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an online version of the magazine Winter 2005
In Spite of All Odds
  The chances of surviving brain cancer are minimal. But that doesn’t dampen neurosurgeon Henry Brem’s belief that you never take hope away from people.
BY Marjorie Centofanti

The first glimpse I had of Henry Brem has stuck with me.

It was in 1987, well before he'd become head of neurosurgery at Johns Hopkins. As a media specialist for Hopkins , I was wedged into a corner of an elevator, watching a man I presumed was Brem on his way to a press conference. He was talking about how he had been placing therapeutic wafers of some sort into the brains of tumor patients. I remember less about the science than Brem's demeanor. Though his voice was soft, it was excited and genuine. He radiated an optimism that left us mesmerized as the doors opened. An E.F. Hutton moment. We'd have bought stock in his technique that afternoon, had it existed.

More unsettling was a contact in the summer of 1995. Brem e-mailed me, suggesting a press release timed to an upcoming Lancet article. The results of key Phase III trials of the Gliadel wafers were out. During second surgeries on patients whose cancer had returned, the dime-size porous discs laced with standard chemotherapy had been put straight into their brains. And they'd helped. But reading the article, I couldn't get past the hard fact: Median survival of the patients with Gliadel was 31 weeks compared with 23 weeks for those on placebo.

How could I trumpet a technique that appeared to extend life no more than eight weeks? I bristled.

Now, almost a decade later, I cringe at how I misunderstood brain cancer, at how blind I was to a seminal therapy. I also misread Henry Brem by a mile.



Harvey Cushing performing an early neurosurgery at Hopkins  
> Harvey Cushing performing an early neurosurgery at Hopkins.

Compared with other body parts, the brain has been cancer therapy's Waterloo . As the proportion of U.S. cancer survivors has tripled in the last 30 years, brain cancer's cut has doggedly stayed low. Close to 17,000 will be diagnosed this year with primary tumors. Another 170,000 will learn their brains have been colonized by cells from distant tumors. With the best treatment, few patients live much more than a year. As Harvey Cushing, father of neurosurgery, observed at Hopkins in 1907, “We have long stood helpless in the presence of brain tumors.”

When Cushing started out, only 10 percent of brain tumor patients survived the actual craniotomies. Without good images at hand, operations were seat-of-the-pants procedures, terrifying in their crude removal of tissue. Yet in a decade, Cushing's attention to bleeding, blood pressure and hygiene had pulled 90 percent of his patients through. Today, Hopkins ' surgical mortality for brain tumors is less than 1 percent.

For Brem, Cushing's legacy at Hopkins isn't long out of mind. He's reminded of it daily when he walks under the Cushing nameplate that's over his office door. A portrait of Cushing's successor, neurosurgical pioneer Walter Dandy, hangs in Brem's entryway. Brem's response to the legacy is both simple and profoundly difficult.

“What it boils down to,” he says, “is hope. The only way we can justify patients coming all this way and trusting us is to offer more than compassion. You give them hope by making your technical skills the best. You create a scientific environment that promises progress in therapy. And just as critical: You give them hope that comes from really caring about them. I know this model works. I've seen it work.”

It's no fluke that Brem carries around parts of two episodes of the TV show ER on his laptop. There's ashen Mark Greene, the doctor with a brain tumor, grasping at straws with his clinician.You hear the clinician say, “Even if you consented, I wouldn't consider operating.” Brem scoffs, “That's so typical.” Then he punches up the second episode, where a surgeon at another hospital tells Greene he is indeed a candidate for surgery and for “wafer therapy.” You hear the terror drain from Greene's voice.

“They've got it,” Brem affirms, “right on the mark.”

A tumor nestled in the brainstem.  
> A tumor nestled in the brainstem.

Within the team of surgeons Brem leads, the ability to remove brain tumors has never been so good. The operation I observed one day last June showed a seamless integration of technology and surgical art. The middle-age woman on the table had a slow-growing meningioma—a not-uncommon tumor that sprouts from brain membranes—that Brem had watched for five years, a fruit ripe for plucking. Ultrahigh-resolution MRI scans were clipped to lightboxes. A nearby video monitor showed the most useful sagittal view of her brain. As Brem scrubbed outside OR “F,” the surgical team had just removed a square of the woman's skull. The burnt-feathers smell of high-speed saw on bone lingered.

Henry Brem looks younger than fiftyish, a benefit, probably, of sun-deprived hours in the OR. Also a researcher, member of 25 committees and head of the neurosurgical residency program, he typically starts work around 6:30 a.m. His office phone's often busy at 10 at night. Weekends are a sandwich of visits to patients and family doings, the latter made intense by stolen time. In the State of Brem , work and home are all of a piece; time becomes like clay, to be stretched thin or piled up, briefly, as needed.

Now, in the OR, Brem and his neurosurgical resident confirm the surgical route, their fingers tracing the monitor. It's sharply angled through the top of the skull and behind an eye socket. They've rejected a simpler but infection-risky path through sinuses. Brem eases in and down just far enough with his forceps, teasing tumor from surrounding membranes. He pulls it out, a pale squashed grape, and drops it in the proffered jar of saline that goes to pathology. “Tumor's out!” he announces. The atmosphere lightens. Then he runs a pen-shaped wand along the cavity, watching the monitor with the residents, intent on small X'es that correspond to the wand's actual brain position. When Brem developed the surgical wand a decade earlier with neuroradiologist James Zinreich, it brought a sea change in brain surgery. No X'es overlap the tumor zone on the screen. The surgical surface is clean.

While no brain surgery is trivial, this case was a brain-tumor tonsillectomy: a two-hour affair, not the typical five or six. “If only they were all like that,” says Brem. The tumor was obvious in the images. Had it not been, new techniques refined here, like the MR spectroscopy that detects chemical differences in tissue, could help define it. Functional MRI could map vital brain parts to avoid. And an MRI scanner newly built into the surgical suite could increase chances surgeons “got it all” before closing the skull.

With 20 full-time neurosurgeons and the country's most extensive dedicated neurocritical care unit, Hopkins performs more brain tumor surgery than anywhere in the nation. “We do extremely well with some patients,” Brem says, “but very poorly with others. We'd like to say routinely, We'll cure your brain cancer. We can't. For now our satisfaction comes from having surgery at its highest state. We do the best job possible.”

The problem, then, isn't surgery; it's biology.

Unfortunately, most incurable tumors lack hard boundaries. All but impossible to detect and remove, malignant cells at that ragged edge lie ready, postsurgery, to infiltrate adjacent brain. “Ninety percent of patients die,” he says, “because of this residual area.”

Further, destroying such cells with whole-body chemotherapy has a dismal record, thanks to the blood-brain barrier. Capillaries in that layer between circulation and brain have cells so tightly abutted that chemotherapy barely slips through. And within the brain itself, molecular “bouncers” dismantle a broad range of drugs. Any dose of systemic chemo high enough to overwhelm these defenses risks the death of healthy cells.




Brem wasn't born with scalpel in hand. Instead, what was built in, says his wife, Rachel, a radiologist who specializes in breast cancer, was a drive to help people. “Henry wasn't keen on his father's clothing manufacturing company.” He considered law. But his older brother, Steven, gave off sparks whenever he came home from Harvard Medical School , to a family already fueled on high-octane enthusiasm. At NYU, Brem found himself hooked on science. In three years, he had finished his degree and signed on to work in Judah Folkman's Harvard lab for a year before med school.

The head of pediatric surgery at Children's Hospital, Boston, Folkman also led a scientific team. The group was bent on explaining cancer angiogenesis, a tumor's Svengali-like ability to conjure blood vessels from the host to keep itself fed and watered. In 1973, the year Brem joined the lab, Folkman's work aimed at blocking tumor angiogenesis, wasn't popular. Radiation and chemo ruled cancer therapy. Folkman toiled on the outskirts. But he became Brem's first role model: a surgeon who was also a basic scientist, an unflappable man who struggled against public opinion to show that the best therapies come from a sound understanding of nature. “He drilled me in the need to ask the important questions,” Brem says.

