Anthracycline cardiotoxicity can present as either acute, early-onset chronic progressive, or late-onset chronic progressive cardiotoxicity [12]. Acute cardiotoxicity often presents within the first week of anthracycline exposure and usually recovers with withdrawal of the offending agent. Recent prospective observational data in 2625 adults treated with anthracyclines suggests that the majority (98 %) of anthracycline cardiotoxicity presents early within the first year of therapy [13]. This can progress to chronic cardiomyopathy , with a predominantly dilated phenotype in adults and a restrictive phenotype in pediatric patients [14]. Anthracyclines can also cause a more subtle, chronic cardiomyopathy which presents years to decades after anthracycline treatment [15]. This form of anthracycline-associated cardiomyopathy often results in ventricular dysfunction [15] with the subsequent development of clinical heart failure and arrhythmias [16].

There are no reported risk factors for the development of acute cardiotoxicity related to anthracycline administration. Risk factors for early- and late-onset anthracycline cardiotoxicity include cumulative anthracycline dose, concurrent mediastinal radiation, extremes of age, female gender, and cardiac risk factors or preexisting heart disease [14]. A formula for estimating the likelihood of developing cardiomyopathy from anthracycline exposure is shown below:
where Y = the likelihood of developing cardiomyopathy, X = the number of cycles of anthracycline therapy, and a = a correction constant determined by the cycle dose and the duration between cycles [3].

Asymptomatic cardiomyopathy can progress to symptomatic heart failure and carries an adverse prognosis. Since the physical exam alone may miss over 50 % of early and potentially reversible cases of anthracycline-induced cardiomyopathy [17], serial and post-therapy monitoring with electrocardiograms (ECGs) , echocardiograms , and biomarkers , such as troponin I , may be beneficial in high-risk patients and has been recommended by some groups [18]. However, this strategy is not universally agreed upon and is an active area of guideline development.

Traditionally, multi-gated blood pool imaging (MUGA) was used to assess serial left ventricular ejection fractions (LVEF) during chemotherapy. Due to concerns related to the radiation exposure associated with MUGA, two-dimensional echocardiography has become the accepted modality for assessing serial LVEF in patients treated with anthracyclines. Based on data using MUGA, a baseline evaluation of LVEF is recommended prior to starting anthracyclines. If the baseline LVEF is >50 %, serial measurement is recommended after a cumulative anthracycline dose of 250–300 mg/m², then after 450 mg/m², and after each subsequent cycle at doses >450 mg/m². Anthracycline therapy should be discontinued if the LVEF declines ≥10 % from baseline to ≤50 % [19]. For patients with preexisting LV dysfunction (baseline LVEF <50 %), anthracycline therapy is not recommended for LVEF <30 %. Patients with an LVEF 30–50 % can receive anthracyclines, but their LVEF should be carefully monitored before each subsequent dose, and anthracyclines should be discontinued if the EF falls ≥10 % from baseline to <30 % [19].

A recent consensus statement released by the American Society of Echocardiography and the European Association of Cardiovascular Imaging updated these recommendations to suggest that in patients receiving ≤240 mg/m² of anthracyclines, echocardiograms should be performed at baseline, at completion, and 6 months after the completion of anthracycline therapy [18]. In patients receiving >240 mg/m², additional imaging is recommended before each additional 50 mg/m². Newer echocardiographic techniques such as strain rate imaging, a marker of myocardial deformation, may predict early cardiotoxicity prior to the development of overt LV dysfunction [20]. Measurement of global longitudinal strain along with LVEF has also been recommended to identify at-risk patients who may benefit from early intervention [20]. None of these screening recommendations have been incorporated into guidelines or uniformly accepted in clinical practice.

Biomarkers, such as B-type natriuretic peptide (BNP) and troponins, have been used in research settings to stratify patients into baseline risk categories prior to anthracycline administration. There is data to suggest that the presence of an elevated troponin at any time during anthracycline administration increases the risk of cardiotoxicity [21]. The likelihood of toxicity is even greater among patients with a persistently elevated troponin, even after discontinuation of anthracycline therapy [22]. An elevated troponin , at any time during anthracycline administration, has been used as a marker to identify high-risk patients who might benefit from early initiation of cardiac therapy [23].

