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 cardiotoxicity, 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, survival of breast cancer patients is increasing but the side effects of adjuvant breast cancer therapy, including cardiotoxicity, remain clinically important. A single breast cancer patient may receive anthracyclines, trastuzumab, and radiation therapy before commencing hormonal therapy. We summarize preclinical and clinical data on incidence, monitoring, and management of both acute and chronic cardiac cardiotoxicity in breast cancer survivors. This information should assist clinicians in advising their patients of the risks and benefits of adjuvant treatments. Awareness of cardiac sequelae will help oncologists contribute to their “cured” patients' life long well being during long term follow-up (1).

Chronic heart failure (CHF) is a clinical syndrome caused by cardiac dysfunction. (2) Left ventricular dysfunction may be systolic, diastolic, or a combination of both. Asymptomatic and symptomatic left ventricular dysfunction are managed with β-blockers and angiotensin-converting enzyme (ACE) inhibitors. Patients who are fluid overloaded benefit from loop diuretics. The percentage of blood expelled from the resting left ventricle with each systolic contraction or left ventricular ejection fraction (LVEF) is a measure of systolic function. Normal LVEF is 50% or more. Left ventricular dysfunction occurs both in patients with decreased and normal ejection fraction. Left ventricular dysfunction with normal LVEF is commonly called diastolic dysfunction and when accompanied with dyspnea, fatigue, and fluid retention is known as diastolic heart failure.

Anthracyclines are believed to cause immediate damage to myocardial cells by free radical generation, although it may take months or years for this damage to become clinically apparent. Dexrazoxane is used to prevent free radical generation by chelating intracellular iron. ACE inhibitors and β-blockers may delay further expression and slow clinical progression to CHF by limiting ventricular remodeling. These treatments may be of benefit when asymptomatic systolic dysfunction is detected. LVEF decrease during adjuvant therapy may indicate cardiac damage and thus require dose reduction or discontinuation of cardiotoxic medications and initiation of CHF management. The American College of Cardiology recommends initiation of ACE inhibitors for patients with stage A heart failure and other cardiovascular risk factors and the addition of β-blockers to patients with stage B heart failure (3) However, it is not current practice to always commence these medications in patients who have received cardiotoxic chemotherapy and are asymptomatic. We recommend following the ACC guidelines in patients with asymptomatic decline in LVEF, who should be seen by a cardiologist to discuss treatment. There are no randomized trials of ACE inhibitors post–standard adjuvant chemotherapy for breast cancer. However, when 114 patients treated with high-dose chemotherapy who had at least one elevated serum 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 randomized to 1 year of prophylactic enalapril post chemotherapy (n = 56) or no treatment (n = 58), the enalapril group did not have significant LVEF decline and suffered fewer cardiac events (1 of 56 versus 30 of 58, P < 0.001; ref. 4).

Although several classification systems (3, 5) for heart failure severity have been established (Table 1), a recent editorial proposed a new system for chemotherapy-related cardiac dysfunction (6). Type I is caused by anthracyclines, and type II is caused by trastuzumab. Type I seems to have a greater tendency to result in cell death; type II has a greater tendency to be reversible and results in cell dysfunction. However, a recent retrospective analysis of breast cancer patients with doxorubicin-induced CHF found that 87% improved with cardiac medications and that combined treatment with β-blockers, ACE inhibitors seemed superior to ACE inhibitors alone (7). Retrospective reviews had initially reported mortality rates of 43% to 59% in patients who developed CHF after anthracycline treatment (8). Retrospective analyses of patients treated with trastuzumab have shown that patients who develop CHF improve with standard medical therapy for heart failure (ACE inhibitors and the Food and Drug Administration–approved β-blockers carvedilol or metoprolol; ref. 9) In a recent study of 38 patients (10), trastuzumab cardiotoxicity resolved on discontinuation of treatment with or without cardiac medications and did not always recur on rechallenge. Whereas this system has not been generally accepted and may not fully acknowledge the clinical reversibility of anthracycline-induced chemotherapy-related cardiac dysfunction, it does highlight differences between anthracycline-induced and trastuzumab-induced cardiotoxicity.

Table 1.

Comparison of five different classifications of cardiotoxicity focusing on CHF

Classification system (reference)Grade IGrade IIGrade IIIGrade IV
NYHA No limitation of activities Mild limitation of activity Marked limitation of activity Confined to bed or chair 
American College of Cardiology/American Heart Association (3) Stage A; at high risk but without structural heart disease or symptoms Stage B; structural heart disease but without signs or symptoms Stage C; Structural heart disease with prior or current symptoms Stage D; Refractory CHF requiring specialized interventions 
Clinical toxicity criteria, version 2.0* Asymptomatic decline of resting EF ≥10% but <20% of baseline value Asymptomatic but resting EF less than LLN for laboratory or decline of resting EF of ≥20% of baseline value; <24% SF CHF responsive to treatment Severe or refractory CHF or requiring intubation 
Common terminology criteria for adverse events version 3.0 Asymptomatic, resting EF <60%-50%; SF <30%-24% Asymptomatic, resting EF <50%-40%; SF <30%-24% Symptomatic CHF responsive to intervention; EF <40%-20%; SF <15% Refractory CHF or poorly controlled; EF <20%, intervention such as ventricular assist device, ventricular reduction surgery, or heart transplant indicated 
Cardiac review and evaluation committee (5) Decline in LVEF of at least 10% to <55% without signs or symptoms of CHF Global decrease in LVEF Signs or symptoms of CHF Decline in LVEF of at least 5% to <55% with signs or symptoms of CHF 
Classification system (reference)Grade IGrade IIGrade IIIGrade IV
NYHA No limitation of activities Mild limitation of activity Marked limitation of activity Confined to bed or chair 
American College of Cardiology/American Heart Association (3) Stage A; at high risk but without structural heart disease or symptoms Stage B; structural heart disease but without signs or symptoms Stage C; Structural heart disease with prior or current symptoms Stage D; Refractory CHF requiring specialized interventions 
Clinical toxicity criteria, version 2.0* Asymptomatic decline of resting EF ≥10% but <20% of baseline value Asymptomatic but resting EF less than LLN for laboratory or decline of resting EF of ≥20% of baseline value; <24% SF CHF responsive to treatment Severe or refractory CHF or requiring intubation 
Common terminology criteria for adverse events version 3.0 Asymptomatic, resting EF <60%-50%; SF <30%-24% Asymptomatic, resting EF <50%-40%; SF <30%-24% Symptomatic CHF responsive to intervention; EF <40%-20%; SF <15% Refractory CHF or poorly controlled; EF <20%, intervention such as ventricular assist device, ventricular reduction surgery, or heart transplant indicated 
Cardiac review and evaluation committee (5) Decline in LVEF of at least 10% to <55% without signs or symptoms of CHF Global decrease in LVEF Signs or symptoms of CHF Decline in LVEF of at least 5% to <55% with signs or symptoms 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.

Adverse events are cardiac general and left ventricular systolic dysfunction; http://ctep.cancer.gov/forms/CTCAEv3.pdf.

Clinical manifestations of anthracycline cardiotoxicity. Risk factors for anthracycline cardiotoxicity include age older than 70 years, hypertension, preexisting coronary artery disease, female sex, and previous cardiac irradiation or previous anthracycline exposure (8, 11). Mediastinal irradiation, even if given many years earlier, is also associated with increased cardiac sensitivity to anthracycline damage (12).

Acute cardiotoxic side effects of anthracyclines include pericarditis and myocarditis (which are rare and may occur during or after the first dose), left ventricular dysfunction, and arrhythmias (13); delayed effects include CHF, which may manifest many years later (14). Systolic dysfunction is 6% higher in patients treated with adjuvant doxorubicin (8% of patients) than with cyclophosphamide, methotrexate, and fluorouracil (CMF; 2%; ref. 15). After a cumulative doxorubicin dose of 240 mg/m2, asymptomatic decline in LVEF is detected by prospective monitoring (16). After a cumulative doxorubicin dose of 400 mg/m2, CHF incidence was estimated at 2% initially (8), but more recently, it has been estimated at 5.1% (11). Doxorubicin toxicity is exponentially dose-dependent and increases dramatically when cumulative doses exceed 500 mg/m2. Among patients ages 65 years or older, a higher CHF risk was associated with anthracycline chemotherapy than with CMF chemotherapy or no chemotherapy (17). Anthracyclines are less cardiotoxic when given by infusion than as a bolus (18). Dose-dense regimens given weekly or every 2 weeks were not associated with excess cardiotoxicity (19), although follow-up was limited. Less cardiotoxicity may be associated with liposome-administered doxorubicin than doxorubicin given by other methods (20); however, this cardiotoxicity should be evaluated in large adjuvant trials.

