Cardiac Toxicity in Breast Cancer Survivors: Review of Potential Cardiac Problems Brian R.J
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Review Cardiac Toxicity in Breast Cancer Survivors: Review of Potential Cardiac Problems Brian R.J. Healey Bird1and Sandra M. Swain2 Abstract As breast cancer survival is increased by the diagnosis of earlier-stage disease and treatments improve, the side effects of cancer treatments, such as cardiotoxicity, remain clinically important. Although physicians have known for 30 years that anthracyclines cause acute and chronic cardio- toxicity, the cardiotoxic effects of radiation therapy, hormonal therapy (including tamoxifen and the aromatase inhibitors), and chemotherapy with taxanes and trastuzumab treatment have emerged more recently. This review examines the cardiac toxicity of adjuvant therapy, monitoring for early changes and existing guidelines for monitoring cardiac function in patients with breast cancer. As methods for detecting and treating breast cancer improve, fraction. Left ventricular dysfunction with normal LVEF is survival of breast cancer patients is increasing but the side commonly called diastolic dysfunction and when accompanied effects of adjuvant breast cancer therapy, including cardiotox- with dyspnea, fatigue, and fluid retention is known as diastolic icity, remain clinically important. A single breast cancer patient heart failure. may receive anthracyclines, trastuzumab, and radiation therapy Anthracyclines are believed to cause immediate damage to before commencing hormonal therapy. We summarize preclin- myocardial cells by free radical generation, although it may take ical and clinical data on incidence, monitoring, and manage- months or years for this damage to become clinically apparent. ment of both acute and chronic cardiac cardiotoxicity in breast Dexrazoxane is used to prevent free radical generation by cancer survivors. This information should assist clinicians in chelating intracellular iron. ACE inhibitors and h-blockers may advising their patients of the risks and benefits of adjuvant delay further expression and slow clinical progression to CHF treatments. Awareness of cardiac sequelae will help oncologists by limiting ventricular remodeling. These treatments may be of contribute to their ‘‘cured’’ patients’ life long well being during benefit when asymptomatic systolic dysfunction is detected. long term follow-up (1). LVEF decrease during adjuvant therapy may indicate cardiac damage and thus require dose reduction or discontinuation of Definition and Treatment of Chemotherapy- cardiotoxic medications and initiation of CHF management. Related Cardiac Dysfunction The American College of Cardiology recommends initiation of ACE inhibitors for patients with stage A heart failure and other Chronic heart failure (CHF) is a clinical syndrome caused by cardiovascular risk factors and the addition of h-blockers to cardiac dysfunction. (2) Left ventricular dysfunction may be patients with stage B heart failure (3) However, it is not current systolic, diastolic, or a combination of both. Asymptomatic practice to always commence these medications in patients who and symptomatic left ventricular dysfunction are managed have received cardiotoxic chemotherapy and are asymptomatic. with h-blockers and angiotensin-converting enzyme (ACE) We recommend following the ACC guidelines in patients with inhibitors. Patients who are fluid overloaded benefit from loop asymptomatic decline in LVEF, who should be seen by a diuretics. The percentage of blood expelled from the resting cardiologist to discuss treatment. There are no randomized left ventricle with each systolic contraction or left ventricular trials of ACE inhibitors post–standard adjuvant chemotherapy ejection fraction (LVEF) is a measure of systolic function. for breast cancer. However, when 114 patients treated with Normal LVEF is 50% or more. Left ventricular dysfunction high-dose chemotherapy who had at least one elevated serum occurs both in patients with decreased and normal ejection troponin I level value (>0.07 ng/mL sampled immediately after and 12, 24, 36, and 72 h after the end of chemotherapy infusion, repeated each cycle of chemotherapy) were random- ized to 1 year of prophylactic enalapril post chemotherapy Authors’Affiliations: 1Breast Cancer Section, Medical Oncology Branch, Center (n = 56) or no treatment (n = 58), the enalapril group did not for Cancer Research, National Cancer Institute, National Institutes of Health and have significant LVEF decline and suffered fewer cardiac events 2 Washington Cancer Institute, Washington Hospital Center,Washington, District of (1 of 56 versus 30 of 58, P < 0.001; ref. 4). Columbia Received 5/2/07; revised 8/8/07; accepted 10/9/07. Although several classification systems (3, 5) for