The American Heart Association and American College of Cardiology define four stages of heart failure that reflect progressive disease and can be used to guide heart failure therapy (Table 4.2). Patients receiving potentially cardiotoxic chemotherapies are defined as having Stage A heart failure or are deemed to be “at risk” for the development of heart failure. As such, several strategies have been examined to reduce the risk of anthracycline cardiotoxicity.

Dose limitation and continuous, rather than bolus, infusions to limit peak serum concentrations appear to decrease cardiotoxicity [24]. There have been modifications of doxorubicin which may reduce the overall cardiotoxic effects; liposomal preparations , epirubicin , and mitoxantrone all appear to be associated with a lower risk of heart failure than doxorubicin [25]. However, the data comparing these agents are not robust except for liposomal-encapsulated doxorubicin which is associated with a significantly lower rate of both asymptomatic and symptomatic heart failure than conventional doxorubicin [26]. Dexrazoxane is an iron chelator that binds free iron and prevents the formation of anthracycline-iron complexes that contribute to oxygen free radical formation. Dexrazoxane has proven to be effective in reducing anthracycline-mediated cardiotoxicity when doxorubicin has been administered at doses ≥300 mg/m², without compromising the efficacy of cancer treatment [27]. Unfortunately, dexrazoxane treatment in children has been associated with an increased risk of myelodysplastic syndrome and acute myelogenous leukemia when given in combination with other drugs known to be associated with secondary leukemias [28]. While there is considerable debate that this increase in late hematologic malignancies may be related to other chemotherapies administered to children rather than dexrazoxane, this observation has led the US Food and Drug Administration and the European Medicines Agency to restrict the use of dexrazoxane to adult patients with advanced or metastatic breast cancer who have already received a certain amount of the anthracyclines: doxorubicin (300 mg/m²) or epirubicin (540 mg/m²). Novel agents such as engineered bivalent neuregulin-1β have been shown to reduce the double-stranded DNA breaks associated with anthracycline exposure and attenuate LV dysfunction in animal models of anthracycline-induced cardiomyopathy [29]. However, neuregulin analogs may have pro-neoplastic effects, and further translational studies are needed to evaluate their utility as cardioprotective agents.

Prophylactic use of angiotensin converting enzyme inhibitors (ACEi) has also been proposed. In a randomized open-label trial, 125 lymphoma patients who had received doxorubicin were assigned 1:1:1 to enalapril, metoprolol, or no therapy. There was no significant difference in left ventricular ejection fraction (LVEF) or heart failure between the three groups over a median follow-up period of 31 months [30]. In another study of 473 patients, troponin I levels were measured following each cycle of anthracyclines . The 114 patients with a positive troponin were randomized to receive enalapril or placebo starting one month after the final cycle. None of the patients in the enalapril-treated group developed subsequent cardiomyopathy (>10 % reduction in LVEF from baseline to <50 %) compared to 43 % in the placebo group [23].

Beta-blockers have also been evaluated for the prevention of heart failure related to anthracyclines. Carvedilol has been shown in a small, randomized study of 50 patients to prevent LV dysfunction in patients being treated with high-dose (mean >500 mg/m²) anthracyclines [31]. By 6 months, patients treated with carvedilol 12.5 mg once daily had no change in their LVEF compared to a mean reduction in LVEF from 69 % to 52 % in the placebo-treated group [31]. Similar findings were noted in a trial of 45 patients being treated with anthracyclines randomized to nebivolol vs. placebo [32].

The OVERCOME (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) trial randomized 90 patients with hematologic malignancies undergoing high-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation, to either placebo or a combination of enalapril (mean daily dose 8.6 mg) and carvedilol (mean daily dose 23.8 mg) [33]. Patients treated with enalapril and carvedilol had no significant change in LVEF, compared to an absolute 3 % reduction in LVEF in the placebo group as estimated both with echocardiography and cardiac MRI at baseline and six months. There was also a significant reduction in the composite end point of death, heart failure, or LVEF <45 % in the treatment group by 6 months (6.7 vs. 24.4 %, p = 0.02) [33]. The recently completed PRADA (PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy ) trial evaluated the effect of prophylactic candesartan and metoprolol in 120 patients with early breast cancer treated with anthracyclines ± trastuzumab and radiation [34]. In this study, patients were randomized in a 2 × 2 factorial design to candesartan (8–32 mg daily), metoprolol (25–100 mg daily), or placebo prior to initiating anthracyclines and were evaluated for change in LVEF by cardiac MRI from baseline to the end of adjuvant chemotherapy. LVEF declined less in candesartan-treated patients relative to placebo (0.6 vs. 2.6 %, p = 0.021). However, there was no difference in LVEF between metoprolol- and placebo-treated patients [34]. Thus, in totality, while there is data supporting the prophylactic use of ACEi, angiotensin receptor blockers, and certain beta-blockers to prevent anthracycline-induced cardiomyopathy, the small size of these clinical trials, limited follow-up, and the large number of patients that would need to be placed on these medications have prevented the routine use of these medications in clinical practice.

