INTRODUCTION — The anthracyclines and related compounds (doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone) are among the chemotherapeutic agents implicated in cardiotoxicity. Anthracycline therapy is associated with an increase in the risk for developing heart failure with significant associated morbidity and mortality [1].
The mechanisms, clinical manifestations, risk factors, monitoring, and diagnosis of anthracycline-induced cardiotoxicity will be reviewed here. Prevention and management of anthracycline cardiotoxicity and cardiovascular complications of other classes of chemotherapy agents are discussed separately. (See "Prevention and management of anthracycline cardiotoxicity" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
MECHANISMS — Anthracyclines appear to affect cardiac function mainly through mechanisms that involve reactive oxygen species formation, induction of apoptosis, DNA damage through interaction with topoisomerase II, and inhibition of protein synthesis [2].
Myocyte damage has previously been attributed to the production of toxic reactive oxygen species (ROS) and an increase in oxidative stress, which cause lipid peroxidation of membranes, leading to vacuolization, irreversible damage, and myocyte replacement by fibrous tissue [3-7]. However, oxidative stress is unlikely to be the sole mediator of cardiomyocyte damage, as treatment with scavengers of ROS have not consistently prevented doxorubicin-related cardiotoxicity [8,9].
Later studies implicate the topoisomerase-II (Top2) enzyme. In cancer cells, doxorubicin targets the enzyme Top2 [10]. Doxorubicin binds both Top2 and DNA to form the ternary Top2-doxorubicin-DNA cleavage complex, which triggers cell death. Adult mammalian cardiomyocytes express Top2-beta, but not Top2-alpha [11]. The Top2-beta-doxorubicin-DNA complex can induce DNA double-strand breaks, leading to cell death [12]. The hypothesis that doxorubicin-mediated cardiomyopathy is mediated by Top2-beta in cardiomyocytes is supported by murine studies showing that cardiomyocyte-specific deletion of the gene Top2b (which encodes the Top2-beta enzyme) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for the formation of reactive oxygen species, and protects mice from the development of doxorubicin-induced progressive heart failure [13]. Other mechanisms proposed to contribute to anthracycline cardiotoxicity include mitochondrial iron accumulation [14] and dysregulation of cardiomyocyte autophagy [15].
DEFINITION — A standardized definition of what constitutes anthracycline-induced cardiotoxicity is lacking. The absence of standardized criteria impacts the frequency and timeliness of diagnosis. Our approach to the diagnosis of anthracycline cardiotoxicity is described below. (See 'Approach to diagnosis' below.)
In clinical practice, cases of anthracycline-induced cardiomyopathy have been most commonly identified as a result of a diagnosis of new-onset heart failure (HF) and/or detection of left ventricular (LV) dysfunction in exposed individuals. LV ejection fraction (LVEF) is the most common measure employed for detection of cardiotoxicity, although the threshold used to identify a significant decrease in LVEF has varied widely.
However, clinicians should be aware of the limitations of clinical management of anthracycline-induced cardiotoxicity based largely upon detection of a decline in LVEF or symptoms and signs of HF. Cardiotoxicity is a broader term than cardiac dysfunction (reflected primarily by a depressed LVEF) since it includes any cardiac injury resulting from toxin exposure. Data have consistently shown that significant cardiac injury/cardiotoxicity can occur without a reduction in LVEF [16,17]. Other limitations of LVEF are that it is affected by transient conditions, such as preload, afterload, and adrenergic state, and is subject to interpretive variation. While our approach to diagnosis of cardiotoxicity continues to be largely based upon LVEF, other earlier and more sensitive markers may be helpful in raising concern and may trigger increased monitoring of LVEF. Some of the additional methods for detection of cardiotoxicity beyond LVEF include serum biomarker levels, myocardial strain (a measure of deformation) using echocardiography, and detection of myocardial fibrosis using cardiac magnetic resonance, as discussed below. (See "Tests to evaluate left ventricular systolic function" and 'Risk assessment and monitoring' below.)
RISK FACTORS — Risk factors for anthracycline cardiac toxicity include older age (ie, age >65 years) or very young age (ie, age <4 years old), female gender, preexisting cardiovascular disorders (eg, left ventricular ejection fraction [LVEF] ≤50 percent), hypertension, smoking, hyperlipidemia, obesity, diabetes, and high cumulative anthracycline exposure [18-23]. Additional risk factors include radiation therapy involving the cardiac silhouette as well as use of trastuzumab. Recognition of these risk factors, and response to them by using non-anthracycline chemotherapy when appropriate, has diminished the incidence of anthracycline-induced heart failure (HF). (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
Cumulative anthracycline exposure is a consistent risk factor. The risk for doxorubicin-related clinical HF ranges from 0.2 to 100 percent for cumulative doses ranging from 150 to 850 mg/m2 [19-21,24]. When cardiotoxicity is defined to include development of asymptomatic LV systolic dysfunction, rates of cardiotoxicity are higher (table 1). In one study, the rate of doxorubicin-induced cardiac dysfunction (either symptomatic or asymptomatic but with a decline in EF) was 6.5, 8.8, 17.9, and 32.4 percent at cumulative doses of 150, 250, 350, and 400 mg/m2 [19]. While limited data are available on the prognosis of an asymptomatic decline in the LVEF among patients treated with anthracyclines, studies of broad populations of patients with asymptomatic systolic dysfunction have identified an increased risk of HF and cardiovascular death. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction", section on 'Prognosis'.)
