One of the most common manifestations of cardiotoxicity associated with exposure to anticancer therapies is the development of left ventricular dysfunction (LVD) and overt heart failure. According to the Cardiac Review and Evaluation Committee [5], LVD is characterized by [1] decrease in cardiac left ventricular ejection fraction (LVEF) that was either global or more severe in the septum; [6] symptoms of congestive heart failure (CHF) ; [7] associated signs of CHF, including but not limited to S3 gallop, tachycardia, or both; and [2] decline in LVEF of at least 5% to less than 55% with accompanying signs or symptoms of CHF or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms. Several chemotherapeutic agents may cause LVD such as antimetabolites, alkylating agents, antitumor antibiotics, and anthracyclines.

Anthracyclines , including doxorubicin and epirubicin, are a class of chemotherapeutics widely used in the management of breast cancer. Risk factors for anthracycline toxicity include cumulative dose; intravenous bolus administration; higher single doses; history of prior mediastinal irradiation; the use of other concomitant agents known to have cardiotoxic effects including cyclophosphamide, trastuzumab , and paclitaxel; female gender; underlying cardiovascular disease; age (young and elderly); increased length of time since completion of chemotherapy; and increase in cardiac biomarkers during or after administration [8–11]. Anthracycline-induced LVD occurs in part from direct myocyte damage that has been ascribed to the production of oxygen free radicals and subsequent rise in oxidative stress [6], either directly through redox cycling of the quinone moiety or indirectly through inhibition of topoisomerase IIb, leading to mitochondrial dysfunction. Iron homeostasis might also have a role in the myocardial injury as anthracyclines inhibit the iron metabolism pathways and induce iron accumulation in the cardiomyocytes [7]. A consequence is cardiac cell death by apoptosis or necrosis after exposure to anthracyclines. Genetic studies have identified several loci associated with sensitivity to anthracycline-induced cardiac damage including polymorphisms of multidrug resistance proteins (MDR) 1 and 2, carbonyl reductase, subunits of NADPH oxidase, and phase II detoxification enzymes such as glutathione-S-transferase P and most recently retinoic acid receptor gamma [12].

Cardiotoxicity induced by anthracyclines can be categorized into acute, early-onset chronic progressive, and late-onset chronic progressive. Acute cardiotoxicity occurs in 1% of patients, and it is usually observed within 14 days from the beginning of the treatment. It manifests as an acute, transient decline in myocardial contractility, which is usually reversible. The early-onset chronic progressive form occurs in 1.6–2.1% of patients, during therapy or within the first year after treatment. Late-onset chronic progressive occurs at least 1 year after completion of therapy in 1.6–5% of patients. Early- and late-onset chronic progressive cardiotoxicity typically present as a dilated cardiomyopathy in adults, which can be progressive. The risk of cardiac complications is relatively lower with the use of liposome-encapsulated doxorubicin, which is associated with lower myocardial accumulation. Some clinical data suggest that patients who previously received conventional anthracyclines can still receive liposomal preparations even if they have received the maximum cumulative dose of the drug [13, 14].

LVD has also been described for two other classes of cytotoxic agents: alkylating agents and inhibitors of microtubule polymerization. In the first case the risk of cardiotoxicity appears to be dose related (≥150 mg/kg and 1.5 g/m²/day) [15]. Cyclophosphamide cardiotoxicity is not well understood. Extravasation of blood, interstitial edema, and myocardial necrosis associated with fibrin microthrombi could have a role in this process [16]. The incidence of heart failure associated with the inhibitors of microtubule polymerization is relatively low. In the Breast Cancer International Research Group trial 001, the overall incidence of congestive HF (including that during follow-up) was 1.6% among patients treated with TAC regimen (docetaxel, doxorubicin, cyclophosphamide) and 0.7% for those treated with FAC regimen (5-fluorouracil, doxorubicin, cyclophosphamide) (P50.09) [17].

Within the past decade, the advent of biologic targeted agents has brought into the clinic additional therapies with cardiotoxic concerns. Trastuzumab , a humanized monoclonal antibody against the HER2 receptor, has revolutionized the treatment for HER2-positive breast cancer, with landmark adjuvant phase 3 trials demonstrating a 50% reduction in recurrence of disease and a 33% improvement in survival [18–21]. Rates of cardiac toxicity reported in the adjuvant trials of trastuzumab are variable and reflect differences in trial design, chemotherapy administration, and definitions of cardiac events. In the trastuzumab adjuvant trials [18–20, 22] (Table 10.2), the highest reported incidence of symptomatic or severe cardiac heart failure (CHF) with trastuzumab was 4%, which occurred when trastuzumab was administered with paclitaxel after anthracycline exposure. A low rate of 0.4% CHF was reported in the BCIRG 006 adjuvant trial examining the trastuzumab/docetaxel/carboplatin combination regimen without prior anthracycline therapy [18]. The exact pathogenesis of trastuzumab-induced cardiac damage remains unclear. Trastuzumab is thought to cause cardiac dysfunction through the interruption of the HER2/ErbB2 signaling pathway in myocardium, thus interfering with normal growth, repair, and survival of cardiomyocytes [24]. Another suggested mechanism of trastuzumab cardiotoxicity is linked to the effect on cardiomyocytes of cytotoxic immune reactions triggered by the IgG1 domain of trastuzumab [25] and the modulation of mitochondrial integrity via the Bcl-X family proteins that leads to ATP depletion and to contractile dysfunction [26]. There is also emerging evidence for a role of NRG/ErbB signaling in regulation of sympathetic tone, which may also play a role in the observed effects on cardiac function [65].