At equimolar doses, epirubicin is less cardiotoxic than doxorubicin because lower levels of secondary alcohol metabolites are produced from epirubicin (21). Cumulative epirubicin doses of >950 mg/m2 are associated with an exponential increase in CHF risk (22). Disease-free survival associated with a cumulative epirubicin dose of 600 mg/m2 is superior to that of 300 mg/m2 (23). After an 8-year follow-up, CHF was diagnosed in 2% of the 85 patients who received a cumulative epirubicin dose of 600 mg/m2 but not in any of the 65 patients who received a cumulative dose of 300 mg/m2 (24). Patients treated with cumulative epirubicin doses of 360 to 450 mg/m2 had an asymptomatic decline in LVEF and increased expression of brain natriuretic peptide after a 1-year follow-up (25). Little cardiotoxicity was observed with a cumulative epirubicin dose of 300 mg/m2 (26). Thus, strategies to prevent anthracycline-induced cardiomyopathy include limiting the total cumulative dose, infusional regimens, use of doxorubicin analogues, such as epirubicin, and novel delivery systems, such as liposomal or nanoparticle-bound doxorubicin.

Prevention of anthracycline-induced cardiotoxicity with dexrazoxane. Dexrazoxane (ICRF 187) is the sole cardioprotective agent proved to decrease anthracycline-induced cardiomyopathy; it is given as a closed ring form and is then metabolized to an open-ring iron-chelating form (27). However, dexrazoxane may interfere with anthracycline chemotherapy because anthracyclines enhance DNA cleavage by topoisomerase II, but the closed ring form of dexrazoxane stabilizes DNA–topoisomerase II complexes (28). Lower response rates have been observed in patients with metastatic breast cancer randomly assigned to receive doxorubicin and dexrazoxane than in those who received doxorubicin and placebo (29). Among doxorubicin-treated metastatic breast cancer patients, dexrazoxane seems equally cardioprotective when given before the first doxorubicin dose or when the cumulative doxorubicin dose exceeds 300 mg/m2 (30). Dexrazoxane should also be given to patients who respond to treatment and who may receive high cumulative anthracycline doses. Dexrazoxane is also cardioprotective against epirubicin-induced cardiomyopathy; in a randomized controlled trial with a median cumulative epirubicin dose of 720 mg/m2, dexrazoxane treatment lowered the incidence of cardiomyopathy from 23.1% (placebo) to 7.3% (dexrazoxane; ref. 31). Dexrazoxane remains the only approved preventative agent, but other avenues are being explored. Recently a small randomized single-blind placebo-controlled trial reported that prophylactic carvedilol, a β-blocker with antioxidant properties, had cardioprotective effects in patients treated with anthracyclines (32). Pediatric patients who had completed anthracyclines and were then randomized to the ACE inhibitor enalapril had less increase in left ventricular wall strain than patients on placebo. There was an excess of cardiac deaths in the placebo group, which was not statistically significant (33).

Clinical manifestations of taxane cardiotoxicity. Paclitaxel causes acute asymptomatic bradycardia in up to 30% of patients (34). An early series reported a 5% incidence of serious arrhythmias and myocardial infarction, including ventricular tachycardia in 5 of 140 patients (3.6%; ref. 35). However, a larger database found that only 0.1% of patients suffered from serious bradycardias and could not confirm that taxanes increased the frequency of ventricular tachycardia or myocardial infarction (34). Taxanes interfere with the metabolism and excretion of anthracyclines and potentiate anthracycline-induced cardiotoxicity, especially at high, cumulative anthracycline doses. Excess chemotherapy-related cardiac dysfunction has been found among patients with cumulative doxorubicin doses that exceed 360 mg/m2, who also received short paclitaxel infusions shortly after doxorubicin treatment (36). Slow infusion of paclitaxel and doxorubicin (37) or increased time (24 h) between doxorubicin and paclitaxel treatments (38) decreased cardiotoxicity. When combined with paclitaxel, the cumulative doxorubicin dose should not exceed 360 mg/m2, and doxorubicin should be given before paclitaxel (36). Combination treatments with epirubicin, and taxane may be less cardiotoxic (39, 40). A cumulative epirubicin dose limit of 990 mg/m2 in combination treatments with paclitaxel has been proposed (40). In clinical trials, docetaxel has not been associated with increased cardiotoxicity when combined with doxorubicin or epirubicin.

Adjuvant taxane trials and cardiotoxicity. Modern adjuvant regimens of taxanes apparently do not increase anthracycline cardiotoxicity. A trial comparing doxorubicin (75 mg/m2) followed by CMF with the combination of paclitaxel and doxorubicin (60 mg/m2) followed by CMF found that the incidences of symptomatic cardiac events at 31 months were similar between arms with (0.3% of patients) and without (0.5%) paclitaxel (41). In a randomized controlled trial of three cycles of dose-dense epirubicin followed by three cycles of paclitaxel followed by CMF compared with three cycles of dose-dense epirubicin followed by CMF, no severe cardiotoxicity was observed in either arm (42). Newer paclitaxel formulations, such as nanoparticle albumin-bound paclitaxel, may cause less of an increase in anthracycline cardiotoxicity (43). Thus, cardiotoxicity may be minimized by judicious choice of agents and regimens.

Trastuzumab (44) is a humanized monoclonal antibody that binds to the juxtamembrane extracellular portion (45) of the human transmembrane orphan receptor HER2 (ErbB2; ref. 46), which is the product of the HER2/neu gene. The exact mechanism of cardiotoxicity of trastuzumab is unclear (47).

Physiologic role of cardiac HER2. Investigating trastuzumab cardiotoxicity has led to a better understanding of cardiac physiology. HER2 is required for cardiac development. HER2 expression is high in the fetal myocardium and is required for the development of ventricular muscle and heart valves (48). Knockout mice with no functional HER2 die in utero (49). Conditional knockout mice lacking HER2 only in ventricular cardiomyocytes develop severe dilated cardiomyopathy by 2 months of age (50). Cardiac stress increases the expression of neuregulin, a paracrine peptide messenger that activates HER2 by inducing its phosphorylation; neuregulin is an established marker of cardiac stress (51). Neuregulin heterozygote knockout mice are more vulnerable to doxorubicin-induced CHF (52).

Preclinical data for trastuzumab-induced cardiotoxicity. Although trastuzumab does not prevent HER2-HER3 heterodimization (53), it may crosslink the receptors, which activate the internal tyrosine kinase domain and lead to their endocytosis (54). Single-agent trastuzumab is toxic to rat myocytes in vitro because it induces activation of the mitochondrial apoptosis pathway and the caspase cascade. Doxorubicin treatment of rat myocytes causes disarray of the myofibrils; this myofibrillar disarray is increased by treatment with trastuzumab and decreased by treatment with neuregulin (55). Human patients with CHF have increased levels of serum HER2, but its clinical significance is unclear (56).

Trastuzumab cardiotoxicity in patients with metastatic breast cancer. Although initial trials of trastuzumab in metastatic breast cancer patients did not prospectively assess LVEF, they found that monotherapy was associated with cardiotoxicity in 2% to 4.7% of patients (57, 58). Retrospective analyses estimated the incidence of cardiac dysfunction at 2.6% in patients receiving first-line, single-agent trastuzumab and at 8.5% in those receiving trastuzumab as second-line or third-line therapy (for Cardiac Review and Evaluation Committee definitions, see Table 1; ref. 5, 9). In another trial, cardiac dysfunction occurred in 27% of patients receiving concomitant anthracycline, cyclophosphamide, and trastuzumab; in 8% receiving anthracycline and cyclophosphamide alone; in 13% of patients with earlier anthracycline exposure receiving paclitaxel and trastuzumab; and in 1% receiving paclitaxel alone (59). Patients with cardiac dysfunction who were treated with concomitant doxorubicin and cyclophosphamide (AC) plus trastuzumab were more likely to have New York Heart Association (NYHA) class III or IV CHF (64%) than those treated with concomitant paclitaxel (20%; ref. 59). The synergistic cardiotoxicity of concomitant treatment with anthracyclines and trastuzumab led to their sequential use (60).