Evidence suggests that obesity is associated with an increased likelihood of developing cardiac dysfunction after anthracyclines. For example, in a meta-analysis of 15 studies including approximately 8700 breast cancer patients treated with either anthracyclines or sequential anthracyclines and trastuzumab, the odds ratio (OR) for overweight patients (those with body mass index [BMI] >25) for cardiac dysfunction was 1.38 (95% CI 1.06-1.80) relative to those with BMI <25 [18]. A higher magnitude of risk was observed among those who were obese (BMI ≥30, OR 1.47, 95% CI 0.95-2.28). Although this difference was not significant, the analysis of risk associated with obesity consisted of far fewer patients compared with the one that included all overweight patients.
CLINICAL MANIFESTATIONS
Time course — Understanding of the onset and frequency of anthracycline-induced cardiotoxicity is limited given scant available prospective surveillance data in exposed patients. Reported prevalence rates of anthracycline-induced cardiotoxicity are markedly influenced by how cardiotoxicity or cardiac dysfunction is detected or defined, patient risk factors for development of cardiomyopathy, and the duration of the follow-up period after anthracycline exposure.
Anthracycline-induced cardiotoxicity has traditionally been classified into acute or early (traditionally considered reversible effects occurring during treatment), subacute (effects detected within a year of exposure), and chronic (effects detected years after exposure) disease processes. However, this classification system is arbitrary and based largely upon observations from retrospective studies reporting development of heart failure (HF) in patients treated with anthracyclines.
While in the traditional model early injury is considered to be largely reversible, evidence suggests that treatment with anthracyclines initiates a process of progressive injury starting at the time of exposure that continues for months to years. For example, large studies have documented a significant early increase in serum troponin among 30 to 35 percent of anthracycline-treated patients and have linked early increases in cardiac troponin to subsequent reductions in traditional measures of cardiotoxicity such as left ventricular ejection fraction (LVEF) [25,26]. In the traditional paradigm, the reduction in LVEF was a late event. However, later data suggest that this traditional paradigm may not be correct. Specifically, cardiotoxicity, as manifest by a reduction in LVEF, can also be detected early as shown by a prospective study of 2625 patients receiving anthracycline-containing chemotherapy [27]. In this study, LVEF was assessed at baseline, every three months during chemotherapy and for the following year, every six months for the following four years, and yearly thereafter with median follow-up of 5.2 years (interquartile range, 2.6 to 8 years). Cardiotoxicity was defined as an LVEF <50 percent and decrease in LVEF of >10 percentage points from baseline. The overall incidence of cardiotoxicity was 9 percent. The median time of onset of cardiotoxicity after the end of chemotherapy was 3.5 months (interquartile range, three to six months), and 98 percent of cardiotoxicity was detected within the first year.
Early manifestations — Clinical manifestations of acute anthracycline cardiotoxicity include electrocardiographic abnormalities, arrhythmias (supraventricular or ventricular), atrioventricular block, and a pericarditis-myocarditis syndrome (particularly with mitoxantrone) [8,18,28-36]. Additionally, some patients develop early evidence of ventricular dysfunction with or without symptoms and signs of HF [27,37].
Higher rates of early cardiotoxicity have been reported in individuals over 50 years old. Data are lacking on the potential contributory role of alternate or concurrent cardiovascular conditions, such as coronary artery disease.
In a German 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, complications included atrial fibrillation (n = 12), acute HF (n = 5), myocarditis (n = 2), and myocardial infarction (n = 1) [33]. Higher rates of subacute toxicity have been reported in studies of older adults receiving CHOP or a CHOP-like regimen for treatment of lymphoma; in two such studies, rates of cardiotoxicity (decline in LVEF, atrial fibrillation, acute pulmonary edema, cardiac ischemia) during chemotherapy were 11 and 21 percent [38,39].
Studies suggest that early manifestations of myocardial injury (such as troponin elevation or mild ventricular dysfunction) may predict future development of ventricular dysfunction [40]. In the 2625-patient prospective study discussed above, LVEF measured at the end of chemotherapy was an independent correlate of later development of cardiotoxicity (defined as LVEF <50 percent and decrease in LVEF of >10 percentage points from baseline) [40]. However, further data are needed to determine the predictive value of early signs of cardiotoxicity. (See 'Endomyocardial biopsy' below.)
