices in the wilderness," said Dr. Richard S. Kaplan, program director for brain tumor research at the National Cancer Institute. "Now there's just a tremendous outburst of interest."
By April, when Perone got her diagnosis, more than 150 clinical trials were under way.
She immediately went to Montgomery Ward, bought equipment that gave her access to the Internet from her TV, and printed out a bewildering ream of data. A house cleaner who earned her GED and took some community college courses, she didn't know how to type and had never used a computer.
But soon, she was sorting information on dozens of studies in stacks in her basement. Hours passed without her realizing it. So did the days.
Obsessed with data
"I was obsessed," said Perone, who often worked until midnight and finally had to install a clock to make sure she went to bed. "I mean, how many rats died, how many lived?"
Perone knew from her research that a minority of the approximately 34,000 Americans in whom primary brain tumors are diagnosed every year -- meaning the tumors arise in the brain rather than spread from somewhere else -- can be successfully treated.
Despite major advances in many other cancers, malignant brain tumors have proved difficult to defeat. The brain is protected by a barrier that filters out toxins, including the chemicals that might kill tumors; drugs powerful enough to cross that barrier could hurt precious healthy tissue.
In nearly every case, tumors come back. About 17,000 people a year die.
Scientists can't tell patients such as Perone why they developed this kind of cancer, but many researchers believe the causes are environmental, with heredity accounting for a small portion.
Over the past several years, the numbers of brain tumors reported nationwide has steadily increased, and scientists disagree about what this means. Kaplan said new research shows there is no increased incidence of the disease, but that technology like magnetic resonance imaging (MRI) has allowed doctors to diagnose cases they might have missed before.
Like many patients, Perone decided to enroll in a trial even though she was worried about being in an experiment.
"Once in a while, you think about it, that we're just lab rats," she said. "I can see those doctors coming home from work, saying, 'Good, we got our group.' But they don't cry. They're going to be waking up for the next 60 years."
She refused to enroll in any study in which she might be randomly picked to receive either a placebo -- a "dummy" treatment that has no therapeutic effect -- or a standard therapy with limited benefit. These randomized studies, which directly compare two treatments, are considered the gold standard for research, but patients, fearing they'll get the placebo, are reluctant to enter them.
This makes it difficult to answer pressing questions, such as whether bone marrow transplants help breast cancer patients. Perone understands the scientific dilemma. But she believes anyone facing a death sentence should always be able to get a potentially lifesaving therapy.
"It's one thing when you're looking at a headache medicine, and it's another thing when people could die," she said.
Figuring out which trial to gamble on was wrenching for Perone. Because of the aggressiveness of brain tumors, patients must decide what to do quickly.
Perone's tumor type, glioblastoma multiforme, can double its size every 10 to 11 days. Adding to her anguish was the discovery that once she selected a trial, it would automatically bar her from many others.
"It's very confusing for patients and families," said Dr. Stuart Grossman, who is directing the trial Perone eventually joined. "They wonder why every center is doing something different, but that's the way it should be."
Grossman, director of neuro-oncology at the Johns Hopkins Oncology Center, also runs the New Approaches to Brain Tumor Therapy Consortium, one of two lead groups in the United States created by NCI to direct trials.
Variety of approaches
The Hopkins center is running 30 experiments, including tests of gene therapy, implanting a disc filled with chemotherapy material at the tumor site, and increasing chemotherapy doses (seizure drugs that brain tumor patients take can lower chemo levels).
"We don't know the best way to treat these patients," Grossman noted. "One of us is going to hit pay dirt."
Researchers acknowledge, though, that it may take a while.
"We are very early on in testing these [ideas]," said Dr. Lawrence Chin, assistant professor of neurosurgery at University of Maryland School of Medicine. "We are just at the edge."
Ultimately, Perone picked a trial that taps the strategy of starving a tumor of its blood supply, a concept called anti-angiogenesis. In that trial, researchers are studying copper, an essential factor in the development of blood vessels. Drop the amount of copper in a person's system, doctors theorize, and it might inhibit the growth of blood vessels that feed the tumor.