Phase III clinical trials of adjuvant trastuzumab. We focus on cardiac side effects rather than efficacy in our discussion of the adjuvant trials. Improvements in disease-free survival and the incidence of NYHA grades III and IV CHF in each trial at latest follow-up are presented in Fig. 1, and cardiac data are presented in Table 2.

Fig. 1.

The incidence of CHF from the Finnish Herceptin Study (FINHER), Herceptin Adjuvant trial (HERA), Breast Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the North Central Cancer Treatment Group trial 9831 (N9831), and NSABP B-31 (B-31). CHF control, percentage of the incidence of NYHA grades 3 and 4 CHF in the nontrastuzumab arm; CHF-T, percentage of the incidence of NYHA grades 3 and 4 CHF in trastuzumab arm; DFS, disease-free survival at the time of the last follow up. FINHER, 3 y (64); HERA, 2 y (69), 006, 23 mo (70), N9831, 4 y (67), and B-31, 4 y (66).

Fig. 1.

The incidence of CHF from the Finnish Herceptin Study (FINHER), Herceptin Adjuvant trial (HERA), Breast Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the North Central Cancer Treatment Group trial 9831 (N9831), and NSABP B-31 (B-31). CHF control, percentage of the incidence of NYHA grades 3 and 4 CHF in the nontrastuzumab arm; CHF-T, percentage of the incidence of NYHA grades 3 and 4 CHF in trastuzumab arm; DFS, disease-free survival at the time of the last follow up. FINHER, 3 y (64); HERA, 2 y (69), 006, 23 mo (70), N9831, 4 y (67), and B-31, 4 y (66).

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Table 2.

Cardiac events and rules for starting, holding, and discontinuing trastuzumab in four adjuvant trials

TrialNo. patientsEvents and no. patientsRule for starting HRule for holding HLVEF evaluation
NSABP B-31      
Cardiac safety analysis at 3-y follow-up (61, 65) Total = 1,664; AC-T arm = 814; AC-TH arm = 850 Asymptomatic decrease in LVEF requiring suspension of H*: data for control arm = NA; H arm = 102 (14%) Free of cardiac symptoms during AC, post-AC LVEF ≥ LLN, and absolute decline ≤15% LVEF declines of 10% to 15% and below LLN or ≥15% absolute fall in LVEF by MUGA 0, 3, 6, 9, 18 mo by MUGA 
  Cardiac events: control arm = 5 (0.8%); H arm = 31 (4.1%) Hazard ratio = 5.1   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 4; H arm = 31    
Cardiac safety analysis at 5-y follow-up (66) Total = 1845; AC-T arm = 898; AC-TH = 947 Cardiac events: control arm = 6 (0.9%); H arm = 35 (3.8%) Hazard ratio = 6.6   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 5; H arm = 35    
N-9831 Initial 3-y follow-up (61, 68) 3 y Total = 1967; AC-T arm = 670; AC-T-H arm = 718; AC-TH arm = 579 Asymptomatic decrease in LVEF requiring suspension of H§: control arm = NA; AC-T-Hb arm = 57 (10.8%); AC-TH arm = NA Free of cardiac symptoms during AC and post-AC LVEF ≥ LLN and absolute decline ≤15% LVEF < LLN or 15% absolute fall in LVEF 0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac events: control arm = 2 (0.3%); AC-T-H arm = 17 (2.5%); AC-TH arm = 20 (3.5%)    
  CHF: control arm = 1; AC-T-H arm = 16; AC-TH arm = 20    
  Cardiac deaths: control arm = 1; AC-T-H arm = 1; AC-TH arm = 0    
Updated 3 y follow-up (67) AC-T arm = 767; AC-TH arm = 875 Updated 3 y follow-up;    
  Cardiac events: control arm = 2 (0.2%), AC-TH arm = 22 (2.5%)    
HERA(62, 69), 2-y follow-up, postadjuvant chemo at discretion of investigator Total = 3387; observation = 1708; 1-y H = 1678 Decrease in LVEF: control arm = 9 (0.5%); H arm = 51 (3.0%) LVEF ≥ 55% after all chemo and radiotherapy LVEF <45% or LVEF <50% and fall >10% 0, 3, 6, 12, 18, 24, 36 mo by MUGA or ECHO 
  Symptomatic CHF**, including severe CHF††: control arm = 2 (0.1%); H arm = 36 (2.0%)    
  Severe CHF††: control arm = 0; H arm = 10 (0.6)    
  Cardiac deaths‡‡: control arm = 1 (0.1%); H arm = 0    
BCIRG 006 (70), 23-mo follow-up Total = 3174; AC-D arm = 1050; AC-DH arm = 1068; DC*H arm = 1056 Cardiac events§§; control arm = 10 (0.95%); AC-T^H arm = 25; T^C*H arm = 14   0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac deaths: none in any arm    
  CHF: control arm = 3 (0.3%); AC-T^H arm = 17; T^C*H arm = 4    
  Ischemia/infarction: control arm = 0; AC-T^H arm = 4; T^C*H arm = 1    
  Arrhythmias: control arm = 7 (0.7%); AC-T^H arm = 4; T^C*H arm = 9    
  Decline in LVEF >10%: control arm = 91 (9%); AC-T^H arm = 180 (9%); T^C*H arm = 82    
FinHeR (64), 3-y follow-up Total = 232 Decline in LVEF >10%: control arm = 0; H arm = 3 (2.6%)   Pre-chemo, post-FEC and at 12 and 36 mo after chemo by ECHO or MUGA 
  Decline in LVEF<50% or LVEF 15% less than baseline: control arm = 7 (6.0%); H arm = 4 (3.5%)    
  Cardiac infarction: control arm = 1 (0.86%); H arm = 0    
  Cardiac failure: control arm = 3 (2.6); H arm = 0    
TrialNo. patientsEvents and no. patientsRule for starting HRule for holding HLVEF evaluation
NSABP B-31      
Cardiac safety analysis at 3-y follow-up (61, 65) Total = 1,664; AC-T arm = 814; AC-TH arm = 850 Asymptomatic decrease in LVEF requiring suspension of H*: data for control arm = NA; H arm = 102 (14%) Free of cardiac symptoms during AC, post-AC LVEF ≥ LLN, and absolute decline ≤15% LVEF declines of 10% to 15% and below LLN or ≥15% absolute fall in LVEF by MUGA 0, 3, 6, 9, 18 mo by MUGA 
  Cardiac events: control arm = 5 (0.8%); H arm = 31 (4.1%) Hazard ratio = 5.1   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 4; H arm = 31    
Cardiac safety analysis at 5-y follow-up (66) Total = 1845; AC-T arm = 898; AC-TH = 947 Cardiac events: control arm = 6 (0.9%); H arm = 35 (3.8%) Hazard ratio = 6.6   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 5; H arm = 35    
N-9831 Initial 3-y follow-up (61, 68) 3 y Total = 1967; AC-T arm = 670; AC-T-H arm = 718; AC-TH arm = 579 Asymptomatic decrease in LVEF requiring suspension of H§: control arm = NA; AC-T-Hb arm = 57 (10.8%); AC-TH arm = NA Free of cardiac symptoms during AC and post-AC LVEF ≥ LLN and absolute decline ≤15% LVEF < LLN or 15% absolute fall in LVEF 0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac events: control arm = 2 (0.3%); AC-T-H arm = 17 (2.5%); AC-TH arm = 20 (3.5%)    
  CHF: control arm = 1; AC-T-H arm = 16; AC-TH arm = 20    
  Cardiac deaths: control arm = 1; AC-T-H arm = 1; AC-TH arm = 0    
Updated 3 y follow-up (67) AC-T arm = 767; AC-TH arm = 875 Updated 3 y follow-up;    
  Cardiac events: control arm = 2 (0.2%), AC-TH arm = 22 (2.5%)    
HERA(62, 69), 2-y follow-up, postadjuvant chemo at discretion of investigator Total = 3387; observation = 1708; 1-y H = 1678 Decrease in LVEF: control arm = 9 (0.5%); H arm = 51 (3.0%) LVEF ≥ 55% after all chemo and radiotherapy LVEF <45% or LVEF <50% and fall >10% 0, 3, 6, 12, 18, 24, 36 mo by MUGA or ECHO 
  Symptomatic CHF**, including severe CHF††: control arm = 2 (0.1%); H arm = 36 (2.0%)    
  Severe CHF††: control arm = 0; H arm = 10 (0.6)    
  Cardiac deaths‡‡: control arm = 1 (0.1%); H arm = 0    
BCIRG 006 (70), 23-mo follow-up Total = 3174; AC-D arm = 1050; AC-DH arm = 1068; DC*H arm = 1056 Cardiac events§§; control arm = 10 (0.95%); AC-T^H arm = 25; T^C*H arm = 14   0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac deaths: none in any arm    
  CHF: control arm = 3 (0.3%); AC-T^H arm = 17; T^C*H arm = 4    
  Ischemia/infarction: control arm = 0; AC-T^H arm = 4; T^C*H arm = 1    
  Arrhythmias: control arm = 7 (0.7%); AC-T^H arm = 4; T^C*H arm = 9    
  Decline in LVEF >10%: control arm = 91 (9%); AC-T^H arm = 180 (9%); T^C*H arm = 82    
FinHeR (64), 3-y follow-up Total = 232 Decline in LVEF >10%: control arm = 0; H arm = 3 (2.6%)   Pre-chemo, post-FEC and at 12 and 36 mo after chemo by ECHO or MUGA 
  Decline in LVEF<50% or LVEF 15% less than baseline: control arm = 7 (6.0%); H arm = 4 (3.5%)    
  Cardiac infarction: control arm = 1 (0.86%); H arm = 0    
  Cardiac failure: control arm = 3 (2.6); H arm = 0    

