Version May 2024
INTRODUCTION — The anthracyclines and related compounds (doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone) are among the chemotherapeutic agents implicated in cardiotoxicity. Most commonly, anthracycline therapy is associated with left ventricular (LV) systolic dysfunction due to myocyte damage and replacement by fibrous tissue [1].
The clinical manifestations, diagnosis, management, and prognosis of anthracycline-induced cardiotoxicity will be reviewed here.
The mechanisms, risk factors, and approach to prevention of anthracycline cardiotoxicity and the cardiovascular complications of anthracyclines are presented separately. (See "Risk and prevention of anthracycline cardiotoxicity".)
The cardiotoxicity of other classes of chemotherapy agents is discussed separately. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)
CLINICAL MANIFESTATIONS
Specific presentations — The clinical manifestations of anthracycline toxicity are primarily those of heart failure (HF) and arrhythmias:
●Heart failure – The clinical manifestations of LV systolic dysfunction induced by anthracycline exposure are similar to those observed in patients with other causes of HF and include dyspnea, fatigue, edema, orthopnea, and cardiogenic shock. The details on the clinical manifestations and diagnosis of HF are discussed separately. (See "Heart failure: Clinical manifestations and diagnosis in adults".)
●Palpitations or other signs of an arrhythmia – Patients may present with palpitations or other signs of an intermittent or sustained arrhythmia (eg, sudden death) [2]. In acute toxicity, atrial fibrillation may be a more common presentation than HF. For example, in a cohort of 1697 patients aged 18 to 75 years old receiving a doxorubicin-based regimen for lymphoma, 55 (3.2 percent) developed evidence of acute cardiotoxicity; among 44 cases reviewed in detail, the early manifestations of anthracycline toxicity included atrial fibrillation (n = 12), acute HF (n = 5), myocarditis (n = 2), and myocardial infarction (n = 1) [3]. Once anthracycline-associated cardiomyopathy is diagnosed, arrhythmias do not appear to be more common than in other causes of cardiomyopathy [4].
●Other findings – Patients with anthracycline cardiotoxicity may undergo testing that reveals an elevated troponin, an elevated B-type natriuretic peptide (BNP), or decreased LV systolic or diastolic function.
•Systolic dysfunction – Patients who present with abnormal LV systolic function as the result of routine screening may be symptomatic or asymptomatic.
•Diastolic dysfunction – After anthracyclines, some studies have reported subclinical diastolic dysfunction [5-8], HF with preserved ejection fraction, or restrictive cardiomyopathy [9-11].
•Elevated troponin – Anthracycline exposure does not primarily lead to acute myocardial infarction, myocarditis, or pericarditis. However, in prospective studies, elevated troponin levels or evidence of myocardial injury occurred in up to 30 percent of patients [12,13].
•Elevated BNP – In a patient with ongoing or remote anthracycline exposure, an elevation in BNP levels may be a sign of ventricular dysfunction caused by anthracyclines [14].
•Prolonged QT interval – Prolongation of the QT interval (ie, QTc) is a rare manifestation of anthracycline toxicity [15].
Time course of presentation — The available evidence suggests that anthracycline-induced injury to the heart occurs during exposure and evolves over time [16]. In our experience, HF and arrhythmias can manifest acutely (within weeks of exposure), while most patients who present in the months to years after anthracycline exposure present with HF and complications of LV systolic dysfunction (eg, congestion, cardiogenic shock).
Further details on the mechanisms of anthracycline toxicity and the time course of injury can be found separately. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Mechanisms and time course of cardiotoxicity'.)
EVALUATION
When to suspect anthracycline cardiotoxicity — The diagnosis of anthracycline cardiotoxicity is typically suspected in one of the following scenarios:
●Presentation with symptoms of HF, an arrhythmia, or another cardiac abnormality during or remote from anthracycline exposure.
●Detection of reduced systolic function with routine monitoring during or after anthracycline treatment. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Monitoring during and after treatment'.)