Late manifestations — Late clinical manifestations of anthracycline cardiotoxicity include symptoms and signs of HF such as dyspnea, fatigue, edema, and orthopnea. Depressed LVEF may be detected with or without HF. As noted above, the distinction between early and late manifestations may be somewhat arbitrary since early subclinical cardiac injury may lead to LV dysfunction and HF detected later. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Determining the etiology and severity of heart failure or cardiomyopathy".)
The overall prevalence of late symptomatic anthracycline-induced cardiotoxicity varies widely depending on the age of the population treated; the dose of anthracycline; hematologic cancer; presence of cardiovascular risk factors; history of heart disease, including low or impaired LVEF before chemotherapy; and the length of follow-up and the definitions used [19,41,42]. In adults, symptomatic HF appears to occur predominantly within two to three years of anthracycline exposure [43,44]. In a study of 135 patients with a median age of 59 with non-Hodgkin lymphoma who were treated with anthracyclines, 20 percent developed a significant cardiac event within one year of treatment. Older data suggest that the prognosis of symptomatic anthracycline-induced cardiomyopathy is poor, with greater than 60 percent mortality at one year [45]; however, recent data suggest that the prognosis of clinical HF related to anthracyclines is similar to that of the non-anthracycline population [46].
The prevalence of asymptomatic LV dysfunction depends on the population, methods, and definition [2,27]; however, the prevalence is much higher than symptomatic disease, with reported rates varying from 7 percent using LVEF to 45 percent using cardiac strain [47]. For example, in an echocardiographic study of 1853 adult survivors of childhood cancer with a median age of 31 years, an asymptomatic reduction in LVEF to <50 percent was noted in 7 percent of participants, and nearly all of these patients were asymptomatic [48]. Similarly, in a cardiac magnetic resonance (CMR) imaging study among 114 adult survivors of childhood cancer who were free of cardiovascular symptoms, the prevalence was 14 percent [49]. In a CMR study of adults treated with low to moderate doses of anthracycline-based chemotherapy, 26 percent of subjects had an asymptomatic reduction to LVEF <50 percent at six months after anthracycline exposure [20].
Identification of cardiotoxicity late after exposure has been described mainly in survivors of childhood cancers. The latent period between exposure and identification of a cardiomyopathy could be as long as 30 years [50,51]. Compared with sibling controls, survivors of childhood cancer have a nearly sixfold greater risk of developing HF (largely attributed to anthracycline exposure) [48].
RISK ASSESSMENT AND MONITORING
Rationale — The rationale for baseline risk assessment, monitoring, and early detection of cardiotoxicity in patients who are treated with anthracyclines is that early detection of subclinical cardiotoxicity and intervention can decrease the risk of progression to heart failure (HF) and thus improve quality of life and outcomes. For patients deemed to be at highest risk of developing anthracycline-induced cardiotoxicity and HF, individualized risk-benefit analysis may include consideration of alternatives to anthracycline therapy.
Identification of patients at increased risk — As described in the American Society of Clinical Oncology (ASCO) expert consensus guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers [52], we use the following criteria to identify patients with cancer at risk for developing cardiac dysfunction from anthracycline use:
●Treatment that includes any of the following:
•High-dose anthracycline (eg, doxorubicin ≥250 mg/m2, epirubicin ≥600 mg/m2)
•High-dose radiotherapy (RT; ≥30 Gy) where the heart is in the treatment field
•Lower-dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) in combination with lower-dose RT (<30 Gy) where the heart is in the treatment field
●Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) or trastuzumab alone, and presence of any of the following risk factors:
•Multiple cardiovascular risk factors (≥2 risk factors), including smoking, hypertension, diabetes, dyslipidemia, and obesity, during or after completion of therapy
•Older age (≥60 years) at cancer treatment
•Compromised cardiac function (eg, borderline low left ventricular ejection fraction [50 to 55 percent], history of myocardial infarction, moderate or greater valvular heart disease) at any time before or during treatment
•Treatment with lower-dose anthracycline (eg, doxorubicin <250 mg/m2, epirubicin <600 mg/m2) followed by trastuzumab (sequential therapy)
Approach to baseline assessment and monitoring — Limited data are available to guide assessment and surveillance of patients receiving anthracycline chemotherapy, and improved methods are needed. Given the limited available data, the authors recommend the following approach:
●A clinical history, cardiac examination, and electrocardiogram should be performed in all individuals prior to initiation of anthracycline-based chemotherapy, and patients should have a repeat clinical history and examination at least every three months by a clinician during the treatment course. Although guidelines do not require a baseline electrocardiogram in this setting, as a practical matter some clinicians have found this helpful to serve as a basis for comparison for evaluation of later cardiovascular symptoms or signs.
While baseline clinical evaluation has limited ability to predict anthracycline-induced cardiotoxicity, it can help identify individuals who require treatment for existing cardiovascular risk factors, such as hypertension, or who should avoid anthracycline therapy, such as those with HF.