NOTE: All trials used the National Cancer Institute's Clinical toxicity criteria version 2.0 except NSABP trial B-31 (65), which used Cardiac Review and Evaluation Committee toxicity criteria (5).

Abbreviations: A, doxorubicin; C, cyclophosphamide; C*, carboplatin; H, trastuzumab; T, paclitaxel; D, docetaxel; CE, cardiac event; HERA, Herceptin Adjuvant trial; FEC, 5-flurouracil, epirubicin, and cyclophosphamide; NA, not available; chemo, chemotherapy.

*

A decrease in LVEF of <10% and ≥6% less than the LLN or of 10% to 15% and less than the LLN or of ≥15%.

Repeat MUGA after 4 wk. If two consecutive holds or total of three holds occur, discontinue trastuzumab treatment.

NYHA class III or class IV symptoms with absolute LVEF decrease of ≥10% to ≤55% or a decrease of >5% to less than the LLN.

§

LVEF decrease of ≥15% or of <15% and less than the LLN.

Patients enrolled before April 25, 2004, with satisfactory post-AC LVEF and completed paclitaxel (n = 528).

Absolute decrease of ≥10% to an LVEF of <50%.

**

CHF was considered symptomatic by a cardiologist and decrease in LVEF of ≥10% to <50%.

††

NYHA functional class III or class IV confirmed by cardiologist and decrease in LVEF ≥10% to <50%.

‡‡

Death due to CHF, cardiac infarction, documented primary arrhythmia, sudden unexpected death within 24 h of a definite or probable cardiac event.

§§

Clinically significant cardiac events as per independent review panel; Cardiac death or grade 3 or grade 4 toxicities (CHF, cardiac ischemia, cardiac infarction, arrhythmias).

Trials of adjuvant trastuzumab incorporated careful monitoring of LVEF and contained protocol stopping rules, typically stopping the study when a 4% excess of cardiac events was detected (6164). The first 1,000 patients recruited to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial underwent cardiotoxicity analysis, and those with a normal post-AC LVEF were randomly assigned to receive paclitaxel with or without weekly trastuzumab. Those treated with trastuzumab had 3.3% more cardiac events after 3 years than those treated with paclitaxel alone (65), which was essentially unchanged after 5 years of follow-up (Table 2). Independent risk factors for trastuzumab-associated CHF were post-AC LVEF, age of older than 50 years, and hypertension medications. In a combined analysis of the North Central Cancer Treatment Group trial N9831 and the NSABP B-31, 6.7% of patients who had completed anthracycline treatment had a lower LVEF or developed cardiac symptoms preventing the initiation of trastuzumab treatment (61). Nearly one third of patients who started trastuzumab discontinued it: 4.7% with symptomatic CHF, 14.2% with confirmed asymptomatic decline in LVEF, and the rest for noncardiac reasons. Among trastuzumab-treated patients, NYHA class III or class IV CHF or death from cardiac events occurred in 4.1% in NSABP B-31 (66) and in 2.5% in North Central Cancer Treatment Group N9831(67). In an early analysis of the North Central Cancer Treatment Group N9831 trial, a trend toward increased risk of trastuzumab-associated cardiac toxicity was associated with increased patient age. Trastuzumab-associated cardiac events were not related to post-AC LVEF. Among patients who initiated trastuzumab treatment after paclitaxel (i.e., taxane), there was one cardiac death and a 2.2% incidence of CHF (68).

The Herceptin Adjuvant trial (62) allowed physicians to choose adjuvant chemotherapy regimens and then randomly assigned patients who completed chemotherapy and radiation therapy to observation or to either 1 or 2 years of trastuzumab given every 3 weeks. Only 20% of patients received taxanes. Severe CHF was rare among patients receiving 1 year of trastuzumab (0.5%); after a 2-year follow-up, the incidence of grade III or grade IV CHF was 0.6% and incidence of grade II CHF was 1.5%, and 3% had a clinically significant decline in asymptomatic LVEF (69). The broader variety of possible pretrastuzumab regimens and the entry criteria of a pretrastuzumab LVEF of ≥55% may account for the lower incidence of cardiac end points, as the baseline anthracycline damage may have been less in this trial than in others.

The Breast Cancer International Research Group trial 006 compared the following adjuvant trastuzumab (given weekly during chemotherapy and every 3 weeks thereafter) and chemotherapy combination treatments: AC plus docetaxel (AC-T); AC plus docetaxel and trastuzumab (AC-TH); and docetaxel, carboplatin, and trastuzumab (TCH). In its first interim analysis (70), symptomatic cardiac events were reported in 0.95% of patients in the AC-T arm, 1.33% in the TCH arm, and 2.3% in the AC-TH arm. Grade III or grade IV CHF was uncommon in AC-T and TCH arms (Table 2 and Fig. 1). Thus, the docetaxel-trastuzumab combination may be less cardiotoxic than the paclitaxel-trastuzumab combination.

A retrospective analysis of Breast Cancer International Research Group trial 006 found that anthracycline-based chemotherapy was associated with increased disease-free survival among patients with HER2-positive tumors that overexpressed topoisomerase II and HER2/neu but not among patients with tumors that only overexpressed HER2/neu (70). Other trials have found similar results (71).

The Finnish Herceptin study randomly assigned 1,010 patients to three cycles of either docetaxel or vinorelbine, followed by three cycles of 5-flurouracil, epirubicin, and cyclophosphamide (64). The 232 patients with HER2-overexpressing tumors were further randomly assigned as described above to receive nine weekly doses of trastuzumab or placebo during their first three cycles of chemotherapy. This short course of trastuzumab was not associated with LVEF decline or CHF. Use of trastuzumab before epirubicin may have allowed the myocardium to recover from HER2 inhibition before chemotherapy, although trastuzumab, which has a long half-life, may still have been present during anthracycline treatment.

A randomized neoadjuvant trial of 42 patients that compared concomitant trastuzumab and chemotherapy (four cycles of paclitaxel followed by four cycles of FEC75) to chemotherapy alone was stopped before completion of its planned accrual because of an interim analysis that found evidence of improved pathologic complete response in the 23 patients who received trastuzumab (72). Subsequently another 22 patients received neoadjuvant chemotherapy and trastuzumab. A combined analysis showed a 5% decrease in mean LVEF from 65% but no symptomatic cardiac toxicity in the trastuzumab group (73).

Adjuvant trastuzumab summary. To summarize, adjuvant trastuzumab treatment is associated with improved disease-free survival, but it is cardiotoxic, especially when given concomitantly with paclitaxel after AC (Fig. 1). The optimal duration of adjuvant trastuzumab treatment is unknown. If patients must stop trastuzumab treatment because of a declining LVEF, a short course of trastuzumab concomitant with adjuvant chemotherapy still has substantial benefit. Future trials should assess whether patients with tumors that do not overexpress topoisomerase II can avoid anthracycline treatment and thus its cardiotoxicities. Regimens used in the Finnish or Herceptin Adjuvant trials may be beneficial for patients with a high risk of recurrence and low LVEF or patients with multiple cardiac risk factors.

