Addressing the Cardiac Complications of Cancer Treatment
By Stephanie Deming
Patients with cancer are surviving longer than ever after treatment, and new targeted therapy agents are being introduced into the clinic with increasing frequency. These advances are cause for optimism, but they have also led to an increased incidence of cardiac complications of cancer therapy.
As with any complication of cancer therapy, clinicians seek to avoid cardiac complications if possible and to detect and treat any complications early to minimize their impact on patients’ lives. Researchers at The University of Texas MD Anderson Cancer Center are working to develop improved methods for early detection of heart problems and for prediction of which patients are at highest risk for cardiac complications of anticancer therapy.
Heart failure: the most dreaded cardiac complication
According to Edward Yeh, M.D., chair of and a professor in the Department of Cardiology at MD Anderson, there are six major types of cardiovascular complications of cancer therapy:
Hypertension, bradycardia, and QT interval prolongation can be easily managed, but the other complications are more challenging to treat. Of all the cardiac complications of cancer therapy, Dr. Yeh said, “the most dreaded complication is left ventricular dysfunction, or, in its more serious form, heart failure.”
Heart failure often occurs without obvious clinical signs. Heart failure can be acute, with onset immediately after the first or second course of anticancer therapy, or it may occur during treatment or later—sometimes 10 or even 20 years after completion of therapy.
Many anticancer drugs can cause left ventricular dysfunction, but the most problematic drugs are the anthracyclines, particularly doxorubicin. Anthracyclines have been in use for more than 40 years, and they are the most common cause of cardiac complications in cancer patients. Anthracyclines cause heart failure by directly damaging the heart muscle, and the risk of heart failure increases as the cumulative dose increases.
Trastuzumab, a monoclonal anti body that targets the HER2 cell surface receptor, and some other targeted therapies—including bevacizumab, dasatinib, imatinib mesylate, and sunitinib—may also cause left ventricular dysfunction.
According to Dr. Yeh, trastuzumab by itself does not usually cause heart problems. However, the combination of trastuzumab and doxorubicin can cause heart problems owing to a phenomenon called sequential stress. “If you already have underlying cardiac damage from the doxorubicin, and then you impose another stress in the form of trastuzumab, that can cause a problem,” he said. “The reason is that trastuzumab binds to a cardiac surface receptor called HER2 that is important for cardiac cells to survive. If you have damaged cardiomyocytes from doxorubicin treatment and then you block those prosurvival signals with trastuzumab, you can get into big trouble.”
The problem with sunitinib and some other targeted therapies is that the cancer-causing pathways they block may also be important for the survival of heart cells. “Sunitinib kills cancer cells by blocking the formation of blood vessels,” Dr. Yeh said. “So this drug can deprive cancer cells of their blood supply, but it also may cause harm to the heart.” A recent study also found that sunitinib blocks the heart cells’ response to stress. This is important because another possible side effect of sunitinib is hypertension.
Minimizing heart failure risk
Given the potential for heart failure due to anticancer therapy, oncologists generally screen patients before and during potentially cardiotoxic therapy to make sure that the heart is healthy enough to withstand treatment. The pretreatment screening includes a history to determine whether the patient has risk factors for therapy-induced heart damage, such as high blood pressure, high cholesterol, diabetes mellitus, or a history of smoking, heart disease, anthracycline therapy, or radiation therapy that included the left side of the chest. Echocardiography is performed to determine the left ventricular ejection fraction.
On the basis of this screening, the oncologist decides what type of therapy should be avoided, and this information is considered when deciding whether the patient is eligible to participate in a clinical trial or should receive the standard of care. “We have to personalize therapy,” said Apostolia M. Tsimberidou, M.D., Ph.D., an associate professor in the Department of Investigational Cancer Therapeutics, which conducts phase I clinical trials. “The type of therapy has to be carefully selected on the basis of the tumor characteristics and the patient’s history and characteristics, including risk factors for heart disease.” Patients who have had a myocardial infarction within the preceding 6 months may be able to receive therapy with agents not associated with cardiotoxicity; however, these patients are usually excluded from participation in clinical trials. Most other patients are eligible to participate in clinical trials with anticancer therapy.