●Baseline cardiac imaging (generally by echocardiogram) to assess left ventricular ejection fraction (LVEF) should be performed prior to initiation of anthracycline therapy. The baseline assessment may identify individuals at risk for HF for whom alternatives to anthracycline therapy should be considered. (See 'Assessment of LVEF' below.)
•Measurement of LVEF should be performed.
-Echocardiography is the recommended initial test, with 3D echocardiography preferred if available and image quality is adequate. Otherwise, 2D echocardiography, with the administration of echocardiographic contrast agent as needed, is recommended. (See 'Echocardiography' below.)
-In cases of inadequate echocardiographic results, a cardiac magnetic resonance (CMR) exam with quantitation of LVEF is recommended. (See 'Assessment of LVEF' below.)
-If CMR is not available, radionuclide ventriculography (RVG, also known as multiple gated cardiac blood pool imaging [MUGA]) is used to assess LVEF in some centers based upon availability. Advantages include high degree of reproducibility, although the test entails radiation exposure. (See "Tests to evaluate left ventricular systolic function" and "Tests to evaluate left ventricular systolic function", section on 'Radionuclide ventriculography'.)
•Some UpToDate experts (TN, MS-C) also suggest assessment of global longitudinal strain (GLS) in baseline and follow-up echocardiograms (in centers that provide accurate and reliable results) [21,53], although other UpToDate experts follow LVEF only. (See 'Strain and strain rate imaging' below.)
●Follow-up evaluation:
•A history and cardiac exam should be performed prior to every cycle.
•For patients who develop symptoms or signs of HF, repeat echocardiography should be performed.
•The optimum frequency of surveillance echocardiography in patients receiving anthracycline-based chemotherapy without symptoms or signs of HF is uncertain.
-Some UpToDate contributors suggest the following approach: For asymptomatic patients with cumulative doxorubicin dose ≤240 mg/m2, an evaluation of cardiac function (LVEF and GLS) is performed at baseline, at the completion of therapy, and at six months thereafter. For patients whose cumulative doxorubicin dose will exceed 240 mg/m2, evaluation is performed at 240 mg/m2 and after each additional 50 mg/m2. This approach is consistent with the 2014 expert consensus statement of the American Society of Echocardiography and the European Association of Cardiovascular Imaging [21].
-A similar approach that targets high-risk patients is included in the 2017 ASCO guideline, which suggests that echocardiograms may be performed during treatment and 6 to 12 months after completion of cancer-directed therapy in asymptomatic patients considered to be at increased risk of cardiac dysfunction, as described above [52] (see 'Identification of patients at increased risk' above). The frequency of surveillance during treatment and after the 6 to 12 months echocardiogram is left to the clinician’s judgment.
-Other UpToDate contributors obtain surveillance echocardiograms only in patients who have been treated with a cumulative doxorubicin dose of ≥360 mg/m2, and repeat echocardiograms after every two subsequent cycles.
•After completion of anthracycline therapy, monitoring should include at least an annual review of systems and physical exam. In the absence of symptoms or physical findings to suggest cardiomyopathy, there are no clear data to support routine imaging or blood work.
Management of decreases in LVEF or development of symptoms or signs of HF are discussed separately. (See "Prevention and management of anthracycline cardiotoxicity", section on 'Management of heart failure or subclinical cardiac dysfunction occurring after treatment initiation'.)
Guideline recommendations — The importance of routine monitoring during cancer treatment and post-treatment surveillance was emphasized in the ASCO guidelines, but a specific schedule and thresholds for intervention were not defined [52,53]. Other societies have provided differing recommendations [21,54]. (See 'Approach to baseline assessment and monitoring' above.)
Assessment of LVEF — As noted above, for baseline and surveillance cardiac imaging of patients receiving anthracycline therapy, we prefer echocardiography among the available modalities given its wide availability, evidence base for its use for LVEF (as well as more sensitive measures such as strain), and its utility in diagnosing various types of heart disease [2]. CMR is indicated when other noninvasive imaging is inconclusive and avoidance of additive radiation exposure is preferred. Nuclear methods are another option given the high reproducibility of LVEF by RVG, particularly when other methods are not available or are suboptimal.
If available, the use of 3D echocardiography rather than 2D is suggested based upon studies showing low variability and strong correlation between LVEF measured by 3D echocardiography and the clinical gold standard CMR; 2D echocardiography with contrast offers results nearly approaching those with 3D echocardiography, particularly in cases with LV systolic dysfunction. (See "Tests to evaluate left ventricular systolic function", section on 'Diagnostic performance'.)
There are limited data on the prognostic value of a low LVEF on the occurrence of subsequent HF and/or cardiac mortality. In a large, single-center study with 2285 subjects, 45 patients had a baseline LVEF t 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 [42]. Having a 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 [42].