Initial testing — In patients who present with signs or symptoms of potential cardiotoxicity during or remote from anthracycline therapy, a complete cardiac assessment is required. The initial assessment should include:
●Focused history and physical examination – Each patient should undergo a history and physical examination with a focus on cardiovascular risk factors or preexisting cardiovascular disease (eg, coronary artery disease, atrial fibrillation, echocardiographic abnormalities).
●Anthracycline exposure history – We obtain a detailed history of anthracycline exposure that includes the specific agent(s), cumulative dose, the age at which the anthracycline was administered, and method of delivery (eg, infusional versus bolus). The specific risk factors for anthracycline toxicity are described elsewhere. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Risk factors'.)
●Exposure to other cardiotoxic cancer therapies – Other cancer therapies can cause or exacerbate cardiotoxicity. Thus, we obtain a detailed history of exposure to other potentially cardiotoxic cancer therapies such as:
•Radiation to the chest. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies".)
•Human epidermal growth factor receptor 2 (HER2)-targeted therapies (eg, trastuzumab). (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
•Cyclophosphamide. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Cyclophosphamide'.)
•Fluoropyrimidine agents. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)
•Protein kinase inhibitors. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".)
●ECG – We obtain an electrocardiogram (ECG) to evaluate for conduction system abnormalities (eg, QTc prolongation, arrhythmias such as atrial fibrillation).
●Echocardiography – If not already performed, we obtain a complete echocardiogram with use of echo contrast as appropriate. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique".)
Additional diagnostic testing — Following the initial evaluation, additional testing is only required in scenarios where the results of initial evaluation are not definitive (eg, nondiagnostic echocardiography images) or there is a clinical need to differentiate anthracycline-related cardiotoxicity from other potential causes of cardiac disease (eg, coronary artery disease, alcohol-induced LV dysfunction).
●Suspected systolic dysfunction with nondiagnostic images – In patients suspected of anthracycline toxicity in whom the results of echocardiography are not definitive, cardiovascular magnetic resonance (CMR) imaging or, much less commonly, nuclear quantification of LV ejection fraction (LVEF) can be used to identify the presence of LV dysfunction. The advantages and limitations of these tests are described elsewhere. (See "Tests to evaluate left ventricular systolic function".)
The role of CMR imaging (eg, detection and quantification of myocardial edema and fibrosis) for the diagnosis of anthracycline-induced cardiotoxicity has not been established but has been described [17]. Several studies suggest that CMR may detect abnormal myocardial tissue characteristics and regional myocardial dysfunction following anthracycline therapy in patients with normal global systolic function [18-20].
●Patients with borderline evidence of systolic dysfunction – In patients who have a decrease in LVEF that does not meet criteria for diagnosis of anthracycline cardiomyopathy or who have other signs of LV systolic dysfunction (eg, decreased or low global longitudinal strain) without a decrease in LVEF, serial testing with echocardiography should be obtained. The formal criteria for anthracycline-associated LV dysfunction are discussed elsewhere in this topic. (See 'Anthracycline-associated left ventricular dysfunction' below.)
In such patients with borderline evidence of LV dysfunction, we recommend repeat testing no later than at the end of the next cycle of planned anthracycline-containing chemotherapy or, if the patient is no longer receiving an anthracycline, approximately four weeks from the initial test.
●Evaluation identifies other causes of myocardial injury – In patients with suspected anthracycline cardiotoxicity whose evaluation identifies other causes of LV dysfunction, further testing may be required to confirm or exclude the presence of anthracycline cardiotoxicity. Some patients may have multiple etiologies of LV dysfunction, such as other cancer therapies [21], infiltrative cardiomyopathies, or coronary artery disease.
In patients for whom the presence or absence of anthracycline cardiotoxicity may alter management, an endomyocardial biopsy (EMB) can support the presence of anthracycline cardiomyopathy. The pathologic appearance of anthracycline cardiotoxicity includes the findings of myocardial edema, fibrosis, myofibrillar loss, and vacuolization [22,23]. However, EMB is an invasive test, and the pathologic findings of anthracycline toxicity are nonspecific [24]. Thus, EMB is rarely used to diagnose anthracycline-induced cardiomyopathy; the diagnosis is generally made by history and noninvasive testing.