Although estrogen has a positive effect on the lipid profiles of postmenopausal women, it has not been shown to protect against ischemic heart disease (74). Serum levels of some lipid moieties may be associated with higher risk of myocardial infarction in women than men, including low high-density lipoprotein-cholesterol and elevated triglycerides (75). The effects of adjuvant hormonal therapy on lipid profiles have been reviewed elsewhere (76). Tamoxifen has antiestrogenic effects on breast cells and proestrogenic effects on the endometrium and bone, but it has not been shown to protect against ischemic heart disease in large placebo-controlled trials (77) despite earlier metaanalysis which raised this possibility (78). Tamoxifen and other selective estrogen receptor modulators reduce levels of plasma cholesterol (79) and homocystine (80) but increase the level of serum triglyceride (81). Tamoxifen is associated with higher rates of venous thromboembolic disease and stroke than the placebo control (77). Aromatase inhibitors inhibit the conversion of androgens to estradiol in fat and other tissues, including tumors, and thus reduce estrogen levels in plasma and tissue. One large phase III trial of the aromatase inhibitor letrozole versus tamoxifen reported increased cardiac events in the letrozole arm at a median follow-up of 26 months (82), which persisted in subgroup analysis at 51 months (83). This observation has not been confirmed in trials of other aromatase inhibitors (84). Additional research into the long-term effects of aromatase inhibitors on cardiac disease is required.

The most frequently diagnosed cardiac problems during radiotherapy are acute pericarditis, pericardial effusion, and arrhythmias. Acute radiation damage to pericardial and intimal coronary endocytes eventually leads to myocyte ischemia and fibrosis (85). Constrictive pericarditis is a serious long-term complication that may require pericardectomy. It is more frequently seen in patients who receive mediastinal radiation for Hodgkin's lymphoma than those who receive adjuvant tangential breast irradiation. The incidence of constrictive pericarditis with modern techniques is as yet unknown as the median presentation is 13 years postradiation (86). Radiotherapy damage to coronary endocytes triggers inflammation and eventually leads to atherosclerosis (87). The risk of cardiac disease seems to increase for decades after radiation therapy and has been fully reviewed elsewhere (88).

Although an initial metaanalysis of adjuvant breast cancer radiation trials showed that improved disease-free survival was counteracted by excess cardiac mortality (89), a recent metaanalysis that included trials with modern radiation techniques found that increased overall survival was associated with radiotherapy (90). Most cardiac disease has been observed in patients receiving radiation to left chest wall after a left-side mastectomy, but current radiotherapy techniques deliver less radiation to the heart than those of 30 years ago even to patients with left-side tumors (91). Earlier epidemiologic cohort studies observed a higher risk of cardiac death (92) among patients with left-side breast cancer than those with right-side breast cancer, and this risk increased with time since treatment (Table 3). However, a Surveillance Epidemiology End Results analysis (93) of patients who received left-side versus right-side irradiation between 1986 and 1993 did not find significant differences in hospitalization for cardiac disease or heart failure. Although these studies were large and adequately powered, right-side breast irradiation does expose the heart to some radiation, especially if internal mammary lymph nodes are also irradiated. Consequently, a more appropriate control group would have been nonirradiated patients. A recent Dutch study (94) compared 4,414 10-year survivors of breast cancer, treated between 1970 and 1986, to the Dutch female population. The authors divided the group into patients treated before and after 1980 when breast-conserving therapy was introduced. Breast irradiation alone did not increase the incidence of cardiovascular disease. Internal left or right mammary chain radiation in the period 1970 to 1979 increased the risk of myocardial infarction and CHF. In the cohort who received internal mammary chain radiation after 1979, the risk of CHF and valvular dysfunction remained elevated but not that of myocardial infarction. Left but not right chest wall irradiation increased the risk of myocardial infarction for the entire treatment period 1979 to 1986. Interestingly patients treated after 1979 who also received adjuvant CMF chemotherapy had an increased risk of CHF compared with those who received radiation alone. Smoking and radiation seemed to have a synergistic effect on increasing the risk of myocardial infarction (94). Patients treated with tangential field irradiation post–left-sided breast conserving surgery had more coronary artery stenosis, especially in the left anterior descending artery than patients with right-sided breast cancer (95). Patients treated with modern techniques that irradiate <5% of heart volume may still develop subtle defects in cardiac perfusion, which could result from irradiation of the left-anterior descending coronary artery causing arteritis (96), but this report was not confirmed in another study (97). Although new techniques, including intensity-modulated radiotherapy (98) combined with free breathing gating (99) and helical tomotherapy (100), may further reduce radiation-induced cardiac toxicities (101), the most important factors in limiting cardiac radiation are associated with the techniques used and the skill of the radiation oncologist.

Table 3.

Relative risk of cardiac death after radiation for left versus right breast cancer: laterality

Laterality after diagnosis, RR (95% CI)
Diagnosis <10 y 10-14 y ≥15 y 
    1973-1982 1.2 (1.04-1.38) 1.52 (1.11-1.82) 1.58 (1.29 - 1.95) 
    1983-1992 1.04 (0.91-1.18) 1.27 (0.99-1.63) NA 
    1993-2001 0.96 (0.82-1.12) NA NA 
Laterality after diagnosis, RR (95% CI)
Diagnosis <10 y 10-14 y ≥15 y 
    1973-1982 1.2 (1.04-1.38) 1.52 (1.11-1.82) 1.58 (1.29 - 1.95) 
    1983-1992 1.04 (0.91-1.18) 1.27 (0.99-1.63) NA 
    1993-2001 0.96 (0.82-1.12) NA NA 

NOTE: Data were from ref. 92.

Abbreviations: RR, relative risk; CI, confidence interval; NA, not available.

Cardiac monitoring should ideally identify patients at high risk for cardiotoxicity before treatment and patients with asymptomatic toxicity during or after treatment, so that breast cancer treatments can be modified and cardiac medication can be started (102). Cardiac function is usually measured by using echocardiography (ECHO) and multiple-gated acquisition (MUGA), also known as radionucleotide angiocardiography (103), to measure resting LVEF. It is important to remember that the two techniques cannot be compared directly and that patients should always be assessed with the same technique when monitoring cardiac changes during treatment. Stressing the myocardium by use of exercise or ionotropic agents before measuring LVEF may yield earlier evidence of cardiotoxicity. Another cardiac variable, the early/atrial (E/A) filling ratio, reflects ventricular compliance (i.e., the ability of the ventricle to relax and fill during diastole). Changes in the E/A ratio may predict diastolic dysfunction and so herald a decline in LVEF (104). Diastolic dysfunction seems to be predictive of cardiac morbidity and mortality (105, 106). Whereas resting LVEF is not a perfect measure of cardiac function neither measuring the LVEF during stress nor diastolic function has been prospectively assessed in large adjuvant trials. Trials of adjuvant trastuzumab use the rules for stopping cardiotoxic agents from Schwartz et al. (107). Among 1,487 metastatic breast cancer patients who were monitored by MUGA for 7 years, they identified subset of 282 high-risk patients by one or two of the following three criteria: (a) a decline of 10% or more in absolute LVEF from a normal baseline to 50% or less, (b) a high cumulative dose of doxorubicin (>450 mg/m2), and/or (c) an abnormal baseline LVEF (<50%). Patients who stopped taking doxorubicin after an LVEF decline were less likely to develop CHF than those who did not.

Cardiac monitoring techniques. MUGA, a nuclear medicine technique, is highly reproducible and able to detect a decline in LVEF in patients treated with anthracyclines, some of whom are symptomatic (107, 108), but it is not able to predict the development or severity of CHF (109). In a retrospective cost-benefit analysis of MUGA among 265 patients, the total cost of all monitoring was less than that for 1 year of care for 15 CHF patients (102). Each scan delivers a dose of 800 mSv, and cumulative radiation exposure limits the suitability of this technique for frequently repeated monitoring.

