Clinical and Health Affairs
Cardiac Complications from Cancer Therapy
By Anne Hudson Blaes, M.D., M.S.
In 2005, more than 10 million people in the United States were cancer survivors, and that number is expected to grow as therapies for cancer improve and the population ages. Although survival is something to be celebrated, it can be accompanied by a number of health problems secondary to the initial disease and its treatment. Cardiovascular problems are emerging as a particular concern among the survivor population. This article reviews what is known about the kinds and rates of cardiovascular complications common to cancer survivors, the treatments that caused them, and the risk factors for them. It also presents guidance for primary care providers caring for survivors who may be at risk of cardiovascular complications.
Over the last four decades, the number of cancer survivors has increased dramatically, with breast, colorectal, and prostate cancer survivors being the most common. In 2005, the Institute of Medicine reported there were more than 10 million cancer survivors in the United States (roughly one in 30 individuals).1 Because of earlier detection, new drugs and treatments, combined therapies, prolonged adjuvant and/or maintenance therapies, and the prevention of second malignancies, and because the population is aging, the number of cancer survivors is expected to increase sharply during the next 25 years.
Despite the improvement in cancer treatments and outcomes, individual cancer survivors are not necessarily healthy. In a population-based study that compared the health of cancer survivors with that of age-matched individuals who had not had cancer, Yabroff et al. found that 31% of cancer survivors (n=1,817) reported their health as fair or poor as compared with only 18% of the controls (n=5,465).2 The cancer survivors also had a greater number of comorbidities. In addition, 11.4% of the cancer survivors as compared with 6.5% of the control subjects (P<0.001) needed help with instrumental activities of daily living, and 4.9% compared with 3.0% (P=0.003) needed help with activities of daily living.
In recent years, it has become evident to the medical community that many of these patients are at risk for long-term consequences of their cancer therapy. Hodgkin lymphoma survivors, for example, suffer from second malignancies, cardiovascular disease, pulmonary disease, hypothyroidism, and sexual and gonadal dysfunction, depending on the therapies they received.
Cardiovascular problems are emerging as a particular concern. Two-thirds of the more than 270,000 young adults who have survived childhood cancers in the United States have been exposed to a cardiotoxic agent. The standard mortality ratio of cardiac death in these survivors is 7.0 as compared with that in people of similar age in the general population.3 More than 2 million women were treated for breast cancer between 1996 and 2006 and may have been exposed to cardiotoxic chemotherapy agents.4 According to analyses by Doyle et al., the odds ratio for developing cardiomyopathy was 3.51 (95% CI, 2.63-4.69) for women older than 65 years of age who were treated for breast cancer with chemotherapy between 1992 and 1999, compared with women who did not receive chemotherapy. The overall incidence of cardiomyopathy at five years for those who received chemotherapy was 10% as compared with 4% for those who did not.4
Cardiovascular Complications from Chemotherapy
Several types of chemotherapy are known to cause cardiac complications (Table 1). Cisplatin can cause ischemia, heart failure, and hypertension.5 Long-term complications associated with cisplatin are not entirely known, although testicular cancer survivors who receive cisplatin, bleomycin, and etoposide, and/or radiation are known to have long-term elevated rates of cardiovascular disease as compared with individuals who have not had chemotherapy and/or radiation (relative risks 2.4 to 2.59).6 Cyclophosphamide and paclitaxel have been associated with congestive heart failure (CHF) on rare occasions.5 Antimetabolites such as 5-FU and capecitabine have been associated with ischemic cardiac events.5 Additionally, as more biologic agents and monoclonal antibodies such as trastuzumab, sorafenib, and sunitinib have become available, concern that these drugs may affect the myocardium and lead to heart failure has been increasing.