●Tests not used for diagnosis – In patients suspected of anthracycline toxicity, we do not routinely measure troponin or B-type natriuretic peptide (BNP) levels or obtain CMR or stress images (eg, exercise stress) to diagnose anthracycline cardiotoxicity. However, these tests may help to confirm the diagnosis by suggesting the presence of myocardial injury consistent with anthracycline toxicity. Further information on the role of these tests to monitor for anthracycline cardiotoxicity can be found elsewhere. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Monitoring during and after treatment'.)
DIAGNOSIS
Anthracycline-associated left ventricular dysfunction — In a patient who has received anthracycline treatment, the diagnosis of anthracycline-associated LV dysfunction is confirmed when other causes of LV systolic dysfunction have been reasonably excluded and there is a decrease in LVEF by ≥10 percent from baseline to an LVEF less than the local laboratory’s lower range of normal for the test [25,26]. In most cases, the diagnosis of anthracycline-associated LV systolic dysfunction is a diagnosis of exclusion; other causes of LV dysfunction (eg, coronary artery disease, other toxicities) must be reasonably excluded. (See 'Differential diagnosis' below.)
In patients with smaller reductions in LVEF or a significant change in another measure of LV function (eg, a >15 percent reduction in global longitudinal strain), cardiotoxicity may be present, and serial testing is suggested to detect a drop in LVEF. Clinicians should be aware of the limitations of the clinical diagnosis of anthracycline-induced cardiotoxicity, which relies upon the accurate detection of a decline in LVEF. In the absence of other signs of abnormal LV structure and function (eg, LV dilation, functional mitral regurgitation, HF symptoms), we advise repeat testing and judicious management before major decisions regarding cancer therapy are made. Smaller decreases of LV function can be misleading, as LV function is subject to factors that are transient, such as LV loading condition and the adrenergic state, as well as interpretive variation. (See "Tests to evaluate left ventricular systolic function", section on 'Variability'.)
Other forms of cardiac injury — Anthracycline cardiotoxicity may manifest in forms other than LV systolic dysfunction, such as a decrease in LV mass [27]. Data have consistently shown that significant cardiac injury or cardiotoxicity can occur without a reduction in LVEF [24,28]. For patients who develop diastolic dysfunction, arrhythmias, or other cardiac abnormalities following anthracycline exposure, there are no specific diagnostic criteria; a short interval between exposure to anthracycline and new onset of signs or symptoms of cardiac dysfunction are indicators of anthracycline-induced cardiotoxicity.
DIFFERENTIAL DIAGNOSIS — Since criteria for the diagnosis of anthracycline-induced cardiomyopathy are nonspecific, alternative or concurrent causes of LV systolic dysfunction should be excluded. The differential diagnosis of anthracycline-associated LV systolic dysfunction includes the other causes of LV dysfunction (table 1 and table 2). The history, specific signs and symptoms, ECG findings, echocardiographic features, or additional laboratory tests may suggest the presence of an alternative cause of LV dysfunction or cardiotoxicity. The approach to evaluating for other etiologies of LV systolic dysfunction is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Determining the cause and severity of heart failure or cardiomyopathy'.)
In patients with suspected anthracycline cardiotoxicity who present with arrhythmias, the differential diagnosis is broad and includes volume overload, occult infection, and electrolyte abnormalities. The specific causes of arrhythmias are specific to the observed rhythm abnormality and are discussed separately. (See "Paroxysmal atrial fibrillation" and "Etiology of atrioventricular block" and "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Mechanisms for PVCs'.)
MANAGEMENT OF SYSTOLIC DYSFUNCTION
Patients currently receiving anthracyclines — Once the diagnosis of anthracycline-induced LV systolic dysfunction is confirmed, we take the following steps (see 'Anthracycline-associated left ventricular dysfunction' above):
●Cease anthracycline therapy – For most patients with confirmed anthracycline-induced LV systolic dysfunction who are currently receiving an anthracycline, we immediately discontinue anthracycline therapy.