Echocardiography — Echocardiography is the most widely used method for assessment of LVEF in patients receiving chemotherapy [1]. The use of echocardiography is based on the relative low cost, safety, wide availability, and extent of published supportive data. In addition, echocardiography enables detection and assessment of preexisting, alternate, or concurrent cardiac conditions such as pericardial disease, valve disease, and coronary artery disease [55]. As described below, echocardiography allows detection of diminished amplitude of GLS. However, reliable GLS measurements are available only in selected centers and when available, results are used to guide intensity of screening rather than to directly guide management. (See 'Strain and strain rate imaging' below.)
However, limitations also exist that primarily include dependency on acoustic windows and limitations of accuracy. The wide variability in confidence intervals for the standard 2D measurement of LVEF is significant and approaches approximately 8 to 10 percent in research studies [56,57]. Limitations in acoustic windows and variability of LVEF can be partially addressed by the use of contrast agents to better define the endocardial border and by the use of three-dimensional imaging [49,57]. (See "Tests to evaluate left ventricular systolic function", section on 'Echocardiography'.)
Cardiac MR — CMR imaging is indicated when echocardiography results are inconclusive or inconsistent, and the use of CMR avoids exposure to ionizing radiation. CMR is the clinical gold standard imaging technique for measurement of LV volumes and LVEF and also enables assessment of other cardiac conditions. With safety checks for MR-incompatible objects or devices, CMR is safe and provides excellent spatial resolution and good temporal resolution without exposure to ionizing radiation [58]. Administration of exogenous contrast agent is not required for assessment of LV global (LVEF) and regional systolic function. CMR improves the detection of asymptomatic LV dysfunction as compared with echocardiography [49]. However, the availability of appropriate expertise and technology for CMR is more limited than for other major cardiac imaging modalities. In preliminary studies, CMR detected declines in LV mass and LVEF after anthracycline-based chemotherapy [59,60] and lower LV mass was associated with worsened HF symptomatology [60,61] ; further study is required to determine clinical significance of these observations. (See "Tests to evaluate left ventricular systolic function", section on 'Cardiovascular magnetic resonance imaging'.)
Nuclear imaging — Nuclear cardiac imaging methods are an alternative to echocardiography and CMR, particularly when echocardiography results are technically suboptimal and CMR is not available. Imaging of technetium-labeled red blood cells is a standard clinical tool used in the assessment of cardiac function among patients receiving chemotherapy [62]. These techniques are known as radionuclide ventriculography and also known as multigated acquisition angiogram (MUGA) or equilibrium radionuclide angiogram (ERNA). In a single-center study published in 1979, an asymptomatic reduction in LVEF using nuclear techniques predicted those patients who developed HF [62]. Additionally, cessation of anthracyclines due to an asymptomatic reduction in LVEF was associated with a 40 percent reduction in HF [63]. However, limitations of nuclear imaging for LVEF assessment include the significant and potentially repetitive radiation exposure involved. (See "Tests to evaluate left ventricular systolic function", section on 'Radionuclide ventriculography'.)
Endomyocardial biopsy — Although endomyocardial biopsy is the gold standard for detection of cardiac injury after chemotherapy [16], it is invasive and subject to sampling error [64]. Thus, it is rarely used to diagnose anthracycline-induced cardiotoxicity and the diagnosis is generally made by history and noninvasive testing. It is reserved for situations in which the cause of cardiac dysfunction is uncertain, selected cases in which administration of greater than the usual upper limit of an agents is being considered, or clinical studies of toxicity of newer agents and regimens. (See "Endomyocardial biopsy", section on 'Anthracycline cardiotoxicity'.)
Investigational tests — Other tests have been investigated but are not established predictors of anthracycline-induced cardiotoxicity. Although the standard method for detecting cardiotoxicity from anthracyclines is echocardiography, other methodologies such as global longitudinal strain (at centers where this is available) may enhance sensitivity for detection of cardiotoxicity, although evidence of clinical impact on outcomes is not available. Since significant cardiac injury can occur without a clear reduction in LVEF, earlier and more sensitive markers of cardiotoxicity have been sought. Several methods for detection of anthracycline-induced cardiotoxicity beyond a reduction in LVEF have been investigated. These methods include serum biomarkers of cardiac injury, more sensitive echocardiographic measures of cardiac function, and tissue characterization using CMR.