That's what it did in rabbits and rats. Perone is the first patient enrolled nationwide.
"I'm Human No. 1," she says, laughing.
Pills and seizures
Every day, she swallows four horse-sized pills that deplete her body of copper, and she banishes foods high in copper such as tomatoes, chocolate and shellfish from her diet. She also must account for everything -- even mustard or salt -- that she puts in her mouth.
But over time, she's learned shortcuts, sizing up how much sprinkled cheese she can have without using her postal scale. More troubling to her are the seizures that have left her unable to drive, and the medicine that has swollen her fingers so badly that she can't wear her wedding ring. She wears her husband's instead.
All the while, her anxiety builds, waiting for the MRI she gets every other month to see whether the tumor has grown back. Even though most of it was removed, her tumor infiltrated her brain with unseen fingers, intimately mixing with healthy tissue. Even the best neurosurgeons in the world can't remove all of a malignant brain tumor.
Such cancers couldn't even be studied well until 10 or 15 years ago, when imaging techniques such as MRIs were developed. Since then, advances mostly have been confined to new imaging technology that guides surgeons during operations and precisely focuses radiation in the brain, allowing for higher doses.
"People 20, 30 years ago, without the benefit of new technology or imaging, were doing nearly as well as we are now," said Dr. Donald M. O'Rourke, an assistant professor of neurosurgery and pathology at the University of Pennsylvania Medical Center.
A surgeon, he spends much of his time in the lab now, working on defining the molecular mechanisms of brain tumors. "Surgery will always be palliative for this disease," O'Rourke said.
Patients realize that the standard treatments only buy them time. On some days, Perone sees the sugar maples she planted in front of her house and bursts out crying.
"They're going to be real big someday," she muses.
She and Jim Perone had meant to retire in this cozy house on the corner. They had planned to sit in the covered wooden swing in the back yard and watch their grandchildren play on the grass. Many days, though, she fights off those feelings.
"If I make myself crazy about controlling life," she said, "then I ruin the life I have left."
It could be worse
She knows she's escaped the worst. She has friends in a support group who have lost their memories, their sense of who they are. Sometimes, their personalities are changed.
Brain tumor patients can quickly lose the ability to walk and talk, and they may find themselves stigmatized by those who assume they've lost cognitive abilities. Humiliated, many will hide the diagnosis as long as possible.
Perone mows her lawn, walks her dogs, scours the Internet for the latest cancer news. But in the past few months, she finds herself struggling with glitches in speech and memory.
She says power surge instead of storm surge. She walks into the kitchen many times a day and doesn't remember why. Just having a conversation with someone is taxing.
Any of these symptoms might mean the tumor is growing back. But the brain surgery and radiation have created trauma in her head that can reverberate for months, and her body is being depleted of copper. Nobody knows what that can do.
One July night, Perone felt a stabbing pain in her left side. She couldn't move without screaming. At the emergency room, morphine did nothing. For five days, the stabbing sensation continued, landing her in the hospital again.
"I don't think I've ever been in that much pain before," she said to Grossman at an appointment a few weeks later. "I'd rather have more brain tumors removed."
She wanted to know whether the non-copper diet caused the pain.
Peering intently at her, in a gentle voice, Grossman told her, "I have to be honest with you. When you're the first one down the pipeline, we don't know."
In one week, she will have her next MRI.
Once again, she will joke with the technician about the brunet wig she finally got because too many people stared at the scarred and naked side of her head.
And she will climb on the long, skinny platform in the chilly room, where they'll pull a plastic helmet device over her head.
Then, as she lies still as a corpse, her body will slide into the huge white machine.
Inside, as the buzzing and hammering noises start, she will whisper, "God, God, God. Jesus, Jesus, Jesus," and she will dream that she is safe.
The University of Maryland Medical Center's Brain Tumor Support Group: 410-328-8875
The American Brain Tumor Association: 1-800-886-2282, or www.abta.org
The Brain Tumor Society: 1-800-770-8287, or www.tbts.org
National Cancer Institute: 1-800-4-CANCER, or cancertrials.nci.nih.gov