“Patients with a history of heart disease should avoid the use of potentially cardiotoxic drugs,” Dr. Tsimberidou said. “Patients who are treated with potentially cardiotoxic drugs—especially anti–vascular endothelial growth factor agents such as bevacizumab, sorafenib, and particularly sunitinib—should be followed closely with blood pressure monitoring and echocardiography.” More recently, levels of troponin I, a marker with almost absolute cardiac specificity and high sensitivity to cardiac damage, together with B-type natriuretic peptide have been used to monitor patients treated with potentially cardiotoxic drugs.
Dr. Tsimberidou added that because of the potential development of heart failure in some patients treated with sunitinib, physicians should suspect this complication when these patients develop fatigue or other symptoms suggesting heart failure. In such cases, physicians should withhold sunitinib until completion of a cardiac workup. If heart failure is proven, sunitinib should be discontinued. “This applies to patients participating in clinical trials and those treated in the community,” she said.
However, with trastuzumab, if screening shows a drop in the left ventricular ejection fraction, the next steps in therapeutic management are to stop trastuzumab; give a drug or drugs used to treat heart failure, such as an angiotensin-converting enzyme inhibitor or the combination of an angio tensin II receptor blocker and a beta-blocker; wait until heart function improves; and then consider starting trastuzumab again.
“Heart failure is heart failure, whether the damage results from a heart attack or from anticancer therapy,” said Dr. Yeh. In general, he said, the drugs used to treat heart failure in patients without cancer work equally well in patients with a drop in left ventricular ejection fraction due to anticancer therapy. The catch, though, is that therapy-induced heart failure has to be detected fairly early (i.e., within a couple of months) for heart failure treatment to be effective. In addition, some kinds of anticancer therapy–induced heart failure, such as heart failure caused by doxorubicin, generally are not reversible.
If the original anticancer therapy cannot be resumed, a switch to a non-cardiotoxic agent may be possible. Treating patients with cancer and heart disease is a balancing act, said Dr. Tsimberidou. “We should always think about the cost-benefit ratio,” she said. “If a patient is at high risk of dying from heart disease and the patient’s cancer is in remission, the physician should optimize the patient’s risk factors for heart disease and his or her cardiovascular medication, hold anticancer therapy, and monitor the patient’s cancer with imaging studies and tumor markers as applicable.”
Another issue that should be considered is how long treatment for anticancer therapy–induced heart failure needs to be continued. If a patient had heart failure, was successfully treated for that, resumed anticancer therapy (e.g., with trastuzumab), and is now finished with anticancer therapy, can the heart failure therapy be stopped? “The short answer to that is no,” Dr. Yeh said. “You should probably continue the heart failure therapy for some time after the completion of anticancer therapy, although that period has not been defined.”
Better screening on the horizon
Unfortunately, according to Dr. Yeh, ejection fraction as determined by either echocardiography or nuclear imaging is an imperfect measurement because it does not reveal abnormal left ventricular function until after substantial cardiac damage has occurred. The Department of Cardiology at MD Anderson has been investigating a number of alternatives that may allow earlier detection of cardiac damage from anticancer therapy and earlier intervention to limit or reverse this damage.
One alternative already in use is to measure the amount of the cardiac enzyme troponin I in the blood. Troponin I is released by damaged heart muscle cells, and measurement of troponin I is used in the diagnosis and monitoring of patients with myocardial infarctions. In patients with cardiac damage due to anticancer therapy, the level of troponin I increases before the ejection fraction decreases. “This test is not in wide use right now,” Dr. Yeh said, “but I think it has a lot of potential.”
Another potentially promising approach uses specialized echocardiography techniques to determine left ventricular strain, which is a measurement of how much each segment of the heart muscle deforms with each contraction. Strain usually becomes abnormal before left ventricular ejection fraction does. “We are routinely doing this now in our lab, and we are the only cancer center that does it,” said Dr. Yeh. “We are doing a larger-scale study to prove that this is indeed useful in our patients.” Dr. Yeh and his group are also pursuing “a very clear lead” indicating that it may be possible to identify through a blood test patients who have a genetic predisposition to cardiac damage caused by certain types of anticancer therapy.
As anticancer therapy becomes more personalized, the assessment and treatment of cardiac complications should also become personalized. “We have created a new field called onco-cardiology,” Dr. Yeh said. “Our goal is to foment a close collaboration between cardiologists and oncologists so that our patients will have healthy hearts to enjoy their new lives.”
For more information, contact Dr. Edward T.H. Yeh at 713-792-6242 or Dr. Apostolia M. Tsimberidou at 713-792-4259.
Other articles in OncoLog, August 2011 issue: