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Default A Direct Hit of Drugs to Treat Brain Cancer - 11-09-2010, 02:07 PM

November 8, 2010
A Direct Hit of Drugs to Treat Brain Cancer

By DENISE GRADY

It was a desperate measure, for a desperate disease. Fourteen months ago, Dennis Sugrue let doctors thread a fine tube through his blood vessels and up into his head, so they could spray the drug Avastin directly into the part of his brain where a tumor had been cut out. It was an experiment, devised mainly to find out whether the procedure was safe, and to gauge how much Avastin the brain could tolerate. But Mr. Sugrue, then 50, was hoping the experiment would also free him of cancer.
He had glioblastoma, a brain tumor that fights off every known therapy. The same disease killed Senator Edward M. Kennedy last year. Mr. Sugrue’s cancer was diagnosed in April 2009 and bombarded with the usual weapons: surgery, radiation and chemotherapy. Within months, the tumor was growing back. That was when he signed up for the Avastin study.
About 10,000 Americans a year develop glioblastoma. Nearly all find that the standard treatments seem to work — for a while. And then the clock starts to run down. With treatment, the median survival is about 15 months. Only 25 percent of patients make it to two years.
The disease is the focus of much research, and will almost certainly be for years to come. Hundreds of studies are being conducted in glioblastoma and other brain cancers. Among other things, they involve vaccines, drug combinations and special drug-delivery techniques. Progress is measured in small steps — a few more months of survival, more patients managing to survive two years. On paper the gains may seem minute, but for patients the added time may translate into a graduation or wedding that might otherwise have been missed.
There are two enormous obstacles to treating glioblastomas. First, no drug is highly effective. Second, even if there were such a drug, getting it to the tumor would be difficult. Many drugs cannot squeeze through the blood-brain barrier, a system of tightly packed cells lining capillaries in the brain. The barrier makes all brain tumors hard to treat.
The study that Mr. Sugrue entered, for people with recurring glioblastomas, is being conducted by Dr. John Boockvar, a brain surgeon at NewYork-Presbyterian/Weill Cornell. Doctors first inject a substance called mannitol, which temporarily opens the blood-brain barrier, and then flood the tumor zone with Avastin. Avastin blocks the growth of new blood vessels, which tumors need. The drug is approved for glioblastoma, but tumors can become resistant to it.
Normally, Avastin is dripped into a vein. But Dr. Boockvar and his colleagues wanted to try hitting the cancer with a much higher dose by guiding tiny tubes called microcatheters through blood vessels to the tumor site and then unleashing the drug.
Mr. Sugrue was the second patient to be treated, with a small dose. Since then, the study has shown that higher amounts — seven times the dose he received — can be safely used.
A report on the first 30 patients was published online last month in The Journal of Neurosurgery. Tumors shrank in some, particularly those who had not had Avastin before. But one patient suffered a stroke from the treatment, which caused weakness on one side. And it is still too soon to tell whether this approach can prolong survival.
“We started a year ago,” Dr. Boockvar said, adding that the early patients were quite ill and had only one dose of Avastin. “We’ve lost about 15, or half the patients. The rest are alive and kicking.”
His team has begun new experiments using mannitol and microcatheters to deliver other drugs directly into the brain. In the future, certain drugs may be combined with Avastin.
Dr. Keith Black, chairman of neurosurgery at Cedars-Sinai Medical Center in Los Angeles, and an expert on breaching the blood-brain barrier, said it was not clear that Avastin would work well enough to improve survival very much, even when infused right into the brain. Better drugs are needed.
“We can get drugs in, but there’s a belief in glioblastoma, for example, that even if you push the limit of the drugs you still won’t increase the survival all that much,” Dr. Black said. “It’s kind of like having the Trojan horse before we have the soldiers to put in it.”
He said vaccines looked promising for some patients with glioblastoma. In addition, research with animals suggests that Viagra or Levitra — the drugs for erectile dysfunction — can open the blood-brain barrier, particularly around tumors, and let chemotherapy in. In theory, the drugs could be taken in pill form, unlike mannitol. Dr. Black said he was planning to study the idea in people with various types of brain tumors, including those that had spread from other sites, like the breast or lung. Cancer from other organs invades the brain in about 100,000 Americans a year.
The study that Mr. Sugrue entered is still going on. And so is Mr. Sugrue. He lives in Stamford, Conn., with his wife, Donna, and their teenage children, Molly and Tim. Molly, a high school senior, is about to apply to nursing schools. Mr. Sugrue is still receiving intravenous Avastin regularly. (He had only one dose infused into his brain.) There is no sign of tumor recurrence.
But it has not been an easy year. An infection in his incision required many operations. He has lost some peripheral vision and no longer drives. He needs physical and occupational therapy. Though he does some work, he has not been able to return full time to his job at a hedge fund. But he never lost his quick wit or sense of humor, his wife said, adding, “What he went through would have killed a lesser man.”
If he had it to do again, would he enter the study?
“Absolutely,” Mr. Sugrue said in a telephone interview last week. “In fact, I’m going to ask Dr. Boockvar if there are any more trials out there.”
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