Targeting Cancer and Monitoring the Heart
A surprise no one wants during the final stage of a clinical trial is to learn that a cancer drug can cause heart failure. But that is exactly what happened with the breast cancer drug trastuzumab (Herceptin).
The preclinical work and early phase I trials did not turn up any signs of cardiac side effects. Yet, as so often happens, a rare toxicity - in this case congestive heart failure - was discovered when more people took the drug.
Heart failure was first reported in the late 1990s during the definitive trials involving women with metastatic breast cancer, and it occurred most often in women also taking doxorubicin. All subsequent trials have included careful cardiac monitoring.
Today, the risks are measured against the enormous potential benefits. Trastuzumab has helped many women with HER2-positive breast cancer survive their disease and, when used in the adjuvant setting, it reduces the risk of recurrence by half.
"We have to be very cautious in administering the drug, and we have to be very cautious in not administering it, because the benefits for some patients are astonishing," says Dr. Daniel Hayes, director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center.
This assessment may apply to other "targeted" cancer therapies as well. Drugs such as bevacizumab (Avastin), sunitinib (Sutent), imatinib (Gleevec), and dasatinib (Sprycel) are effective but may slightly increase the risk of heart failure, and this has raised concerns.
In articles and at scientific meetings, oncologists and cardiologists have called for rigorous evaluations of cardiac side effects early in drug development, and for careful monitoring of cardiac health throughout clinical testing.
"We need to be vigilant for toxicities, and any emerging toxicities need to be balanced with the benefit that's seen for these drugs," says Dr. Walter Stadler of the University of Chicago, who treats prostate and kidney cancers.
The emergence of targeted drugs, he suggests, may force clinicians to relearn treatments for a new set of toxicities, such as hypertension, that previously had not been relevant.
What has changed, of course, are the targets. Unlike traditional chemotherapy drugs, these therapies mainly inhibit proteins involved in angiogenesis - the growth of blood vessels - and proteins that transmit signals within cells called tyrosine kinases.
Virtually all of the proteins are present in both normal cells and cancer cells.
The genetic similarity between normal cells and cancer cells all but guarantees that interventions will have some effects in normal tissues, according to Dr. Gabriel Hortobagyi, who chairs the Department of Breast Medical Oncology at the University of Texas M.D. Anderson Cancer Center.
"None of these targeted agents has a single and absolutely specific activity, and that clarification needs to go out to the public and to our colleagues in medicine," says Dr. Hortobagyi, who is also president of the American Society of Clinical Oncology (ASCO).
"We have been talking about these drugs as though they have no toxicities at all," he continues. "In this exciting time of targeted therapies, we need to be clear that we still don't have free lunches."
People in the field are aware of the problem, and most clinical trials are looking for signs of heart failure, notes Dr. Sandra M. Swain, an investigator in NCI's Medical Oncology Branch who is planning breast cancer clinical trials.
Candidates for the drugs are routinely screened for health conditions that increase the risk of cardiac toxicities, such as diabetes and high blood pressure.
Most cases of heart failure caused by trastuzumab are treatable, but the long-term consequences for patients who experience heart failure are not known. Nor is it known how long patients treated for heart failure will need to take heart medications.
Another common question is whether all tyrosine kinase inhibitors have cardiac toxicities. No one knows the answer, but some experts say that each drug has different targets and will need to be evaluated individually.
"We have to do the studies to understand targeted drugs better so we can treat patients in a safe way," says Dr. Arthur Feldman, a cardiologist and chair of the Department of Medicine at Jefferson Medical College. "Right now we don't have the data."
To get answers, oncologists need to reach out "pretty aggressively" to cardiologists and involve them early in clinical trials as a way to ensure that the right kinds of cardiac evaluations are done in these patients, he says.
In this spirit of cooperation, cardiologists and oncologists recently met in Houston to discuss ways to eliminate cardiovascular disease as a barrier to treatment for cancer. Chemotherapy was the focus, but targeted drugs were discussed.
"We think the future looks really bright for these drugs, but the way we deliver them is going to require teamwork," says co-organizer Dr. Jean-Bernard Durand of the Cardiomyopathy Service at M.D. Anderson.
"Good medical management with drugs already approved by the FDA for heart failure may solve a number of these issues," he adds.
The meeting was the first initiative of CONQUER (Cardiology Oncology International Quest to Educate and Research Heart Failure). The presidents of ASCO and the Heart Failure Society of America both participated.
"The issues of efficacy and toxicity go hand in hand," says Dr. Hortobagyi. "The best we can do is to assume that toxicities are going to occur and take all of the proper precautions without slowing down progress."
By Edward R. Winstead