Miércoles 20 de Julio de 2005, Ip nº 118

Making Chemo Easier to Take
Por Joan Raymond and Barbara Kantrowitz

James Bond usually gets a laugh when people hear his name. But the 56-year-old accountant from Shaker Heights, Ohio, figured it might be a good sign that he was assigned the patient number of 007 when he entered an experimental-drug trial at Boston's Dana-Farber Cancer Institute. He needed all the help he could get in his fight against multiple myeloma, a cancer in which white blood cells called plasma cells invade the bone marrow. Bond says that when he was diagnosed in 1992, an X-ray of his skull "looked like Swiss cheese," and he had broken several ribs simply by sneezing. Over the next decade, he tried a number of treatments, including three stem-cell transplants, that put the cancer in remission. But by 2002, Bond had reached what he and his wife, Kathleen, thought was the end of the road. "It was clear I was in trouble and needed something," he says. The couple started to look at the possibility of entering a clinical trial and found that Bond was a candidate for a drug that at the time was called PS-341. It was the break he desperately wanted. After only two weeks, the drug (now known as Velcade) removed virtually all of the cancer cells in his body and put him in remission. When his cancer slowly returned, he took part in a trial of the drug Revlimid, now on the fast track for approval. "Research is saving my life," says Bond.

Patients like Bond are not only benefiting from new cancer treatments; as volunteers for clinical trials, they're providing vital information that scientists need to help even more people in the future. Cancer therapies can be almost as bad as the disease itself. Doctors burn patients with radiation, scar them with surgery or dump toxins into their bodies in hopes of destroying malignant cells. Many patients endure severe nausea and vomiting, extreme fatigue, hair loss and other incapacitating side effects. New and far less debilitating approaches to treatment have meant that Bond and many others like him can view their cancer as a manageable chronic disease rather than an acute, life-threatening crisis.

Using a range of approaches—targeted drugs that hit only cancer cells rather than healthy tissue, new methods of delivering medication and new drug combinations—researchers are making cancer treatment not only more tolerable, but also often more effective. Doctors say these new treatments represent the most significant advances in patient care since the start of the war on cancer three decades ago. "If you can eliminate inappropriate and unnecessary treatment and improve the quality of care, that's as much of a morale booster for a doctor as it is for the person undergoing treatment," says Dr. Andy von Eschenbach, head of the National Cancer Institute.

Many of these new efforts are still in clinical trials or awaiting approval by the Food and Drug Administration. A few that have won FDA approval are reserved for patients like Bond, who have advanced disease. But researchers believe that, ultimately, studies will show that using these treatments earlier will slow or even stop the progression of the disease. That's because the new approaches focus on the mechanisms of specific cancers. Scientists have identified hundreds of kinds of cancer cells, so treating them all the same way makes little sense anymore. If traditional chemo is a sledgehammer, these new treatments are highly specialized and delicate instruments with very precise functions.

Targeted therapy
The most promising of the new approaches is the result of decades of research dedicated to understanding the differences between malignant and normal cells, and between one type of cancer cell and another. Traditional treatment generally concentrates on only one of these differences: the fact that cancer cells divide rapidly. The problem is, some normal cells divide rapidly as well. That's why chemo can be so devastating. Targeted therapy finds cancer cells by recognizing their specific markers or attacks a specific chemical pathway necessary for the malignant cell to live and multiply. Some of these new drugs use large molecules to block growth-promoting proteins from attaching to receptors on the surface of the cell, the first step of uncontrolled cell growth. Others use small molecules to actually get inside the cancer cell and block the chemical signals that drive the cell to multiply uncontrollably. Still others, such as anti-angiogenesis drugs, take a completely different route and target the blood vessels that supply oxygen and nutrients to cancer cells.

Velcade, the drug that initially helped Bond, belongs to a class of agents called proteasome inhibitors, which regulate protein turnover. It was initially developed as a treatment for muscle-wasting conditions because it could prevent the destruction of proteins needed for healthy cell growth. But research showed that it could also selectively stop the unhealthy growth of some types of cancer cells, particularly the cancerous plasma cells in multiple myeloma.

At about the time that Velcade was being tested, researchers were looking into Revlimid. It's a small-molecule drug related to thalidomide, a mainstay of multiple-myeloma treatment. But it's more potent than thalidomide and has fewer side effects. Revlimid works by targeting the destruction of myeloma cells and blocks the blood and nutrient supply required for these cells to grow in bone marrow, says Dr. Ken Anderson, director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber, which took the lead in laboratory and clinical trials of both Velcade and Revlimid. "There weren't any new treatments for myeloma in years, and then you have two new treatments in just months," says Anderson. "It's an amazing time."