Strain and strain rate imaging — Although some contributors to this topic rely on LVEF alone to assess cardiotoxicity from anthracyclines, others also utilize GLS as another echocardiographic measure. GLS use is suggested only when the laboratory has the experience and expertise to reliably generate accurate results. GLS measures myocardial deformation and may enable early detection of subclinical cardiotoxicity, with either a relative reduction in GLS of >15 percent from baseline or an absolute value of −19 percent after anthracyclines both being associated with a marked increase risk for subsequent LVEF decrease [21,47,65]. A number of studies have explored the utility of strain and strain rate imaging in the detection of cancer therapy-induced cardiac toxicity and in the prediction of subsequent decreases in LVEF [47,65-68]. Echocardiographic strain and strain rate imaging are sensitive, noninvasive methods for assessment of myocardial function [69]. In comparison with strain evaluation, measurement of strain rate is less influenced by physiological conditions and strain rate measurements in expert hands may be more sensitive than strain to early changes in cardiac function [70]. However, due to measurement variability, the routine use of strain rate appears to be more challenging in clinical practice and therefore most studies have focused on the use of strain imaging [65]. Strain can be measured in the longitudinal, circumferential, or radial direction with GLS identified as the optimum parameter for early detection of cardiotoxicity. Limitations of this approach include the lack of data determining the optimal timing for assessments, the lack of standardization across echocardiographic vendors, and the lack of data testing the reproducibility of GLS outside specialized centers.
Troponins — We do not routinely measure troponin levels in patients receiving anthracyclines given the limited data to support this approach.
While some data have supported the predictive value of elevated cardiac troponin levels during anthracycline therapy for subsequent LV systolic dysfunction (identified by fall in LVEF) [17,25,47,66], in general the studies have been small and heterogenous in populations and definitions, and the timing and frequency of troponin testing is not standardized.
As an example, in a prospective single-center study with 703 subjects, cardiac troponin I concentrations were assessed immediately following and one month after chemotherapy. An increase in troponin I concentrations at one time-point was associated with a 37 percent increased risk of a subsequent decline in LVEF, while elevation of both measures of troponin I was associated with an 84 percent increased risk [25]. Similarly, in a multicenter cohort of 78 patients, for every one standard deviation increase in ultrasensitive troponin I, there was a 38 percent increase in the risk of a subsequent decline in LVEF [17]. More data are required to determine the role of troponin testing in this setting.
Natriuretic peptide — We do not recommend routine measurement of natriuretic peptide levels in patients receiving anthracycline-based chemotherapy, as there are conflicting data on the role of natriuretic peptides (brain natriuretic peptide and N-terminal pro-brain natriuretic peptide) in predicting a decline in LVEF or subsequent HF after anthracyclines [71-73].
Investigational approaches to imaging — While CMR has an established role for assessment of LVEF, its role as a technique for the detection and quantification of cardiac edema and fibrosis in anthracycline cardiotoxicity is not established [58]. Edema and fibrosis are pathologic findings observed on invasive endomyocardial biopsy after anthracycline therapy [64]. Preliminary studies suggest that CMR may detect abnormal myocardial tissue characteristics and regional myocardial dysfunction following anthracycline therapy in the presence of normal LV systolic function by echocardiography and CMR [74]. Further study is required to determine the utility of myocardial tissue characterization by CMR in assessing anthracycline-induced cardiotoxicity.
While echocardiographic assessment of systolic function plays a central role in monitoring anthracycline-induced cardiotoxicity, data do not support the measurement of diastolic function for risk assessment or surveillance after anthracyclines [21]. Stress echocardiography may be of help in the determination of contractile reserve among patients but data are limited [75], and a predictive value has not been determined.
Other tests — Genetic variations might modulate the risk of cardiovascular toxicity from cancer treatment and while promising, available data do not support routine genetic testing [33,76-79].
Exercise tolerance on cardiopulmonary exercise testing is a robust predictor of outcomes among various patient populations, and data have shown that VO2max is reduced in patients treated with anthracyclines [80]. However, the predictive value of VO2max for anthracycline-induced cardiomyopathy has not been determined.
DIAGNOSIS — Anthracycline-induced cardiotoxicity should be suspected in a patient with history of recent or remote anthracycline exposure who develops symptoms and signs of heart failure (HF) and/or is found to have left ventricular (LV) systolic dysfunction. Given the importance of timely diagnosis and management of anthracycline-induced cardiotoxicity, we recommend baseline assessment and monitoring to detect subclinical signs of cardiotoxicity. (See 'Approach to baseline assessment and monitoring' above.)
Approach to diagnosis — The diagnosis of anthracycline-induced cardiotoxicity is typically confirmed in a patient with new symptoms of HF or a significant decline in LVEF (LVEF, most frequently detected by echocardiogram) following exposure to anthracycline after exclusion of other causes. Specific criteria for management are discussed elsewhere. (See "Prevention and management of anthracycline cardiotoxicity", section on 'Approach to new LV systolic dysfunction or heart failure'.)
As noted above, the fall in LVEF may be detected while the anthracycline course is underway or years later. Symptoms of HF may or may not be present. Anthracycline-based chemotherapy is one of the causes of dilated cardiomyopathy (dilated LV with depressed systolic function).
For patients who develop HF with preserved EF (HFpEF) after anthracycline-based chemotherapy, a diagnosis of anthracycline-induced cardiotoxicity is uncertain. A causal link between anthracycline exposure and HFpEF has not been established. While some studies have reported subclinical diastolic dysfunction following anthracycline exposure [81-83], only scant case reports have described HFpEF or restrictive cardiomyopathy (nondilated ventricles with impaired ventricular filling with normal or depressed systolic function) in patients treated with anthracyclines with or without radiation therapy [84-86]. (See 'Assessment of LVEF' above and "Definition and classification of the cardiomyopathies".)