During his time with Folkman, Brem showed that tumor angiogenesis could be blocked. With lab mate Bob Langer, a chemical engineer, Brem saturated some porous plastic pellets that Langer had devised with various extracts of cartilage—cancer in cartilage is almost nonexistent—and placed them near rabbits' tumors. One lot squelched vessel growth. It was a clear proof of principle, Folkman said, and it helped spur the lab on.

The dime-sized gliadel wafer that ferries potent chemotherapies directly into brain tumors.  
> The dime-sized gliadel wafer that ferries potent chemotherapies directly into brain tumors.

Brem left for med school, also at Harvard, and during six more years of training in neurosurgery worked research in where he could, including a year at Hopkins . But as soon as he joined the faculty here in 1984, one of his first moves was to reinstitute the Hunterian Neurosurgery Laboratory that Cushing originally founded, putting basic science to work on problems facing neurosurgeons. He also looked up Langer, now at MIT. By then, Langer had created a plastic that could disintegrate, leaving no trace in tissues. Brem, meanwhile, had operated and re-operated on enough brain tumor patients to see a howling need for a direct, local way to stop recurrence. He suggested that Langer mold the plastic into wafer- shapes that he could lay down deliberately, like cards in solitaire, in the brain cavity that is left behind when a tumor is excised. Langer loaded the wafers with BCNU, the standard systemic agent for brain tumors. “I'd lie in bed, just before the alarm,” says Brem, “and visualize the drug diffusing out of the wafers toward malignant cells.”

By 1994, Brem and a cadre of Hopkins neurosurgeons had moved with care through animal tests and a small clinical trial. Now came a controlled, 22-institution study of more than 200 patients. The FDA had approved trials only for the seriously ill patients whose tumors had recurred and who had failed standard radiation and in some cases, chemotherapy. Two-thirds had the worst sort of brain tumor, the aggressive glioblastoma multiforme. This was the study I'd balked at, whose results showed Gliadel extended median survival eight weeks.

But the Brem team knew that any extension of average survival is a crucial step. “In brain cancer,” Brem says, “reaching statistical significance, as this did, means you're helping hundreds. You've changed the average outlook for the disease, altered its natural progression. A lot of people at one end of the curve are still alive who wouldn't be after two years.”

In 1996, the FDA approved Gliadel for patients with recurring gliomas—the first brain tumor therapy in 23 years. And last year, they extended its use to newly diagnosed tumors. Today, Gliadel is routine in cancer centers worldwide. Dozens of new trials have arisen to test it for other brain tumor types, including children's. But the wafers have done more. They've sanctified the local approach—putting chemotherapy directly into the brain. “Now we're seeing a surge in trials,” says Brem. “The old reticence to try something new is past.”

Brem's colleague Alessandro Olivi is using the wafer to deliver higher doses of chemotherapy.  
> Brem's colleague Alessandro Olivi is using the wafer to deliver higher doses of chemotherapy.

We've become psyched, says Brem's colleague Alessandro Olivi. “Henry's created this gigantic machine that's clarifying basic science at one end and turning out useful therapy at the other. An attack is being engineered here on multiple fronts. As far as I can tell, it's unparalleled.”

There are basic results: The Hunterian's researchers have shown, for example, that cancer clears a swath through the brain by killing brain cells with much the same chemistry as strokes. Drugs that might block that destruction are under study. And recently, Brem recruited brain tumor geneticist Gregory Riggins—unusual for Neurosurgery—who's identified specific combinations of genes turned on in distinct brain cancers. It's an indirect way to expose tumors' vulnerable underbelly.