Lapatinib is an oral receptor tyrosine kinase inhibitor of HER2 and EGFR and is estimated to have a risk of cardiotoxicity of 1.6%. In clinical study, asymptomatic cardiac events were reported in 53 patients (1.4%), and symptomatic events occurred in 7 (0.2%). In patients treated with prior anthracyclines, trastuzumab, or neither, the incidence of cardiac events was 2.2%, 1.7%, and 1.5%, respectively. The mean time to onset of cardiac events was 13 weeks [27].

Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF) and is not longer an approved regimen for breast cancer. Cardiac toxicity associated with bevacizumab appears to be relatively low. In the major phase III trials in metastatic breast cancer, reported rates of CTCAE grade 3/4 congestive heart failure were 0.8–2.2% in a mostly anthracycline-pretreated population [28]. To date, clinical trial data do not suggest significant increases in cardiac toxicity during treatment with bevacizumab, even in the setting of concurrent treatment with other cardiotoxic agents.

At present, the most frequently used modality for detecting LVD is the periodic measurement of LVEF by either echocardiography or multigated acquisition scanning. However, LVEF measurement is a relatively insensitive tool for detecting cardiotoxicity at an early stage because there is little change in resting LVEF until a critical amount of myocardial damage has taken place, and it may only be apparent after compensatory mechanisms are exhausted. In addition, measurement of LVEF presents a number of challenges related to image quality, assumption of left ventricular geometry, load dependency, and expertise. Multiple-gated acquisition (MUGA) scan can reduce interobserver variability; however disadvantages include exposure to radioactivity as well as limitations in information that can be obtained about cardiac structure and diastolic function. Magnetic resonance imaging (MRI) is considered the gold standard for the evaluation of LV volumes, mass, and function. However, lack of availability and high cost limit its routine use. Novel ultrasound imaging techniques, such as contrast echocardiography and real-time 3D echocardiography, are under investigation.

The treatment of LVD induced by anticancer drugs includes standard therapy for heart failure with ACE inhibitors (ACE-I) and beta blockers (BB) , which may be highly effective [29, 30]. Randomized prospective clinical trials are evaluating the use of prophylactic ACE inhibitors and beta blockers in the prevention of chemotherapy-induced LVD [31]. The OVERCOME trial showed that the combined treatment with enalapril and carvedilol may prevent heart failure in patients treated for hematologic malignancies [31]. The MANTICORE study is evaluating the efficacy of perindopril and bisoprolol in the prevention of trastuzumab-mediated left ventricular remodeling in HER2-positive breast cancer [32]. Dexrazoxane, an iron-chelating agent and topoisomerase II inhibitor, significantly reduces anthracycline-related cardiotoxicity in adults with different solid tumors including breast cancer and in children with acute lymphoblastic leukemia and Ewing’s sarcoma [33]. Dexrazoxane is not routinely used in clinical practice, and it is recommended as a cardioprotectant only for patients with metastatic breast cancer who have already received more than 300 mg/m² of doxorubicin.

Although rare, acute coronary syndromes including myocardial infarction have been associated with administration of cytotoxic, hormonal, and targeted agents for cancer treatment. Antimetabolites and inhibitors of microtubule polymerization are most frequently responsible for ischemic heart disease. The antimetabolite 5-Fluorouracil (FU) is associated with cardiac ischemia, including angina pectoris and acute myocardial infarction [34]. Ischemia can take place in patients without underlying coronary artery disease (CAD) (incidence, 1.1%), but the incidence is higher in patients with known CAD (4.5%) [35]. Cardiac events typically occur early (within 2–5 days of starting therapy) and with return of risk to baseline after cessation of the 5-FU and implementation of preventative medical therapy. High doses (>800 mg/m²) and continuous infusions of 5-FU have been associated with higher rates of cardiotoxicity (7.6%) as compared with bolus injections (2%) [36, 37]. Other commonly cited risk factors include history of cardiovascular disease, prior mediastinal radiation, and the concurrent use of additional chemotherapy [38]. The incidence and risk factors of cardiotoxicity of capecitabine, an oral 5-FU analog, are poorly defined. From the four retrospective reviews published, the incidence of cardiotoxicity ranges from 3 to 9% [39–42]. Coronary artery thrombosis , arteritis, or vasospasm secondary to drug exposure have been proposed as the most likely underlying mechanisms of acute coronary syndromes associated with 5-FU and capecitabine. Other alternative mechanisms could be involved, including direct toxicity on myocardium, interaction with coagulation system, and autoimmune responses [43].

Paclitaxel administration has been associated with cases of myocardial ischemia and infarction. In a large study of approximately 1000 patients, the incidence of cardiac toxicity was 14% [44]. The etiology of myocardial ischemia associated with paclitaxel is thought to be multifactorial, with other drugs and underlying heart disease as possible contributing factors [45]. In addition, the Cremophor EL vehicle in which paclitaxel is formulated may play a role in its cardiac toxicity, which has been attributed to its induction of histamine release [45].

Endocrine agents , such as tamoxifen [46], and aromatase inhibitors [47], which are widely used in the treatment of hormone receptor-positive breast cancer, are associated with rare cardiac ischemia risk. Cardiac events, including myocardial infarction and cardiac failure, have been reported at very low frequency in the major adjuvant trials comparing use of AIs to a control arm of 5 years of tamoxifen [48]. Differential changes in lipid profile have been proposed as an etiology for these observations; however, a strong signal linking AIs and relevant changes in lipid levels is lacking.

The management of cardiac ischemia and coronary heart disease is similar to the management of patients with coronary artery disease without cancer, with an emphasis after intervention on platelet inhibition [49].