Most of the literature on cardiac toxicity from chemotherapy has focused on the anthracyclines. Doxorubicin is an anthracycline chemotherapeutic agent that has been used for breast cancer, non-Hodgkin lymphoma, and Hodgkin lymphoma for the last 25 years. Anthracyclines are also often part of the chemotherapy regimen for sarcomas, leukemias, and many other childhood cancers. Although the immediate side effects of doxorubicin treatment such as myelosuppression, nausea, and vomiting are reversible or manageable, doxorubicin has been associated with dose-related cardiotoxicity that is not reversible. This dose-related cardiotoxicity was first described by Lefrak et al. in 1973.7 Since then, symptomatic CHF has been known to occur in 3% to 4% of patients at doxorubicin cumulative doses of 400 mg/m2 to 500 mg/m2, in up to 18% of patients at 550 mg/m2, and in more than 30% of patients at doses greater than or equal to 600 mg/m2. Asymptomatic decrements in ejection fraction occur in up to 25% of patients treated with moderate doses of doxorubicin (ie, 240mg/m2 to 400 mg/m2), typical doses for treating breast cancer or lymphoma. In addition to receiving larger doses of doxorubicin, risk factors for these complications include being 65 years of age or older, being 18 years of age or younger, prior treatment with radiation, having a history of hypertension, and being female (Table 2).
Doxorubicin chemotherapy can induce cardiomyopathy, with signs and symptoms of CHF developing immediately or later on. Some patients may develop pericarditis/myocarditis during the first 24 hours following administration or show signs and symptoms of heart failure (eg, edema, shortness of breath, dyspnea on exertion, and change in exercise tolerance). If this is the case, cardiac myocyte damage has occurred and may lead to long-term cardiac dysfunction and heart failure. Other patients may develop cardiomyopathy several years after therapy. In these late-onset patients, the signs and symptoms can be more subtle, with changes in exercise tolerance and dyspnea on exertion being commonly reported; however, the typical signs and symptoms of CHF may also be seen.
Although rare, patients have been known to have atrioventricular block, bradycardia, bundle branch block, extrasystoles (atrial or ventricular), sinus tachycardia, supraventricular tachycardia, tachyarrhythmia, and ventricular tachycardia while receiving doxorubicin.
Patients who have also received radiation therapy may be at risk for accelerated coronary artery disease and valvular dysfunction. In a study of 1,474 Hodgkin lymphoma survivors (median age at the start of treatment: 25.7 years) treated between 1965 and 1995 in the Netherlands, Aleman et al. found the risk of heart disease, myocardial infarction, and valvular disease was significantly higher in those who received radiation as compared with those who did not. In addition, the risk of CHF also was subsequently found to be higher in those who received treatment with both mediastinal radiation and anthracycline-based chemotherapy.8,9
Mechanism of Injury
Radiation is thought to cause cellular injury by generating reactive oxygen species, to which the endothelium is particularly sensitive, leading to endothelial damage and fibrosis. In a series of autopsies on patients with Hodgkin lymphoma treated with mantle radiation, fibrosis was visualized in the epicardium or pericardium in 90% of cases, endocardium (70%), and myocardium (60%). Valvular fibrosis was seen in about half of the cases with the aortic and mitral valve being most commonly affected. Additionally, the coronary arteries were thought to have medial and adventitial scarring and accelerated atherosclerosis.
The exact mechanism of doxorubicin-induced cardiac toxicity is unknown. It is hypothesized that the formation of free radicals may cause direct myocardial injury. Other mechanisms thought to play a role include the inhibition of nucleic acids and protein synthesis; inhibition of sarcoplasmic reticulum Ca2+ release; irreversible reductions in mitochondrial Ca2+ loading and ATP content; impaired membrane binding, assembly, and activity of mitochondrial creatine kinase; peroxinitrite-dependent inactivation of mitochondrial creatine kinase or activation of metalloproteinases; and the inhibition of membrane-associated calcium-independent phospholipase A2. Histologically, there is evidence of fibrosis, scattered cardiomyocytes with vacuolar degeneration, and, on occasion, foci of necrotic cardiomyocytes.
For some of the biologic agents such as trastuzumab, no ultrastructural changes are visible. Instead, it is thought the mechanism that induces heart failure is blockade of the ErB2 pathway. In this case, heart failure is often reversible when the drug is stopped. For other agents such as imatinib, it is believed that changes within the mitochondria lead to vacuolar degeneration of the sarcoplasmic reticulum. It is not clear whether these complications are reversible.
Prevention of Cardiac Complications from Chemotherapy
Increased knowledge about the cardiotoxicity of various chemotherapeutic agents is prompting researchers to explore alternative chemotherapies, look for ways to identify who is most at risk for cardiac effects, and find ways to prevent cardiovascular damage.