Meanwhile, Brem continues to work with Langer, now on a brain-implanted microchip that enables programmed release of several drugs. You can pool them for optimal effect or stagger drug delivery to keep tumors off balance. In animal trials, microchips look good. And Gliadel's scope has broadened. The wafer can safely deliver higher doses of BCNU, Olivi's found, to kill more malignant cells. Colleague Jon Weingart has loaded the wafer with camptothecin, an alkaloid cell-division poison that also shows promise.

But the most unusual possibility for combating brain tumors comes from an approach that has nothing to do with the wafer. It pits biology against biology. And it has a lot to do with a man named Richard Pollhammer.




In the fall of 1990, Pollhammer, a 39-year-old father of two small children, was headed for his home in Baltimore County when he took a wrong exit and stopped his car in the midst of a stream of traffic. As people around him stared, Pollhamer found himself in a fugue state—a type of seizure. Eventually, an ambulance transported him to a nearby hospital, and in short order, he heard doctors describing his condition with phrases like malignant brain tumor, no real cure and average life expectancy of a year.

As a former administrator in Johns Hopkins' Department of Neurosurgery, Pollhammer wasn't ignorant about brain tumors. He also knew about Gliadel. In two days, he'd become Brem's patient and learned that he had the worst of the worst, a grade IV glioblastoma. To make matters worse, a quirk in his pathology report determined that he wasn't eligible for the wafer treatment.

Brem removed all he could of Pollhammer's tumor and began his patient on standard, aggressive chemotherapy. Then, before Pollhammer could start radiation treatment, he developed a rare skull infection at the surgical site. That took weeks of intensive antibiotics and even removal of a piece of his skull to clear. Only then, emotionally drained, could he start radiation. And then, something quite unexpected happened. Richard Pollhammer began to get better.

Today, 14 years later, Pollhammer's brain shows no sign of the cancer that once signaled his death sentence. He's watched his children grow up, and he's CEO of a long-term-care pharmacy company. Doctors are convinced it was his infection that saved him. “Everyone in our field has seen rare spontaneous remissions,” Brem says, “though you never stop being amazed at them. When you investigate, you often find they've occurred in people like Richard who had severe infections.” Bacteria seem to trigger a strong and lasting immune response that mops up tumor cells, Brem explains.

Pollhammer's story has translated into action in Neurosurgery's laboratories. “We used to think the brain lacked immune activity,” Olivi says. “We've overthrown that. It may be low key, but not only is there immune action, we can step it up and focus it by increasing levels of natural immune stimulators like cytokines.”

Following this line of research, Brem and his oncology colleague Drew Pardoll recently engineered mouse tumor cells to secrete the cytokine interleukin-2. Returned to the animals, their “vaccine” prompted a massive antitumor attack. Moreover, when the mice also received rodent-size Gliadel therapy, most of them became rare specimens: long-term survivors of brain cancer.

In the Hunterian lab, neurosurgeon Olivi is readying the most subtle approach yet. It's based on evidence that tumors themselves suppress human immune systems. “That's one reason they recur,” he says. This year, he and colleagues revealed that a receptor-driven “molecular embrace” between the tumor and key, infection-fighting white blood cells ends in the white cells' death—biology's equivalent of a James Bond movie in which the vamp pulls a knife in mid-kiss. Now, the researchers are at work blocking the cell unions, cutting short specific biochemical paths that make tumor cells attractive. “Our approach,” Olivi says, “could give the brain's natural immunity an assist. Combine that with Gliadel or other attacks—it gives us hope.”

In the end, that sums up Brem's whole approach to brain tumor treatment. It's the message he wants to permeate every patient-surgeon contact.

"I was taught,” Brem says, “that you don't take hope away from people. You give patients the statistics. You don't make pronouncements, but you don't stop there.” Then, he looks away. “When my father was liberated from Buchenwald , he weighed 85 pounds. He had three bullet holes. But nobody he knew committed suicide. In the face of the worst human behavior imaginable, people still had hope.”


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