ECHO is used regularly to monitor LVEF and is more widely available than MUGA. Unlike MUGA, it does not expose patients to ionizing radiation. ECHO was considered prone to operator-dependent variability, but better training and use of automation may overcome intraobservor variation (110). ECHO can accurately measure diastolic function, hemodynamics, and pericardial disease, as well as valvular function, which MUGA is unable to perform.

Endomyocardial right ventricular biopsy via the internal jugular vein, followed by examination of tissue by electron microscopy, provides accurate information on anthracycline-induced microscopic changes in heart muscle (111), but it is invasive, remains a research tool, and is unavailable in most institutions (112). Biopsy specimens from doxorubicin-treated patients have loss of myofibrils, vacuolization of cytoplasm, dilation of sarcoplasmic reticulum, and necrosis (113, 114). Electron microscopy of biopsies from patients with trastuzumab-induced cardiotoxicity does not show the classic Billingham changes of anthracycline exposure but have focal vacuoles, pleomorphic mitochondria, myocardial hypertrophy, and interstitial fibrosis (10, 115).

Serial serum measurements of troponin (T and I isoforms) and atrial natriuretic peptide or brain natriuretic peptide as indicators of cardiotoxicity are under investigation. Elevated troponin I post–high-dose chemotherapy predicted LVEF decline (116). In 703 patients who underwent high-dose chemotherapy, serial troponin I measurements enabled stratification into three groups with different risk for cardiac events in the 3 years postchemotherapy (117). In a prospective trial of patients treated with doxorubicin or epirubicin, elevated serum levels of atrial natriuretic peptide or brain natriuretic peptide did not predict LVEF decline (118). Additional investigation is required before serum monitoring can be recommended outside the setting of a clinical trial. Proteomics has been shown to predict anthracycline-induced cardiotoxicity in animal models (119).

Cardiac magnetic resonance imaging measures many cardiac variables (including LVEF and LV muscle mass) and has little between-test variability and good receiver operating characteristics (120), but it is time consuming and not widely available. Cardiac magnetic resonance imaging is able to assess anthracycline cardiotoxicity (121). Delayed enhancement gadolinium imaging detects myocarditis (122). Because of its high reproducibility, use of cardiac magnetic resonance imaging in clinical trials could lower the number of patients necessary to reliably evaluate the cardiotoxicity of new agents.

Decreased uptake of radiolabeled metaiodobenzylguanidine, an analogue of norepinephrine, is associated with damage to cardiac sympathetic nerves and with cumulative doxorubicin dose in rat models (123). Metaiodobenzylguanidine scintigraphy, a method to measure uptake of radiolabeled metaiodobenzylguanidine, seems to detect Adriamycin-induced cardiomyopathy (124) but has not been widely accepted.

Radiolabeled antimyosin antibodies may be useful in diagnosing cardiac dysfunction and predicting toxicity. When cardiac myocytes are damaged, myosin is exposed and can be detected by antimyosin antibodies. Immmunoscintography compares the heart-to-lung ratio uptake of indium-radiolabeled antimyosin antibodies. When LVEF measured by MUGA was compared with antimyosin immmunoscintography in patients who had been treated with high cumulative epirubicin doses, an increase in the heart-to-lung ratio preceded a decline in the LVEF (125). Antimyosin immmunoscintography may also predict severe cardiotoxicity at low doxorubicin doses (126). Although this technique seems to be very sensitive, it may lack the specificity to predict which patients should stop treatment (127). A report of myocardial uptake of radiolabeled trastuzumab predicting subsequent chemotherapy-related cardiac dysfunction (128) has not been confirmed (129).

Our recommendations for cardiac monitoring. Patients treated with adjuvant trastuzumab should have LVEF assessed by ECHO or MUGA at baseline after completing anthracycline treatment, and while on trastuzumab at 3-month intervals, or sooner, if CHF symptoms develop. Clinicians should use the same rules for stopping trastuzumab as the trial in which the regimen was described (Table 2). We recommend holding trastuzumab treatment when an asymptomatic absolute decline in LVEF below the lower limit of normal is detected. If LVEF improves on subsequent reassessments, trastuzumab treatment may be restarted. We do not recommend routine monitoring of unproved serum markers, such as troponin or brain natriuretic peptide outside a research setting. Cardiac magnetic resonance imaging has good receiver operating characteristics and reliability and should be considered for use in phases I and II trials of potentially cardiotoxic agents because changes in a small number of patients are likely to be statistically significant.

Close monitoring of cardiac function in trials of adjuvant trastuzumab has provided new data on the cardiotoxicity of conventional cytotoxic agents. These data indicate that long-term follow-up of cardiac function for breast cancer survivors is required, particularly for those who have received adjuvant radiotherapy and anthracyclines. Symptomatic patients will derive benefit from ACE inhibitors and β-blockers. It is uncertain whether these drugs will help patients with asymptomatic LVEF decline. Because adjuvant trastuzumab trials have excluded patients with cardiac risk factors, there may be a higher incidence of cardiac events when trastuzumab is used in less healthy patients. We recommend following LVEF by use of either MUGA or ECHO before, during, and after trastuzumab treatment. Trials of adjuvant infusional doxorubicin or liposomal doxorubicin should include patients with cardiac risk factors and prospectively study new methods of monitoring and treating cardiotoxicity. Newer radiotherapy techniques may further reduce long-term cardiotoxicity, but recent retrospective reviews suggest that current techniques are less toxic than those used two decades ago. Finally, molecular diagnostics holds promise in identifying patients who do not require anthracyclines or any adjuvant cytotoxic therapy, but this remains to be proved prospectively.

Grant support: Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH.