The above described risk assessment and monitoring protocol enables identification of patients in the following groups. Management of each of the above groups is discussed separately. (See "Prevention and management of anthracycline cardiotoxicity".)
●On baseline examination:
•Patients with (symptomatic) HF and/or LVEF ≤40 percent
•Asymptomatic patients with LVEF >40 and ≤50 percent
•Asymptomatic patients with LVEF >50 percent
●On follow-up examination:
•Patients who develop new significant LV systolic dysfunction (decline of >10 points in LVEF to ≤40 percent or an absolute decline of ≤15 percentage points to an LVEF <50 percent and/or HF).
•Patients with an asymptomatic decline of LVEF to <50 percent but >40 percent. (See "Prevention and management of anthracycline cardiotoxicity", section on 'Approach to new LV systolic dysfunction or heart failure'.)
Smaller changes in LVEF or a significant change in other measures of cardiotoxicity (such as a >15 percent reduction in magnitude of global longitudinal strain if measured) should raise concern for cardiotoxicity and should at least suggest an increased frequency of monitoring of LVEF.
Patients who develop a significant decline in LVEF and/or HF should undergo evaluation to determine the cause(s) since specific management may be indicated for certain causes (eg, myocardial infarction). (See "Determining the etiology and severity of heart failure or cardiomyopathy".)
Role of cardiology consultation — The role of cardiology consultation is discussed separately. (See "Prevention and management of anthracycline cardiotoxicity", section on 'Role of cardiology consultation'.)
Differential diagnosis — Since criteria for diagnosis of anthracycline-induced cardiotoxicity are nonspecific, alternative or concurrent causes of HF or LV systolic dysfunction should be excluded. The differential diagnosis of anthracycline-induced cardiotoxicity includes other causes of HF or cardiomyopathy, particularly coronary artery disease (table 2A-B). Additionally, in patients with leukemia, endotoxemic shock from gram-negative infection is a frequent cause of both acute and chronic HF. Furthermore, in acute promyelocytic leukemia patients specifically, symptoms of HF may be secondary to differentiation syndrome associated with ATRA and arsenic trioxide. These issues are discussed elsewhere. (See "Gram-negative bacillary bacteremia in adults", section on 'Clinical manifestations' and "Initial treatment of acute promyelocytic leukemia in adults", section on 'Differentiation syndrome'.)
The cause of HF or cardiomyopathy is identified by evaluation including the history, signs and symptoms, electrocardiogram, and echocardiography with additional tests as indicated by the initial evaluation. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Determining the cause and severity of heart failure or cardiomyopathy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of symptoms and toxicities of anticancer therapy".)
SUMMARY AND RECOMMENDATIONS
●Anthracyclines appear to affect cardiac function mainly through mechanisms that involve reactive oxygen species formation, induction of apoptosis, DNA damage through interaction with topoisomerase II, and inhibition of protein synthesis. (See 'Mechanisms' above.)
●The absence of standardized criteria to define anthracycline-induced cardiotoxicity impacts the frequency and timeliness of diagnosis. Although identification of cardiac dysfunction (particularly as depressed left ventricular ejection fraction [LVEF]) is a common means of identifying cardiotoxicity, it is important to distinguish cardiac dysfunction from cardiotoxicity. Cardiotoxicity is a broader term that includes cardiac injury beyond a reduction in LVEF. (See 'Definition' above.)
●Anthracycline-induced cardiotoxicity has traditionally been classified into acute (generally reversible effects occurring during treatment), subacute (effects detected within a year of exposure), and chronic (effects detected years after exposure) disease processes. An alternative, more plausible paradigm has been proposed in which anthracycline-induced cardiotoxicity reflects a continuous process that starts during exposure and may be detected at early or late stages as the condition evolves. (See 'Time course' above.)
●The rationale for baseline risk assessment, monitoring, and early detection of cardiotoxicity in patients who are treated with anthracyclines is that early detection of subclinical cardiotoxicity and intervention may decrease the risk of progression to heart failure and thus improve quality of life and outcomes. (See 'Risk assessment and monitoring' above.)
●Baseline assessment and monitoring of patients treated with anthracyclines includes baseline and follow-up clinical evaluation and cardiac imaging (generally echocardiography) during and following completion of anthracycline therapy. After completion of anthracycline therapy, monitoring should include at least an annual review of systems and physical exam to assess for cardiomyopathy. In the absence of symptoms or physical findings, the utility of routine imaging or blood work is uncertain. (See 'Approach to baseline assessment and monitoring' above.)