Targeted therapy is especially critical for the youngest cancer patients. Childhood cancer is generally treated very aggressively, often with a combination of chemotherapy, radiation and surgery—all at a time of life when bodies are growing and developing. But Gleevec, a targeted drug for adults with chronic myeloid leukemia, has now been approved for children with the disease. Doctors still debate whether children with chronic myeloid leukemia should undergo a bone-marrow transplant—a curative but risky therapy with potential long-term side effects—or be put on Gleevec. But as experts learn more about the effectiveness of Gleevec for kids, they're impressed. For Karen and Mark Knudson, there was no question that their daughter would try Gleevec. Katie, now 10, was diagnosed with chronic myeloid leukemia (rare in kids) when she was 6. They were worried about the long-term effects of a transplant. "We decided on Gleevec to give Katie a chance to grow," says Karen Knudson. "It buys her time. And a bone-marrow transplant will remain an option down the road."

New delivery methods
Breast-cancer patients call it the "boobie Jacuzzi." It's a promising part of ongoing hyperthermia clinical trials at Duke Comprehensive Cancer Center. Here's how it works: women rest stomach-down on what looks like a massage table for an hour, as radio-frequency energy warms their affected breast, which lies in a pool of water. The heat directs the chemotherapy the women have just received to be directly deposited into the tumor. The chemo is given intravenously but is encased in a protective coating (a tiny fat bubble called a liposome) and trickles out after it is delivered to the tumor. The tumor becomes a kind of ground zero, getting a large payload of liposomes because its vessels are made very leaky by the heat. The medication seeps slowly to the breast over a three- to four-week period. Using heat with the chemo inside the liposome allows doctors to deliver about five times more medication than they could normally.

Second-grade teacher Connie Townsend of Cheraw, S.C., says she was "devastated" when she was diagnosed at 39 with locally advanced breast cancer. Though she was a candidate for surgery, doctors suggested trying chemo first, using the boobie Jacuzzi. She agreed to enter a clinical trial. "I had heard all of the chemo horror stories and I was terrified," says Townsend. "This was supposed to be easier on you." Townsend underwent hyperthermia four years ago; the tumor shrank and she didn't need a mastectomy. She had a lumpectomy, followed by conventional chemo and radiation. She's now cancer-free. "Anything these scientists can do to help save lives while making treatment more tolerable is so important," she says. "I feel blessed."

Researchers are also experimenting with ways to make older drugs more effective. Abraxane, a recently approved breast-cancer drug, is essentially the older drug Taxol made more potent and more tolerable through nanotechnology. The new drug uses the protein albumin, which carries fatty acids throughout the body, to ferry the active ingredient of Taxol through the bloodstream so it can squeeze into a tumor's leaky vessels. Because doctors no longer need a toxic solvent to get into the cancer cells, they can give extremely high doses of Abraxane. It takes only 30 minutes rather than three hours to administer, so it is much easier on patients. Dr. William Gradishar, a cancer researcher at Northwestern University, thinks that any number of drugs could be attached to the same protein. "That's the real hope here," he says.

Combining drugs
Cancer is so complex that many researchers believe that multiple pathways must be targeted to stop the disease from progressing. Current drugs go after only one stop along the pathway. That's why doctors are combining drugs and also looking for one agent that goes after multiple targets. The big news on this front is in the battle against lung cancer, the leading cause of cancer death in the United States. Many patients become resistant to chemotherapy or develop side effects so severe that they cannot continue treatment. But two new targeted drugs, Avastin and Tarceva, have shown promising results in studies reported at the recent annual meeting of the American Society of Clinical Oncology. Avastin is an anti-angiogenesis drug that was initially approved for advanced colorectal cancer. In one study, Avastin combined with chemotherapy was shown to improve survival for lung-cancer patients. In yet another approach, Tarceva, a small-molecule drug that interferes with growth of malignant cells, was combined with Avastin. Dr. Roy Herbst of M.D. Anderson Cancer Center in Houston and his colleagues found that the two together worked better than either alone.

It certainly worked for Charles Gibson, a 52-year-old long-haul trucker who was first diagnosed with lung cancer in 2001. Doctors told him it was inoperable, and he was put on a devastating chemotherapy regimen. "You start to wonder if treatment is really worth it," he says. Worse, it didn't seem to be working; the cancer continued to progress. Gibson decided to enter a trial of Avastin and Tarceva. "It was a cakewalk," says Gibson. "I started to feel good in about three months." Now his Avastin regimen is over and Gibson takes Tarceva orally every day. His tumors have shrunk by about 90 percent. He's even playing volleyball with his family and fishing with his son, Julian, 13. Herbst says Gibson's is the "wow" response all researchers dream of.

  01/07/2005. Newsweek Magazine.