1
Hewitt M, Greenfield S, Stovall E. From cancer patient to cancer survivor: lost in transition. Washington (DC): National Academies Press; 2005.
2
Adams KF, Lindenfeld J, Arnold JMO, et al. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline.
J Card Fail
2006
;
12
:
10
–38.
3
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Circulation
2005
;
112
:
e154
–235.
4
Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition.
Circulation
2006
;
114
:
2474
–81.
5
Seidman A, Hudis C, Kathryn Pierri M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience.
J Clin Oncol
2002
;
20
:
1215
–21.
6
Ewer MS, Lippman SM. Type II Chemotherapy-related cardiac dysfunction: time to recognize a new entity.
J Clin Oncol
2005
;
23
:
2900
–2.
7
Tallaj JA, Franco V, Rayburn BK, et al. Response of doxorubicin-induced cardiomyopathy to the current management strategy of heart failure.
J Heart Lung Transplant
2005
;
24
:
2196
–201.
8
Von Hoff DD, Layard MW, Basa P. Risk factors for doxorubicin-induced congestive heart failure.
Ann Int Med
1979
;
91
:
710
–7.
9
Suter TM, Cook-Bruns N, Barton C. Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer.
Breast
2004
;
13
:
173
–83.
10
Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment.
J Clin Oncol
2005
;
23
:
7820
–6.
11
Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.
Cancer
2003
;
97
:
2869
–79.
12
Billingham ME, Bristow MR, Glatstein E, et al. Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation.
Am J Surg Pathol
1977
;
1
:
17
–23.
13
Steinberg JS, Cohen AJ, Wasserman AG, Cohen P, Ross AM. Acute arrhythmogenicity of doxorubicin administration.
Cancer
1987
;
60
:
1213
–8.
14
Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients.
Ann Oncol
2002
;
13
:
699
–709.
15
Zambetti M, Moliterni A, Materazzo C, et al. Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation.
J Clin Oncol
2001
;
19
:
37
–43.
16
Perez EA, Suman VJ, Davidson NE, et al. Effect of doxorubicin plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial.
J Clin Oncol
2004
;
22
:
3700
–4.
17
Giordano SH, Pinder M, Duan Z, Hortobagyi G, Goodwin J. Congestive heart failure (CHF) in older women treated with anthracycline (A) chemotherapy (C). Proc ASCO 2006;521.
18
Hortobagyi GN, Frye D, Buzdar AU, et al. Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma.
Cancer
1989
;
63
:
37
–45.
19
Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.
J Natl Cancer Inst
2003
;
21
:
1431
–9.
20
Ewer MS, Benjamin RS, Martin FJ, et al. Cardiac safety of liposomal anthracyclines.
Semin Oncol
2004
;
31
:
161
–81.
21
Minotti G, Menna P, Licata S, et al. Anthracycline metabolism and toxicity in human myocardium: comparisons between doxorubicin, epirubicin, and a novel disaccharide analogue with a reduced level of formation and [4-4S] reactivity of its secondary alcohol metabolite.
Chem Res Toxicol
2000
;
13
:
1336
–41.
22
Ryberg M, Nielsen D, Skovsgaard T, et al. Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer.
J Clin Oncol
1998
;
16
:
3502
–8.
23
Gluck S. Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin.
Oncologist
2005
;
10
:
780
–91.
24
Bonneterre J, Roché H, Kerbrat P, et al. Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French Adjuvant Study Group.
J Clin Oncol
2004
;
22
:
3070
–9.
25
Van Der Graaf WTA, Meinardi MT, Van Veldhuisen DJ, et al. Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients.
J Clin Oncol
2001
;
19
:
2746
–53.
26
Roche H, Fumoleau P, Spielmann M. Five years analysis of the PACS01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel for the adjuvant treatment of node positive breast cancer. Breast Cancer Res. Treat. 2004;88.
27
Schroeder PE, Hasinoff BB. Metabolism of the one-ring open metabolites of the cardioprotective drug dexrazoxane to its active metal-chelating form in the rat.
Drug Metab Dispos
2005
;
33
:
1367
–72.
28
Sehested M, Jensen PB. Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle.
Biochem Pharmacol
1996
;
51
:
879
–86.
29
Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.
J Clin Oncol
1997
;
15
:
1318
–32.
30
Swain SM, Whaley FS, Gerber MC, et al. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy.
J Clin Oncol
1997
;
15
:
1333
–40.
31
Venturini M, Michelotti A, Del Mastro L, et al. Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.
J Clin Oncol
1996
;
14
:
3112
–20.
32
Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy.
J Am Coll Cardiol
2006
;
48
:
2258
–62.
33
Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines.
J Clin Oncol
2004
;
22
:
820
–8.
34
Arbuck SG, Strauss H, Rowinsky E, et al. A reassessment of cardiac toxicity associated with Taxol.
J Natl Cancer Inst Monographs
1993
;
15
:
117
–30.
35
Rowinsky EK, McGuire WP, Guarnieri T, et al. Cardiac disturbances during the administration of taxol.
J Clin Oncol
1991
;
9
:
1704
–12.
36
Giordano SH, Booser DJ, Murray JL, et al. A detailed evaluation of cardiac toxicity: a phase II study of doxorubicin and one- or three-hour-infusion paclitaxel in patients with metastatic breast cancer.
Clin Cancer Res
2002
;
8
:
3360
–8.
37
Holmes FA, Valero V, Walters RS, et al. Paclitaxel by 24-hour infusion with doxorubicin by 48-hour infusion as initial therapy for metastatic breast cancer: phase I results.
Ann Oncol
1999
;
10
:
403
–11.
38
Jassem J, Pienkowski, Pluzanska A, et al. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial.
J Clin Oncol
2001
;
19
:
1707
–15.
39
Grasselli G, Viganò L, Capri G, et al. Clinical and pharmacologic study of the epirubicin and paclitaxel combination in women with metastatic breast cancer.
J Clin Oncol
2001
;
19
:
2222
–31.
40
Gennari A, Salvadori B, Donati S, et al. Cardiotoxicity of epirubicin/paclitaxel-containing regimens: role of cardiac risk factors.
J Clin Oncol
1999
;
17
:
3596
–602.
41
Gianni L, Baselga J, Eiermann W, et al. Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy.
Clin Cancer Res
2005
;
11
:
8715
–21.
42
Fountzilas G, Skarlos D, Dafni U, et al. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncol Group.
Ann Oncol
2005
;
16
:
1762
–71.
43
Nyman DW, Campbell KJ, Hersh E, et al. Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.
J Natl Cancer Inst
2005
;
23
:
7785
–93.
44
Hudziak RM, Lewis GD, Winget M, et al. p185(HER2) monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor.
Mol Cell Biol
1989
;
9
:
1165
–72.
45
Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab.
Nature
2003
;
421
:
756
–60.
46
Slamon DJ, Clark GM, Wong SG. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
Science
1987
;
235
:
177
–82.
47
Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition.
Nat Rev Cancer
2007
;
7
:
332
–44.
48
Camenisch TD, Schroeder JA, Bradley J, Klewer SE, McDonald JA. Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2-3 receptors.
Nat Med
2002
;
8
:
850
–5.
49
Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development.
Nature
1995
;
378
:
386
–90.
50
Ozcelik C, Erdmann B, Pilz B, et al. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy.
Proc Natl Acad Sci U S A
2002
;
99
:
8880
–5.
51
Wang L, Proud CG. Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes.
Circ Res
2002
;
91
:
821
–9.
52
Liu F-F, Stone JR, Schuldt AJT, et al. Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure.
Am J Physiol Heart Circ Physiol
2005
;
289
:
H660
–6.
53
Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth.
Cancer Cell
2002
;
2
:
127
–37.
54
Schneider JW, Chang AY, Rocco TP. Cardiotoxicity in signal transduction therapeutics: ErbB2 antibodies and the heart.
Semin Oncol
2001
;
28
:
18
–26.
55
Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1{β} and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity.
Circulation
2002
;
105
:
1551
–4.
56
Perik PJ, de Vries EG, Gietema JA, et al. Serum HER2 levels are increased in patients with chronic heart failure.
Eur J Heart Fail
2007
;
2
:
173
–7.
57
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer.
J Clin Oncol
2002
;
20
:
719
–26.
58
Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.
J Clin Oncol
1999
;
17
:
2639
–48.
59
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against her2 for metastatic breast cancer that overexpresses HER2.
N Engl J Med
2001
;
344
:
783
–92.
60
Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab.
J Clin Oncol
2004
;
22
:
322
–9.
61
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
N Engl J Med
2005
;
353
:
1673
–84.
62
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.
N Engl J Med
2005
;
353
:
1659
–72.
63
Slamon D, Eiermann W, Robert N. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Proc SABCS 2006.
64
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.
N Engl J Med
2006
;
354
:
809
–20.
65
Tan-Chiu E, Yothers G, Romond EH, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.
J Clin Oncol
2005
;
23
:
7811
–9.
66
Rastogi P, Jeong J, Geyer CE, et al. Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab(H). Proc ASCO 2007;LBA513.
67
Perez EA, Romond EH, Suman VJ, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer.
Proc ASCO
2007
;
25
:
512
.
68
Perez EA, Suman VJ, Davidson NE. Exploratory Analysis From NCCTG N9831: do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy? Proc SABCS 2005;2038.
69
Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.
Lancet
2007
;
369
:
29
–36.
70