●The diagnosis of anthracycline-induced cardiotoxicity is typically confirmed in a patient with history of anthracycline exposure by cardiac imaging (most commonly echocardiography) that confirms the presence of LV systolic dysfunction (generally by detection of depressed LVEF) and excludes other causes. (See 'Approach to diagnosis' above.)
1 : Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues.
2 : Anthracycline-Induced Cardiomyopathy in Adults.
3 : Subcellular effects of adriamycin in the heart: a concise review.
4 : Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2.
5 : Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo.
6 : Adriamycin cardiomyopathy: pathophysiology and prevention.
7 : Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol.
8 : Doxorubicin-induced cardiomyopathy.
9 : Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy.
10 : Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II.
11 : Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development.
12 : Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane.
13 : Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
14 : Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
15 : Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.
16 : A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.
17 : Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab.
18 : Doxorubicin-induced cardiac toxicity.
19 : Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.
20 : Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease.
21 : Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
22 : Predictors of late-onset heart failure in breast cancer patients treated with doxorubicin.
23 : Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood.
24 : 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC).
25 : Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy.
26 : Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury.
27 : Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
28 : Clinical and morphologic cardiac findings after anthracycline chemotherapy. Analysis of 64 patients studied at necropsy.
29 : Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone.
30 : Introducing a new entity: chemotherapy-induced arrhythmia.
31 : Anthracycline-induced cardiotoxicity.
32 : Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk.
33 : NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.
34 : Acute arrhythmogenicity of doxorubicin administration.
35 : Doxorubicin-induced ventricular arrhythmia treated by implantation of an automatic cardioverter-defibrillator.
36 : Doxorubicin-induced second degree and complete atrioventricular block.
37 : Anthracycline-induced acute cardiotoxicity in adults treated for leukaemia. Analysis of the clinico-pathological aspects of documented acute anthracycline-induced cardiotoxicity in patients treated for acute leukaemia at the University Hospital of Zürich, Switzerland, between 1990 and 1996.
38 : Nonpegylated liposomal doxorubicin (MyocetTM) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial.
39 : CHOP is the standard regimen in patients>or = 70 years of age with intermediate-grade and high-grade non-Hodgkin's lymphoma: results of a randomized study of the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Study Group.
40 : Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.
41 : Risk factors for doxorubicin-induced congestive heart failure.
42 : Major Cardiac Events and the Value of Echocardiographic Evaluation in Patients Receiving Anthracycline-Based Chemotherapy.
43 : Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial.
44 : Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer.
45 : Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.
46 : Comprehensive Echocardiographic Detection of Treatment-Related Cardiac Dysfunction in Adult Survivors of Childhood Cancer: Results From the St. Jude Lifetime Cohort Study.
47 : Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
48 : Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort.
49 : Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging.
50 : Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment.
51 : Chronic health conditions in adult survivors of childhood cancer.
52 : Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline.
53 : American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline.
54 : Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines.
55 : Prevalence of abnormal echocardiographic findings in cancer patients: a retrospective evaluation of echocardiography for identifying cardiac abnormalities in cancer patients.
56 : Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography.
57 : Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.
58 : Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.
59 : Anthracycline Therapy Is Associated With Cardiomyocyte Atrophy and Preclinical Manifestations of Heart Disease.
60 : Left Ventricular Mass Change After Anthracycline Chemotherapy.
61 : Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines.
62 : Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography.
63 : Serial radionuclide assessment of doxorubicin cardiotoxicity in cancer patients with abnormal baseline resting left ventricular performance.
64 : Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals.
65 : Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review.
66 : Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.
67 : Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity.
68 : Usefulness of Global Longitudinal Strain for Early Identification of Subclinical Left Ventricular Dysfunction in Patients With Active Cancer.
69 : Experimental validation of a new ultrasound method for the simultaneous assessment of radial and longitudinal myocardial deformation independent of insonation angle.
70 : Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab.
71 : Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction.
72 : N-terminal pro-B-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction?
73 : BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography.
74 : Occult cardiotoxicity in childhood cancer survivors exposed to anthracycline therapy.
75 : Dobutamine stress echocardiography identifies anthracycline cardiotoxicity.
76 : PDGFRB mutation causes autosomal-dominant Penttinen syndrome.
77 : Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group.
78 : The genetic variants underlying breast cancer treatment-induced chronic and late toxicities: a systematic review.
79 : Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation.
80 : Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum.
81 : Altered left ventricular longitudinal diastolic function correlates with reduced systolic function immediately after anthracycline chemotherapy.
82 : Left ventricular strain and strain rates are decreased in children with normal fractional shortening after exposure to anthracycline chemotherapy.
83 : Evaluation of cardiotoxicity by tissue Doppler imaging in childhood leukemia survivors treated with low-dose anthracycline.
84 : Restrictive cardiomyopathy.
85 : Restrictive cardiomyopathy associated with left ventricle and left atria endocardial calcifications following chemotherapy.
86 : Chronic anthracycline cardiotoxicity: haemodynamic and histopathological manifestations suggesting a restrictive endomyocardial disease.