■ Avoiding Anthracyclines
Because of the cardiac toxicity of doxorubicin, investigators have suggested not using anthracycline chemotherapy in the adjuvant treatment of early-stage breast cancer. In 2009, Jones et al. published a study in which 1,016 patients with early-stage disease were treated with combination chemotherapy using either an anthracycline or a taxane.10 In this study, patients were randomized to receive either four cycles of standard doxorubicin and cyclophosphamide (AC) or docetaxel/cyclophosphamide (TC) every three weeks for a total of four cycles. At a median follow up of seven years, four cycles of TC were found to be superior to four cycles of AC with regard to disease-free survival and overall survival in both younger and older patients. A follow-up study of TC versus docetaxel/doxorubicin/cyclophophamide (TAC) is exploring whether anthracycline may still be a necessary part of chemotherapy. In addition, the Breast Cancer International Research Group is conducting a study of women with HER2-positive disease who have been randomized to a nonanthracycline-containing taxane-based regimen (docetaxel, trastuzumab, and carboplatin) or to one of two anthracycline-taxane combinations. Although the second interim analysis suggested that the anthracycline-containing regimens demonstrated an unfavorable risk/benefit ratio, the more recent 2009 interim analysis did not support this conclusion. At a median follow up of 65 months, there were 20% more recurrences and deaths with the nonanthracycline-containing taxane-based regimen as compared with the anthracycline-containing regimen. The greatest benefit was demonstrated in those with early-stage, node-negative disease. As a result, it is felt that the anthracyclines still need to play a role in the treatment of early-stage breast cancer.
In other diseases such as non-Hodgkin lymphoma, for which doxorubicin remains part of the standard chemotherapy regimen (rituximab, cyclophosphamide, doxorubicin, vincrinstine and prednisone), the Cancer and Leukemia Group B is conducting national studies to assess whether agents such as etoposide may be used in combination with lower doses of doxorubicin. The results of these studies are not yet available. Ongoing studies are currently attempting to determine whether less chemotherapy or less radiation can be given to Hodgkin lymphoma patients with the same long-term disease-free results.
■ Identifying High-Risk Patients
Current practice for evaluation of left ventricular systolic function is using ejection fraction (LVEF) by echocardiography or nuclear ventriculography to detect development of cardiomyopathy. But these methods are insensitive and result in unreliable markers of early doxorubicin injury. In some institutions, MRI is being proposed as a means for detecting early cardiac damage in high-risk patients. This remains under investigation. Investigators also are studying whether biomarkers such as troponin I and b-natriuretic peptide (BNP) help predict who will develop cardiac complications from anthracycline chemotherapy. Myocardial cell death is a major structural characteristic of CHF. However, the clinical features of CHF are sometimes absent even in the presence of extensive structural and functional changes in the myocardium. Elevations in cardiac troponin have been shown to correlate with the severity of CHF, and higher levels may identify patients with increased risk of subsequent cardiac events. Cardiac troponin has also been shown to be elevated in some patients after the administration of doxorubicin, even before any decrement in cardiac ejection fraction has occurred.
B-type natriuretic peptide is a polypeptide hormone mainly synthesized and released into circulation from the ventricular myocardium. The main trigger for its manufacture and release is elevation of ventricular end-diastolic pressure and volume. B-type natriuretic peptide has proven valuable as a marker of disease severity and in predicting future cardiac events in patients with CHF. It has also been found to be elevated in some lymphoma patients after they receive doxorubicin. As a result, troponins and BNP may, therefore, identify patients with ongoing myocardial injury and cell death that may not be detected by conventional diagnostic procedures. Further research is ongoing.
■ Administering Protective Agents
The use of angiotensin-converting enzyme inhibitors (ACE-I) in patients who have had an elevation in troponin-I after chemotherapy appears protective. In one study by Cardinale et al., 114 patients who received high-dose chemotherapy and showed a rise in troponin-I following treatment were randomized to receive 20 mg of enalapril or placebo daily for one year.11 Twelve months after therapy, the patients randomized to enalapril had a preserved left ventricular ejection fraction. In contrast, the patients randomized to the placebo group had a decrease in ejection fraction, from 62.8% to 48.3% (P<0.001). A subsequent study of 40 patients with untreated non-Hodgkin lymphoma who were scheduled to undergo standard anthracycline-based chemotherapy were randomized to a daily regimen of 80 mg of the angiotensin receptor blocker valsartan or placebo. Valsartan prevented transient elevations in LV end diastolic diameter on echo, QTc interval changes, and changes in BNP levels that were seen in the control group.