Incidental use of statins has also been associated with a lower rate of heart failure in a small propensity score-matched retrospective study [35]. However, at this point there is insufficient data to recommend initiation of statin therapy in patients without a preexisting indication.

Trastuzumab-induced cardiomyopathy most often presents as an asymptomatic decrease in LVEF and less commonly as overt heart failure during trastuzumab treatment. In contrast to anthracyclines, trastuzumab-induced cardiac dysfunction does not appear to be dose dependent, and the cardiotoxicity is often reversible with discontinuation of therapy.

In a phase III trial of chemotherapy with or without trastuzumab for metastatic breast cancer, 33 patients continued therapy with trastuzumab for an additional 6–7 months despite developing a cardiac event (most often an asymptomatic decline in LVEF). After stopping trastuzumab therapy, the LVEF was stable or improved for 85 % of patients, and heart failure symptoms were completely reversible for 75 % of patients treated with standard heart failure therapy [42].

In the pivotal trial by Slamon et al., the incidence of cardiotoxicity in patients with metastatic breast cancer treated with trastuzumab alone was 3–7 % [43]. The incidence of cardiotoxicity in patients treated with trastuzumab, anthracyclines, and cyclophosphamide was as high as 27 % [44]. In 2012, a meta-analysis of 8 trials and almost 12,000 patients with HER-2-positive breast cancer demonstrated a significantly increased risk of asymptomatic cardiomyopathy (relative risk 1.83) and “severe” heart failure (relative risk 5.11) in patients treated with trastuzumab versus non-trastuzumab chemotherapy . The rate of severe heart failure among those treated with non-trastuzumab regimens was 0.4 % compared to 2.5 % among those treated with trastuzumab-based chemotherapies [45].

Age greater than 50 years and previous or concurrent anthracycline use are the primary risk factors for the development of trastuzumab-induced cardiomyopathy [46]. Patients who receive concurrent anthracyclines, especially when the anthracycline is doxorubicin and the cumulative dose exceeds 300 mg/m², are at the highest risk of developing trastuzumab-induced cardiomyopathy [47–49]. Other cardiovascular risk factors such as hypertension, obesity, and a prior diagnosis of heart disease increase the risk of trastuzumab-induced cardiomyopathy [46, 50]. There is limited data to suggest that in elderly women, the risk of cardiotoxicity is higher among those with diabetes [51].

LVEF should be assessed prior to the initiation of trastuzumab therapy. When trastuzumab therapy follows anthracycline treatment, LVEF should be assessed after the completion of anthracycline therapy and prior to the initiation of the trastuzumab [52]. Patients with a normal baseline LVEF can begin trastuzumab therapy. Patients with a mildly reduced LVEF 40–50 % should have the risks and benefits carefully weighed before initiating trastuzumab and may benefit from pretreatment cardiology consultation.

There are no established guidelines for LVEF monitoring during trastuzumab therapy. In the adjuvant setting, echocardiography is recommended at baseline and every 3 months during trastuzumab therapy [18, 52]. In the metastatic setting, most recommend LVEF monitoring at baseline and thereafter as clinically indicated. If the LVEF declines more than 15 % from baseline or 10 % from baseline to below 50 %, trastuzumab should be held for a month before the LVEF is reassessed. If the LVEF remains low or there is evidence of symptomatic heart failure, trastuzumab should be discontinued [53].

