September 21, 2007

Investigators track chemo’s impact on heart function

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Douglas Sawyer, M.D., Ph.D.

Investigators track chemo’s impact on heart function

Julie Means-Powell, M.D., here with a patient at VICC, is collaborating on the study of chemotherapy and heart failure. (photo by Neil Brake)

Julie Means-Powell, M.D., here with a patient at VICC, is collaborating on the study of chemotherapy and heart failure. (photo by Neil Brake)

Cardiologists from the Vanderbilt Heart & Vascular Institute are teaming up with oncologists from the Vanderbilt-Ingram Cancer Center to understand why and how some cancer therapies cause heart failure and what can be done to prevent it.

“Even though at least one of these chemotherapies has been around for 30 years, the exact molecular mechanisms aren't well understood, and there are not clearly accepted preventive strategies for adult patients,” said Douglas Sawyer, M.D., Ph.D., associate professor of Medicine, and director of the Cardiology Fellowship Program.

Through basic science as well as clinical studies, Sawyer and his colleagues are trying to understand the relationship that exists between cancer therapy and heart trouble. Sawyer estimates that about one in every 100 cancer patients treated with these cancer therapies goes on to develop congestive heart failure, and two out of every 100 heart transplant patients have heart failure related to cancer therapy.

“The prediction is that number will grow as rates of cancer go up compared to heart disease. In addition, there are new cancer therapies coming out that have effects on the heart, and those are not well understood,” Sawyer said. “It is probably more of a problem than randomized clinical trials in oncology show because patients in those studies are so well-selected.”

VICC patient Reva Judy was in sound cardiovascular shape when, at 68, she began treatment with herceptin for stage II breast cancer. Judy, who underwent chemotherapy and radiation prior to taking herceptin, said she knew there was a small percentage of people who had heart failure while on the drug.

“I took the risk,” she said.

She received four cycles of herceptin over two months. She began to experience breathing difficulty and was transported to Vanderbilt and placed in the care of Thomas DiSalvo, M.D., associate professor of Medicine and director of the Advanced Heart Failure Program. Judy's cardiac function had dropped to 10 percent. It was 65 percent before she began taking herceptin.

“I knew there was a small chance this could happen, but I never dreamed it would happen to me,” she said.

Her oncologist stopped herceptin therapy and with the help of heart medication, Judy's heart function has almost returned to normal. She has not had a recurrence of cancer.

How the heart repairs itself has been the focus of Sawyer's basic science research program for the last decade.

“From the time your heart is about 10 years old, the muscle cells in it have to last the rest of your life. The heart cells have to maintain and repair themselves,” he said. “Herceptin appears to interrupt those normal reparative mechanisms and allow for damage to take place. So in this case it's not because the cancer therapy is causing damage, but because it interrupts the normal maintenance system.

“It's like if you stopped changing the oil in your car, as opposed to putting something bad in your car.”

Sawyer and his colleagues hope to begin clinical trials soon to look for early markers of cardiac dysfunction in breast cancer patients receiving anthracyclines, the mainstay of treatment for a broad range of malignancies including breast cancer, leukemia, lymphoma and sarcoma.

They will also study patients receiving anthracyclines in combination with herceptin.

Sawyer thinks an early predictor of toxicity might be the suppression of a pool of cells that help replace and replenish endothelial cells called endothelial progenitor cells, which are needed for normal cardiac repair.

“It's a big enough problem that when a patient is given some of these drugs, particularly herceptin, heart failure is talked about as part of the informed consent,” Sawyer said. “Cardiac toxicity is the major consequence of, and limitation to, the use of these drugs. One of our goals is to understand the mechanisms better so we have a clearer understanding about what's going on with these people so we can predict early who is at risk — without waiting for that to develop.”

According to one of Reva Judy's oncologists, Julie Means-Powell, M.D., assistant professor of Medicine and a collaborator on the study, there is a population of patients who are at greater risk than the general population. It includes those who are over 65 or have uncontrolled hypertension.

“I get a baseline echocardiogram in patients who are receiving an anthracycline if they have some underlying risk for cardiovascular risk. If it indicates any underlying cardiomyopathy, then that is not the right drug to use,” she said. “We have drugs that work just as well as anthracyclines. I think it's important in some patients to do that baseline screening.”

The researchers will be using MRI to detect early changes in cardiac function and will be looking for decreased heart rate variability as a possible indicator of chemotherapy cardiac toxicity.

“We hope that heart failure may, at some point, be preventable when we can identify patients who are at increased risk of developing congestive heart failure and develop a treatment plan that gives them the best chance of breast cancer survival with the least risk of cardiotoxicity,” Means-Powell said. “Wouldn't that be nice if patients didn't have to deal with breast cancer and congestive heart failure?”

Working with Sawyer and Means-Powell on the studies are: Brent Anderson, M.D.; Cheri Silverstein, M.D.; Jeffrey Dendy, M.D.; Mark Lawson, M.D.; David Slosky, M.D.; Ingrid Mayer, M.D.; Ann-Marie Flores, Ph.D.; Pampee Young, M.D., Ph.D.; Charles Matthews, Ph.D.; and Satish Raj, M.D.