The use of beta-blockers to protect the heart has also been studied. Kalay et al. randomized 25 patients with either breast cancer or non-Hodgkin lymphoma to 12.5 mg a day of carvedilol or placebo during the course of their chemotherapy.12 Baseline ejection fractions were 70.5% versus 68.9%, respectively. After chemotherapy, the placebo group’s ejection fraction declined to 52.3% as compared with that of the treatment group, which fell to 69.7% (P< 0.001). Carvedilol is known to have some antioxidant properties, which may explain its role in protecting against cardiac toxicity from doxorubicin chemotherapy.
Other antioxidants such as vitamin E, probucol, and gingko biloba have been suggested in the literature as possibly protecting against doxorubicin cardiac toxicity. Most of the studies of these antioxidants have been done in animal models. It is unclear whether the use of any of these medications in combination with chemotherapy will prevent cardiac complications in humans.
■ Employing Other Strategies
Other strategies being tested include instituting alternate dosing schedules of chemotherapy, liposomal formulations of the drug, and giving cardioprotectant medications such as dexrazoxane concurrently with doxorubicin. Many of these have been tried without success or with concern that tumor outcomes may be compromised. In patients with metastatic breast cancer and in those with sarcoma, the liposomal preparation of doxorubicin may actually decrease the incidence of cardiac complications while achieving the same therapeutic outcomes as nonliposomal formulations.
Screening for Long-Term Cardiac Complications
Few randomized studies have been done on how and when to screen cancer survivors for cardiac complications. Most of the data are based on observational studies. In managing adult cancer survivors, clinicians can either follow the guidelines for pediatric cancer survivors (Table 3), perform random testing based on observation and bias, or wait for symptoms to develop. Given that we know the treatment of asymptomatic and symptomatic cardiovascular disease has an impact on its natural history, I suggest following treatment-based guidelines. There are specific guidelines for Hodgkin lymphoma survivors (www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf) and for childhood cancer survivors (www.childrensoncologygroup.org/disc/le/). For patients who do not fall into one of these categories, it has been suggested that physicians follow the pediatric guidelines, modifying them as appropriate for patients.
Patients with any of the following characteristics are considered to be at elevated risk for developing cardiac complications from their cancer therapy: Having been treated with doxorubicin >300 mg/m2, epirubicin >600 mg/m2, mitoxantrone >100 mg/m2, combined mediastinal radiation and anthracyclines; Having a tumor close to the heart; Having radiation treatment prior to 1970; Receiving total radiation >35 Gy; Having a daily dose of radiation fraction >2 Gy/day; Being younger than 18 or older than 65 years of age at the time of treatment; Having pre-existing cardiac risk factors (hypertension or coronary artery disease); Being pregnant or contemplating pregnancy after therapy with any anthracycline or mediastinal irradiation; Participating in extreme athletics; and Living more than 10 years since completing therapy.
Patients with one or more of these risk factors should have an echocardiogram or radionucleotide angiography five years after completing therapy. If the results are normal and the patient is asymptomatic, testing should be repeated every five years. Patients with subtle changes should either be referred to a specialist or monitored more frequently. For patients who have received chest radiation, a screening EKG and echocardiogram are recommended five years after the completion of therapy. These can be repeated at five-year intervals if the results are normal. Patients should also be counseled regarding lipids, blood pressure, diabetes, tobacco use, obesity, and exercise and be encouraged to change their lifestyle, if necessary.13
Given the increasing number of cancer survivors and the potential for long-term cardiac complications after chemotherapy, particularly in some subsets of survivors, it is imperative that oncologists, primary care physicians, and patients be aware of and discuss these risks. Medical oncologists should give patients and their primary care physicians a treatment summary outlining the specific drugs and treatments such as radiation that these individuals have been exposed to. In addition, primary care physicians need to become aware of the potential long-term complications of cancer and its treatment and assist with aggressive risk-factor and lifestyle management as well as screening, where appropriate. MM
Anne Hudson Blaes is an assistant professor in the Division of Hematology, Oncology, and Transplantation at the University of Minnesota Medical Center. She also helps run the University’s Long-Term Follow-Up Clinic for cancer survivors.
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