heart failure Grant support: Intramural Research Program of the Center for Cancer Research, severity have been established (Table 1), a recent editorial NationalCancerInstitute,NIH. proposed a new system for chemotherapy-related cardiac Requests for reprints: Sandra M. Swain, Washington Cancer Institute, dysfunction (6). Type I is caused by anthracyclines, and type Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010. Phone: 202-877-8112; Fax: 202-877-8113; E-mail: [email protected]. II is caused by trastuzumab. Type I seems to have a greater F 2008 American Association for Cancer Research. tendency to result in cell death; type II has a greater tendency doi:10.1158/1078-0432.CCR-07-1033 to be reversible and results in cell dysfunction. However, a Clin Cancer Res 2008;14(1) January 1, 2008 14 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2008 American Association for Cancer Research. CardiacToxicity in Breast Cancer Survivors Table 1. Comparison of five different classifications of cardiotoxicity focusing on CHF Classification Grade I Grade II Grade III Grade IV system (reference) NYHA No limitation of activities Mild limitation of Marked limitation of activity Confined to bed or chair activity American College of Stage A; at high risk but Stage B; structural Stage C; Structural heart Stage D; Refractory CHF requiring Cardiology/American without structural heart disease disease with prior or specialized interventions Heart Association (3) heart disease or but without current symptoms symptoms signs or symptoms Clinical toxicity criteria, Asymptomatic decline Asymptomatic but CHF responsive to Severe or refractory CHF or version 2.0* of resting EF z10% resting EF less than treatment requiring intubation but <20% LLN for laboratory or of baseline value decline of resting EF of z20% of baseline value; <24% SF Common terminology Asymptomatic, resting Asymptomatic, Symptomatic CHF Refractory CHF or poorly criteria for adverse EF <60%-50%; resting EF responsive to controlled; EF <20%, events version 3.0c SF <30%-24% <50%-40%; intervention; EF intervention such as SF <30%-24% <40%-20%; ventricular assist device, SF <15% ventricular reduction surgery, or heart transplant indicated Cardiac review and Decline in LVEF of at least Global decrease Signs or symptoms Decline in LVEF of at least evaluation 10% to <55% without in LVEF of CHF 5% to <55% with committee (5) signs or symptoms signs or symptoms of CHF of CHF Abbreviations: EF, ejection fraction; LLN, lower limit of normal; SF, shortening fraction. *Adverse events are cardiovascular (general) and cardiac left ventricular function; http://ctep.cancer.gov.forms/CTCv20_4-30-992.pdf. cAdverse events are cardiac general and left ventricular systolic dysfunction; http://ctep.cancer.gov/forms/CTCAEv3.pdf. recent retrospective analysis of breast cancer patients with arrhythmias (13); delayed effects include CHF, which may doxorubicin-induced CHF found that 87% improved with manifest many years later (14). Systolic dysfunction is 6% cardiac medications and that combined treatment with h- higher in patients treated with adjuvant doxorubicin (8% of blockers, ACE inhibitors seemed superior to ACE inhibitors patients) than with cyclophosphamide, methotrexate, and alone (7). Retrospective reviews had initially reported mortality fluorouracil (CMF; 2%; ref. 15). After a cumulative doxorubicin rates of 43% to 59% in patients who developed CHF after dose of 240 mg/m2, asymptomatic decline in LVEF is detected anthracycline treatment (8). Retrospective analyses of patients by prospective monitoring (16). After a cumulative doxorubicin treated with trastuzumab have shown that patients who dose of 400 mg/m2, CHF incidence was estimated at 2% develop CHF improve with standard medical therapy for heart initially (8), but more recently, it has been estimated at 5.1% failure (ACE inhibitors and the Food and Drug Administra- (11). Doxorubicin toxicity is exponentially dose-dependent tion–approved h-blockers carvedilol or metoprolol; ref. 9) In a and increases dramatically when cumulative doses exceed recent study of 38 patients (10), trastuzumab cardiotoxicity 500 mg/m2. Among patients ages 65 years or older, a higher resolved on discontinuation of treatment with or without CHF risk was associated with anthracycline chemotherapy than cardiac medications and did not always recur on rechallenge. with CMF chemotherapy or no chemotherapy (17). Anthracy- Whereas this system has not been generally accepted and may clines are less cardiotoxic when given by infusion than as a not fully acknowledge the clinical reversibility of anthracycline- bolus (18). Dose-dense regimens given weekly or every 2 weeks induced chemotherapy-related cardiac dysfunction, it does were not associated with excess cardiotoxicity (19), although highlight