Slamon D, Eiermann W, Robert N, et al. Phase III Trial Comparing AC-T with AC-TH and with TCH in the Adjuvant Treatment of HER2 positive Early Breast Cancer Patients: First Interim Efficacy Analysis. Proc SABCS 2005;1.
71
Tanner M, Isola J, Wiklund T, et al. Topoisomerase II{α} gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401.
J Clin Oncol
2006
;
24
:
2428
–36.
72
Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer.
J Clin Oncol
2005
;
23
:
3676
–85.
73
Buzdar AU, Valero V, Ibrahim NK, et al. neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen.
Clin Cancer Res
2007
;
13
:
228
–33.
74
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women's health initiative randomized controlled trial.
J Am Med Assoc
2002
;
288
:
321
–33.
75
Korhonen T, Savolainen MJ, Koistinen MJ, et al. Association of lipoprotein cholesterol and triglycerides with the severity of coronary artery disease in men and women.
Atherosclerosis
1996
;
127
:
213
–20.
76
Lewis S. Do endocrine treatments for breast cancer have a negative impact on lipid profiles and cardiovascular risk in postmenoposal women?
Am Heart J
2007
;
153
:
182
–88.
77
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study.
J Natl Cancer Inst
1998
;
90
:
1371
–88.
78
Braithwaite RS, Chlebowski RT, Lau J, et al. Meta-analysis of vascular and neoplastic events associated with tamoxifen.
J General Int Med
2003
;
18
:
937
–47.
79
Chang J, Powles TJ, Ashley SE, et al. The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study.
Ann Oncol
1996
;
7
:
671
–5.
80
Cattaneo M, DN K, Elisaf MS, et al. Does tamoxifen enhance endothelial function by lowering the plasma levels of homocysteine? Effects of tamoxifen on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis effects of tamoxifen on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis response.
Circulation
2001
;
104
:
146
–7e.
81
Hozumi Y, Kawano M, Saito T, Miyata M. Effect of tamoxifen on serum lipid metabolism.
J Clin Endocrinol Metabol
1998
;
83
:
1633
–5.
82
Thurlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer.
N Engl J Med
2005
;
353
:
2747
–57.
83
Coates AS, Keshaviah A, Thurlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.
J Clin Oncol
2007
;
25
:
486
–92.
84
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.
N Engl J Med
2004
;
350
:
1081
–92.
85
Corn BW, Trock BJ, Goodman RL. Irradiation-related ischemic heart disease.
J Clin Oncol
1990
;
8
:
741
–50.
86
Ling LH, Oh KK, Schaff HV, et al. Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy.
Circulation
1999
;
100
:
1380
–6.
87
Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data?
Int J Radiat Oncol Biol Phys
2007
;
67
:
10
–8.
88
Raj KA, Marks LB, Prosnitz RG. Late effects of breast radiotherapy in young women.
Breast Dis
2005
;
23
:
53
–65.
89
Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.
J Clin Oncol
1994
;
12
:
447
–53.
90
EBCTCG Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and on 15 year survival: an overview of the randomized trials. Lancet 2005.
91
Violet JA, Harmer C. Breast cancer: improving outcome following adjuvant radiotherapy.
Br J Radiol
2004
;
77
:
811
–20.
92
Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries.
Lancet Oncol
2005
;
6
:
557
–65.
93
Patt DA, Goodwin JS, Kuo Y-F, et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer.
J Clin Oncol
2005
;
23
:
7475
–82.
94
Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer.
J Natl Cancer Inst
2007
;
99
:
365
–75.
95
Correa CR, Litt HI, Hwang W-T, et al. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer.
J Clin Oncol
2007
;
25
:
3031
–7.
96
Marks LB, Yu X, Prosnitz RG, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects.
Int J Radiatfs Oncol Biol Phys
2005
;
63
:
214
–23.
97
Hojris I, Sand NPR, Andersen J, Rehling M, Overgaard M. Myocardial perfusion imaging in breast cancer patients treated with or without post-mastectomy radiotherapy.
Radiother Oncol
2000
;
55
:
163
–72.
98
Hurkmans CW, Cho BC, Damen E, Zijp L, Mijnheer BJ. Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation.
Radiother Oncol
2002
;
62
:
163
–71.
99
Korreman SS, Pedersen AN, Josipovic M, et al. Cardiac and pulmonary complication probabilities for breast cancer patients after routine end-inspiration gated radiotherapy.
Radiother Oncol
2006
;
80
:
257
–62.
100
Hui SK, Das RK, Kapatoes J, et al. Helical tomotherapy as a means of delivering accelerated partial breast irradiation.
Technol Cancer Res Treat
2004
;
3
:
639
–46.
101
Prosnitz RG, Marks LB, Yu HC. Cardiac toxicity following thoracic radiation. Semin Oncol 2005;32.
102
Mitani I, Jain D, Joska TM, Burtness B, Zaret BL. Doxorubicin cardiotoxicity: prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radinuclide angiocardiography in the current era.
J Nucl Cardiol
2003
;
10
:
132
–9.
103
Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management.
Circulation
2004
;
109
:
3122
–31.
104
Marchandise B, Schroeder E, Bosly A, et al. Early detection of doxorubicin cardiotoxicity: interest of Dopler echocardiographic analysis of left ventricular filling dynamics.
Am Heart J
1989
;
118
:
92
–8.
105
Aurigemma GP. Diastolic heart failure-a common and lethal condition by any name.
N Engl J Med
2006
;
355
:
308
–10.
106
Dabbah S, Reisner SA, Aronson D, Agmon Y. Left ventricular filling hemodynamics in patients with pulmonary edema and preserved versus reduced left ventricular ejection fraction: a prospective Doppler echocardiographic study.
J Am Soc Echocardiogr
2006
;
19
:
733
–43.
107
Schwartz RG, McKenzie WB, Alexander J, et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography.
Am J Med
1987
;
82
:
1109
–18.
108
Ritchie JL, Singer JW, Thorning D. Anthracycline cardiotoxicity: clinical and pathologic outcomes assessed by radionuclide ejection fraction.
Cancer
1980
;
46
:
1109
–16.
109
Nielsen D, Jensen JB, Dombernowsky P, et al. Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer.
J Clin Oncol
1990
;
8
:
1806
–10.
110
Cannesson M, Tanabe M, Suffoletto MS, et al. A novel two-dimensional echocardiographic image analysis system using artificial intelligence-learned pattern recognition for rapid automated ejection fraction.
J Am Coll Cardiol
2007
;
49
:
217
–26.
111
Mason JW, Bristow MR, Billingham ME, Daniels JR. Invasive and noninvasive methods of assessing Adriamycin cardiotoxic effects in man: superiority of histopathologic assessment using endomyocardial biopsy.
Cancer Treat Rep
1978
;
62
:
857
–64.
112
Ewer MS, Ali MK, Mackay B, et al. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.
J Clin Oncol
1984
;
2
:
112
–7.
113
Steinherz LJ, Yahalom J. Cardiac toxicity. In: DeVita VT, Jr., Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncol 6th ed. Philadelphia (PA): Lippincott, Williams & Wilkins; 2001. p. 2904–21.
114
Dardir MD, Ferrans VJ, Mikhael YS, et al. Cardiac morphologic and functional changes induced by epirubicin chemotherapy.
J Clin Oncol
1989
;
7
:
947
–58.
115
Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: The M.D. Anderson Cancer Center Experience.
J Clin Oncol
2006
;
24
:
4107
–15.
116
Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.
J Am Coll Cardiol
2000
;
36
:
517
–22.
117
Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy.
Circulation
2004
;
109
:
2749
–54.
118
Daugaard G, Lassen U, Bie P, et al. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction.
Eur J Heart Failure
2005
;
7
:
87
–93.
119
Petricoin EF, Rajapaske V, Herman EH, et al. Toxicoproteomics: serum proteomic pattern diagnostics for early detection of drug induced cardiac toxicities and cardioprotection.
Toxicol Path
2004
;
32
:
122
–30.
120
Bellenger NG, Grothues F, Smith GC, Pennell DJ. Quantification of right and left ventricular function by cardiovascular magnetic resonance.
Herz
2000
;
25
:
392
–9.
121
Mansky P, Arai A, Stratton P, et al. Treatment late effects in long-term survivors of pediatric sarcoma. Pediatr Blood Cancer 2006.
122
Ingkanisorn WP, Paterson DI, Calvo KR, et al. Cardiac magnetic resonance appearance of myocarditis caused by high dose IL-2: similarities to community-acquired myocarditis.
J Cardiovasc Magn Reson
2006
;
8
:
353
–60.
123
Wakasugi S, Wada A, Hasegawa Y, Nakano S, Shibata N. Detection of abnormal cardiac adrenergic neuron activity in Adriamycin-induced cardiomyopathy with iodine-125-metaiodobenzylguanidine.
J Nucl Med
1992
;
33
:
208
–14.
124
Higuchi T, Schwaiger M. Imaging cardiac neuronal function and dysfunction.
Curr Cardiol Rep
2006
;
8
:
131
–8.
125
Maini CL, Sciuto R, Ferraironi A, et al. Clinical relevance of radionuclide angiography and antimyosin immunoscintigraphy for risk assessment in epirubicin cardiotoxicity.
J Nucl Cardiol
1997
;
4
:
502
–8.
126
Valdes Olmos RA, Carrio I, Hoefnagel CA, et al. High sensitivity of radiolabelled antimyosin scintigraphy in assessing anthracycline related early myocyte damage preceding cardiac dysfunction.
Nucl Med Comm
2002
;
23
:
871
–7.
127
Ng R, Better N, Green MD. Anticancer agents and cardiotoxicity.
Semin Oncol
2006
;
33
:
2
–14.
128
Behr TM, Behe M, Wormann B, et al. Trastuzumab and breast cancer [1] (multiple letters).
N Engl J Med
2001
;
345
:
995
–8.
129
Perik PJ, Lub-De Hooge MN, Gietema JA, et al. Indium-111-Labeled Trastuzumab Scintigraphy in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.
J Clin Oncol
2006
;
24
:
2276
–82.