●Manage LV systolic dysfunction – The management of LV systolic dysfunction in patients with anthracycline-induced LV systolic dysfunction is similar to that for patients who have other causes of LV systolic dysfunction:
•Medical therapy – Therapy for anthracycline-induced LV dysfunction is similar to management of those with LV dysfunction caused by other etiologies. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)
There are limited data on the efficacy of standard therapies for asymptomatic LV systolic dysfunction caused by anthracycline toxicity. Recovery of LV function was studied in a cohort of 2625 patients treated with anthracyclines in whom an echocardiogram was performed every three months during and after therapy [29]. In this study, patients who had a decrease in LVEF >10 percent to <50 percent (defining cardiotoxicity) were treated with a beta blocker and an angiotensin converting enzyme inhibitor. In the 226 (9 percent) patients with cardiotoxicity, 11 percent had complete recovery of LVEF (increase to baseline values), and 71 percent of patients had partial recovery (increase in >5 points to >50 percent).
•Reassessment of LV function – In patients diagnosed with anthracycline-associated LV dysfunction, we repeat imaging after anthracycline cessation and initiation of medical therapy to assess for any improvement in LV function. Further assessment of LV function is individualized.
●Assess risk and benefit of rechallenge with anthracycline – The feasibility of continued anthracycline administration, if indicated, depends on the degree of cardiac toxicity, cancer stage, the availability and effectiveness of non-anthracycline-based regimens, and patient preference. In general, if continued systemic anticancer therapy is indicated, it is preferable to pursue a non-anthracycline-containing regimen.
For patients who developed anthracycline cardiotoxicity but who have recovered systolic LV function, the question of whether to administer additional anthracycline is often relevant. If the benefits of anthracycline rechallenge outweigh the risk of additional toxicity, further anthracycline therapy may be reasonable. Features of patients with prior anthracycline cardiotoxicity in whom reexposure may be reasonable include:
•Patients with recovery of LVEF with no residual symptoms after an anthracycline-free interval.
•Patients for whom the best chance of survival or meaningful palliation from cancer requires anthracycline-based therapy.
However, there are no high-quality studies to guide practice in this clinical scenario.
If the patient will undergo reexposure to anthracycline therapy, we typically reevaluate LV function with echocardiography prior to each cycle of anthracycline administration and use strategies to reduce the toxicity of further anthracycline therapy. The strategies to reduce toxicity are outlined elsewhere. (See "Risk and prevention of anthracycline cardiotoxicity".)
Remote history of anthracycline exposure — Patients with anthracycline-induced LV systolic dysfunction who have no need for ongoing cancer treatment are managed similarly to other patients with LV systolic dysfunction. The approach to management typically depends on the presence or absence of HF symptoms and is discussed separately. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)
MANAGEMENT OF OTHER TOXICITIES
Arrhythmias — Arrhythmias associated with anthracycline toxicity are typically treated with cessation of further anthracycline treatment and acute and chronic management of the arrhythmia. Rechallenge with anthracycline is individualized and is based on the clinical severity of the arrhythmia, cancer stage, and the availability of alternative anticancer treatments.
Diastolic dysfunction — The presence of new-onset diastolic dysfunction presents a challenge. Patients with diastolic dysfunction without symptoms may have toxicity, but withholding therapy in the large number of patients who have diastolic dysfunction would result in numerous patients not receiving optimal cancer therapy. Thus, a finding of new diastolic dysfunction does not alter the approach to chemotherapy.
PROGNOSIS — Patients with clinical HF caused by anthracycline toxicity have similar survival when compared with patients with HF due to other causes [30]. There are limited data on the prognostic value of a low LVEF on the occurrence of subsequent HF or cardiac mortality. In a large, single-center study with 2285 subjects, 45 patients had a baseline LVEF below the lower limits of normal (LVEF of 52 percent in men and 54 percent in women), and 112 patients had an LVEF within 5 percent of the lower limits of normal [31]. Baseline LVEF below the lower limits of normal or an LVEF within 5 percent of the lower limits of normal was predictive of HF and cardiac death; each 5 percent decrement in LVEF predicted a 40 percent greater risk of developing HF or cardiac death.
The details of determining the prognosis in patients with HF can be found separately. (See "Prognosis of heart failure".)
