Johns Hopkins Gazette: April 28, 1997

Waging War
On Cancer:
Taking The

Second in a Series

In recent years, evidence has begun to mount that the so-called "War on Cancer" announced by President Richard Nixon in December of 1971 is turning into a winning war. New drugs, new therapies and a better understanding of how cancer develops have led to increasing survival rates among those afflicted with the disease.

For many, treatments now available hold the possibility not just of remission, but of a return to full health from taking the cure.

What's the next best thing to a brand-new cancer drug that works miracles?

The answer may surprise you. Often, it's an old reliable drug, but one that researchers and clinicians have learned to use in new and exciting ways. Increasingly, say cancer experts, incremental advances in chemotherapy, surgery, radiation therapy and other techniques are helping patients live longer and even beat cancer entirely.

While this is good news for all concerned--especially for patients and their families who don't have the luxury of waiting for new drugs to become available--it is nonetheless the kind of slow, methodical science that rarely gets much attention in the national press. Small refinements--even those that can boost survival rates by as much as 20 or 30 percent--are rarely considered newsworthy. Yet they are significant. Today, thousands of people are alive who might otherwise have succumbed thanks to these kinds of advances.

Researcher Georgia Vogelsang, an associate professor of oncology and clinical director of the Division of Hematologic Malignancies in the School of Medicine, describes this work with a baseball analogy. "Everyone wants the work they're involved in to be the home run," she says, "but most times it isn't. It's the bunt to let the guy on base advance."

Vogelsang's work is a case in point. Since 1968 Johns Hopkins has offered a bone marrow transplant program for the treatment of certain types of cancer, most notably lymphoma, Hodgkin's disease and other cancers of the blood. Her research builds on nearly three decades of experience and observation in bone marrow transplantation to suggest ways it may be possible to markedly reduce the cancer relapse rate of those who have had the procedure.

Bone marrow transplant, explains program director Richard Jones, is a procedure that enables clinicians to administer much higher doses of radiation and chemotherapy than would normally be possible. Often, the increased dosages are enough to eliminate the cancer entirely. But at such high levels the bone marrow-- where all the body's blood cells are produced--is destroyed. Bone marrow transplant is a method of reintroducing healthy marrow to restart the body's blood-producing capacity.

"Bone marrow transplants entered therapeutic use in medicine in the mid-1960s," says Jones, who is an associate professor of oncology in the School of Medicine. "You can't really describe it as a new procedure. The first animal transplants of this type were done 40 or 50 years ago."

What is new is the large role this formerly exotic procedure has come to play in the treatment of certain cancers. When the Hopkins Bone Marrow Transplant Program was established in 1968, it was one of the few such programs in the world. That year, the program performed a total of three transplants, followed by two more the next year, and an additional four from 1970 to 1971.

Today, the program performs in the neighborhood of 200 transplants a year, and is one of hundreds of locations around the world where the procedure is practiced. Not only is the procedure now commonly available in suburban hospitals and other non-teaching centers, here at Hopkins physicians and nurses working in teams have pioneered a program of bone marrow transplantation performed on an outpatient basis.

Jones has a very personal understanding of what these advances in technique can mean to a family. In the 1970s his father contracted chronic mybid leukemia. After a protracted battle, he succumbed to the disease in 1979. At that time, bone marrow transplantation was in its infancy, and Jones' father was considered an unacceptable candidate. Today, thanks to continuous refinements in the procedure, many individuals are treated and cured of the disease.

"The big change has been in donor sources," Jones says. "During the 1970s most transplants were allogeneic_from someone in the family, usually a brother or sister. In that setting, the major issue is histocompatibility. Tissue typing differences between people cause a form of rejection known as graft versus host disease."

Generally, the older the patient, the more serious the consequences were likely to be. As a result, patients older than 40 were considered unacceptable candidates until only 10 years ago.

"In recent years we have learned how to perform autologous bone marrow transplants," Jones says. "These are transplants in which we harvest some of the patient's own marrow cells, freeze them, then reinsert them after radiation or chemotherapy."

Since the patient is receiving his or her own cells, graft versus host disease is not a problem. Yet in the course of performing many of the procedures, clinicians and researchers began to notice that patients receiving an allogeneic transplant who developed a mild, non-threatening form of graft versus host disease (which generally manifests itself as a skin rash of varying intensity on the face, palms and soles of the feet) were significantly less likely to suffer a cancer relapse later on. One of the people to notice this phenomenon was Georgia Vogelsang.

"We began to suspect that a mild form of the disease actually helps charge the immune system to fight off cancer," Vogelsang says of her research, "and we wondered if we could reduce the relapse rate among autologous transplant patients by tricking the body into a mild form of graft versus host disease."

Vogelsang's initial studies indicate this approach may help significantly reduce the rate of cancer relapse among autologous bone marrow transplant patients. "I'm very hopeful that our preliminary research showing a 40 percent improvement will be borne out in the randomized study we will soon be undertaking," she says.

For cancer researchers, numbers that high represent the proverbial home run. But only rarely are they achieved. In large- scale randomized tests, which are the final proof of any new drug or procedure, results measured in single digits are more common. Any development offering improvements of 10 percent or more is considered extremely significant: if a particular cancer claims 5,000 lives annually, a 10 percent reduction in mortality represents 500 lives saved each year.

"If I truly knew this procedure was going to increase survival rates among these patients by 20 percent," says Vogelsang, "I'd be doing cartwheels in the hall of the medical center."

"The reality in cancer research is we make small, steady improvements," says Louise Grochow, an associate professor of oncology and of medicine in the School of Medicine. Grochow is a pharmacologist whose research focuses on learning ways to use old drugs more effectively, and to use new and old drugs in combinations that boost the effectiveness of each. A perfect example is 5-fluorouracil, a 30-year-old drug that has long been a therapeutic mainstay in the fight against colon cancer.

"I would describe 5-fluorouracil as a very good antimetabolite cancer drug. It's a good drug, but not a great drug," she says. "But we have learned that, through research, we can make a good drug better."

In the last few years, researchers have doubled the response rate among patients taking the drug by learning more about how the body reacts to it. "Researchers learned, for instance, that this particular drug is metabolized rapidly by the body, so it's best to administer it around the clock," Grochow says. "Responses can also be increased by administering it with a second drug that helps the 5-fluorouracil bind more effectively. Finally, a new drug that eliminates drug metabolism will make it possible to use 5-FU orally."

Making good drugs better, says Grochow, "may not be sexy stuff, but it saves lives." Often, it involves learning to use the drug in combination with other drugs--either new or old--that attack the cancer from a different direction. "The idea of using multiple drugs was pioneered in the treatment of Hodgkin's disease about 30 years ago," Grochow says. "It may seem obvious to the layman, but it takes extensive research to determine if two or more drugs in combination will make any appreciable difference in survival rates. There's an element of science, but there's also a lot of empiricism in learning how best to administer these drugs."

Next: Early detection of cancer remains the single biggest advantage in curing the disease. There are tests that can save your life.

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