Given that an elevation in troponin predicts cardiotoxicity with anthracyclines, studies have examined the utility of baseline and post-trastuzumab troponin monitoring. In a multivariable analysis of over 250 patients, an elevated troponin at baseline was a significant predictor of trastuzumab-induced decline in LVEF [54]. Older patients, those with a positive troponin, those with a marked reduction in LVEF, or those who develop cardiotoxicity early in the course of trastuzumab treatment are less likely to recover left ventricular function to baseline values [54].

Like anthracyclines, patients receiving HER-2-targeted therapies are believed to have Stage A heart failure. Data supporting the use of prophylactic beta-blockers in patients treated with trastuzumab are derived from a retrospective, propensity-matched cohort study. This study found that breast cancer patients on incident beta-blockers were less likely to develop trastuzumab-induced heart failure, compared to those who were not treated with a beta-blocker [55]. The recent MANTICORE (Multidisciplinary Approach to Novel Therapies In Cardiology Oncology REsearch ) trial evaluated the cardioprotective effects of prophylactic perindopril (target daily dose 8 mg) or bisoprolol (target daily dose 10 mg) in 94 patients with HER-2-positive breast cancer treated with trastuzumab [56]. Neither drug prevented trastuzumab-induced LV remodeling which was the primary end point of the study. However, in a secondary analysis, both perindopril (3 %) and bisoprolol (1 %) resulted in a smaller decline in LVEF from baseline to 12 months, compared to placebo (5 %). Furthermore, both perindopril (1/33) and bisoprolol (1/31) resulted in fewer trastuzumab interruptions compared to placebo (8/30) [56]. Several randomized clinical trials are currently underway to assess whether prophylactic ACEi and/or beta-blockers reduce the risk of trastuzumab-induced cardiotoxicity.

The 2013 American College of Cardiology Foundation/American Heart Association Task Force guidelines and the 2006 Canadian Cardiovascular Society guidelines do not specifically mention chemotherapy-induced cardiomyopathy [57, 58]. The 2010 Heart Failure Society of America guidelines recommend that in patients with established heart failure who are undergoing treatment with potential cardiotoxic chemotherapy, repeat measurements of LVEF should be considered as long as there is no clinical evidence of deterioration [54]. The 2012 European Society of Cardiology guidelines contain a paragraph about cardiomyopathy in the setting of concurrent cancer. These guidelines name anthracyclines and trastuzumab specifically as the “best recognized” chemotherapy agents associated with left ventricular systolic dysfunction. The guidelines state that dexrazoxane may confer some cardioprotection. Finally, the European guidelines recommend at least pre- and post-anthracycline LVEF assessment. Furthermore, they recommend that patients who develop systolic dysfunction should have their anthracyclines stopped and should undergo “standard” treatment for HFrEF [59].

Pharmacologic therapy in heart failure is intended to reverse or prevent progressive adverse left ventricular remodeling, improve clinical symptoms, and reduce morbidity and mortality.

ACEi are one of the most important classes of drugs in the management of HFrEF. ACEi have been shown to improve survival in both asymptomatic (Stage B) and symptomatic (Stage C) patients with LVEF ≤40 [60–62]. Notably, similarly positive results have been seen with angiotensin receptor blockers (ARBs) in patients who are unable to tolerate ACEi [63].

Serial imaging as per the recommended consensus statements permits the detection of left ventricular dysfunction prior to the development of symptomatic heart failure (Stage B). According to published cardiology guidelines, all patients with Stage B heart failure should receive an ACEi or ARB to promote recovery/stabilization of left ventricular function and prevent the development of symptoms. In a prospective study of 2625 anthracycline-treated patients followed by serial echocardiography, 9 % developed cardiomyopathy (defined as a >10 % decline in LVEF from baseline to <50 %) over a median follow-up of 5.2 years. Most of these patients (81 %) had none or minimal heart failure symptoms, and early initiation of ACEi and beta-blocker therapy resulted in either full (11 %) or partial recovery (71 %) of LV function in majority of patients [54]. Similarly, in a cohort of 251 breast cancer patients treated with trastuzumab and followed by serial echocardiography, 17 % developed cardiotoxicity. Interruption of trastuzumab and initiation of ACEi and beta-blockers facilitated recovery of LVEF to >50 % in 60 % of patients [54]. In contrast, the effectiveness of ACEi in childhood cancer survivors with anthracycline cardiotoxicity remains unclear [64].