SUMMARY AND RECOMMENDATIONS
●Clinical manifestations – The clinical manifestations of anthracycline toxicity are primarily those of heart failure (HF) and arrhythmias. (See 'Specific presentations' above.)
●Evaluation
•When to suspect anthracycline cardiotoxicity – The diagnosis of anthracycline cardiotoxicity is typically suspected in one of the following scenarios:
-Presentation with symptoms of HF, an arrhythmia, or another cardiac abnormality during or remote from anthracycline exposure.
-Detection of reduced systolic function with routine monitoring during or after anthracycline treatment. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Monitoring during and after treatment'.)
•Initial testing – In patients who present with signs or symptoms of potential cardiotoxicity during or remote from anthracycline therapy, we obtain a focused history and physical examination, anthracycline exposure history, history of exposure to other cardiotoxic cancer therapies, ECG, and echocardiogram.
•Additional testing – Following the initial evaluation, additional testing is only required in scenarios where the results of initial evaluation are not definitive. Common scenarios include (see 'Additional diagnostic testing' above):
-Suspected systolic dysfunction with nondiagnostic images
-Patients with borderline evidence of systolic dysfunction
-Evaluation identifies other causes of myocardial injury
●Diagnosis
•Anthracycline-associated left ventricular dysfunction – In a patient who has received anthracycline treatment, the diagnosis of anthracycline-associated left ventricular (LV) dysfunction is confirmed when other causes of LV systolic dysfunction have been reasonably excluded and there is a decrease in LV ejection fraction (LVEF) by ≥10 percent from baseline to an LVEF less than the local laboratory’s lower range of normal for that test. (See 'Anthracycline-associated left ventricular dysfunction' above.)
•Other forms of cardiac injury – Anthracycline cardiotoxicity may manifest in a form other than LV systolic dysfunction; it includes any toxicity to the heart that results in an abnormal structural or functional change (eg, arrhythmias). (See 'Other forms of cardiac injury' above.)
●Differential diagnosis – Since criteria for the diagnosis of anthracycline-induced cardiomyopathy are nonspecific, alternative or concurrent causes of LV systolic dysfunction should be excluded (table 1 and table 2). (See 'Differential diagnosis' above.)
●Management of anthracycline-associated systolic dysfunction
•Patients currently receiving therapy – Once the diagnosis of anthracycline-induced LV systolic function is confirmed in a patient currently receiving anthracycline therapy, we take the following steps (see 'Patients currently receiving anthracyclines' above):
-Cease anthracycline therapy – For most patients with confirmed anthracycline-induced LV systolic dysfunction who are currently receiving an anthracycline, we immediately discontinue anthracycline therapy.
-Manage LV systolic dysfunction – Therapy for anthracycline-induced LV dysfunction is similar to management of those with LV dysfunction caused by other etiologies. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)
In patients diagnosed with anthracycline-associated LV dysfunction, we repeat imaging in one to two weeks after anthracycline cessation to assess for recovery. Further assessment of LV dysfunction is individualized.
-Assess risk and benefit of rechallenge with anthracycline – In general, if continued systemic anticancer therapy is indicated, it is preferable to pursue a non-anthracycline-containing regimen.
For patients who developed anthracycline cardiotoxicity but who have recovered systolic LV function, the question of whether to administer additional anthracycline is often relevant.
If the patient will undergo reexposure to anthracycline therapy, we typically reevaluate LV function with echocardiography prior to each cycle of anthracycline administration and use strategies to reduce the toxicity of further anthracycline therapy. The strategies to reduce toxicity are outlined elsewhere. (See "Risk and prevention of anthracycline cardiotoxicity".)
•Remote history of anthracycline exposure – Patients with anthracycline-induced LV systolic dysfunction who have no need for ongoing cancer treatment are managed similarly to other patients with LV systolic dysfunction. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)
●Management of other toxicities – Arrhythmias associated with anthracycline toxicity are typically treated with cessation of further anthracycline treatment and with acute and chronic management of the arrhythmia. (See 'Arrhythmias' above.)
The finding of new diastolic dysfunction does not alter the approach to chemotherapy. (See 'Diastolic dysfunction' above.)
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