Anthracycline-Induced Cardiotoxicity

  1. Kesavan Shan, MD;
  2. A. Michael Lincoff, MD; and
  3. James B. Young, MD
  1. From The Cleveland Clinic Foundation, Cleveland, Ohio. Requests for Reprints: A. Michael Lincoff, MD, Director, Experimental Interventional Laboratory, Department of Cardiology, F25, The Cleveland Clinic Foundation 9500 Euclid Avenue, Cleveland, OH 44195. Current Author Addresses: Dr. Shan: Baylor College of Medicine, Section of Cardiology, 6550 Fannin MS SM 677, Houston, TX 77030. Drs Lincoff and Young: Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Clevelane, OH 44195.
     
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    Abstract

    Purpose: To review the current understanding of the clinical significance, detection, pathogenesis, and prevention of anthracycline-induced cardiotoxicity.

    Data Sources: A MEDLINE search of the English-language medical literature and a manual search of the bibliographies of relevant articles, including abstracts from national cardiology meetings.

    Study Selection: Pertinent clinical and experimental studies addressing the clinical relevance, pathogenesis, detection, and prevention of anthracycline cardiotoxicity were selected from peer-reviewed journals without judgments about study design. A total of 137 original studies and 9 other articles were chosen.

    Data Extraction: Data quality and validity were assessed by each author independently. Statistical analysis of combined data was inappropriate given the differences in patient selection, testing, and follow-up in the available studies.

    Data Synthesis: Anthracycline-induced cardiotoxicity limits effective cancer chemotherapy by causing early cardiomyopathy, and it can produce late-onset ventricular dysfunction years after treatment has ceased. Detection of subclinical anthracycline-induced cardiomyopathy through resting left ventricular ejection fraction or echocardiographic fractional shortening is suboptimal. Conventional doses of anthracycline often lead to permanent myocardial damage and reduced functional reserve. Underlying pathogenetic mechanisms may include free-radical-mediated myocyte damage, adrenergic dysfunction, intracellular calcium overload, and the release of cardiotoxic cytokines. Dexrazoxane is the only cardioprotectant clinically approved for use against anthracyclines, and it was only recently introduced for selected patients with breast cancer who are receiving anthracycline therapy.

    Conclusions: A rapidly growing number of persons, including an alarming fraction of the 150 000 or more adults in the United States who have survived childhood cancer, will have substantial morbidity and mortality because of anthracycline-related cardiac disease. The development of effective protection against anthracycline-induced cardiotoxicity will probably have a significant effect on the overall survival of these patients.

    Anthracyclines are well established as highly efficacious antineoplastic agents for various hemopoietic [1] and solid tumors [2-4]. A clear dose-response relation for anthracyclines in several curative chemotherapeutic regimens has been shown; decreased doses result in inferior survival and remission rates [1, 4]. However, the cardiotoxicity of these agents [4-6], which has been recognized for more than 20 years [7], continues to limit their therapeutic potential and threaten the cardiac function of many patients with cancer.

    Three distinct types of anthracycline-induced cardiotoxicity have been described. First, acute or subacute injury can occur immediately after treatment. This rare form of cardiotoxicity may cause transient arrhythmias [8, 9], a pericarditis-myocarditis syndrome, or acute failure of the left ventricle [10]. Second, anthracyclines can induce chronic cardiotoxicity resulting in cardiomyopathy. This a more common form of damage and is clinically the most important [11-13]. Finally, late-onset anthracycline cardiotoxicity causing late-onset ventricular dysfunction [14-16] and arrhythmias [17-19], which manifest years to decades after anthracycline treatment has been completed, is increasingly recognized.

    Chronic anthracycline-induced cardiomyopathy characteristically presents within 1 year of treatment. In a series of more than 3900 patients treated with anthracycline, Von Hoff and associates [6] noted that congestive heart failure secondary to anthracycline-induced chronic cardiomyopathy occurred 0 to 231 days after the completion of anthracycline therapy. In contrast, late-onset anthracycline-induced cardiac abnormalities have been reported to occur much later, after a prolonged asymptomatic period [14-16]. Other cardiovascular risk factors predisposing to heart failure, such as occult hypertension and subclinical coronary artery disease, may have confounded interpretation of the exact contribution made by anthracyclines in these studies. However, anthracyclines are clearly an important independent risk factor leading to both early and delayed congestive heart failure in survivors of cancer. There is no universally defined point after the onset of chronic cardiomyopathy at which late-onset cardiac abnormalities appear. For the purposes of this review, we broadly define “chronic cardiotoxicity” as cardiotoxicity occurring within 1 year of treatment and “late-onset cardiotoxicity” as cardiotoxicity occurring more than 1 year after the completion of anthracycline therapy.

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    Clinical Significance

    Acute and Subacute Cardiotoxicity

    Acute and subacute cardiac toxicity, which occur immediately after a single dose of an anthracycline or a course of anthracycline therapy, are uncommon under current treatment protocols. Several distinct, early cardiotoxic effects of anthracyclines have been described. First, electrophysiologic abnormalities may result in nonspecific ST and T-wave changes, decreased QRS voltage, and prolongation of the QT interval. Sinus tachycardia is the most common rhythm disturbance, but arrhythmias, including ventricular, supraventricular, and junctional tachycardias, have been reported [8-11]. Atrioventricular and bundle-branch block have also been seen [8]. These electrophysiologic changes are seldom a serious clinical problem [11]. Rare cases of subacute cardiotoxicity resulting in acute failure of the left ventricle, pericarditis, or a fatal pericarditis-myocarditis syndrome have been reported [12].

    Chronic Cardiotoxicity

    The incidence of congestive heart failure secondary to doxorubicin-induced cardiomyopathy depends on the cumulative dose of the drug. At total doses of less than 400 mg/m2 body surface area, the incidence of congestive heart failure is 0.14%; this incidence increases to 7% at a dose of 550 mg/m2 body surface area and to 18% at a dose of 700 mg/m2 body surface area [6] (Figure 1). The rapid increase in clinical toxicity at doses greater than 550 mg/m2 body surface area has made the 550-mg dose the popular empiric limiting dose for doxorubicin-induced cardiotoxicity. Mortality directly related to doxorubicin-induced cardiac failure is substantial; large series have reported rates of more than 20% [5, 6]. However, recent reports have suggested a better prognosis [20-24], with up to 59% clinical recovery in patients with anthracycline-induced congestive heart failure who are treated with digoxin and diuretics [14]. Complete recovery of echocardiographic shortening fraction may also occur if anthracycline therapy is discontinued at an early stage [24], but this does not exclude long-term reductions in functional reserve [23].

    Figure 1. Reproduced from Von Hoff and colleagues with permission of .
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    Figure 1. Reproduced from Von Hoff and colleagues with permission of . Cumulative probability of developing doxorubicin-induced congestive heart failure (CHF) plotted against total cumulative dose of doxorubicin in all patients receiving the drug (3941 patients; 88 cases of congestive heart failure).[6]Annals of Internal Medicine

    Although reports conflict, proposed risk factors for chronic anthracycline cardiotoxicity include higher rates of drug administration [25], mediastinal radiation [10, 26], advanced age [3, 6], younger age [27, 28], female sex [29], pre-existing heart disease, and hypertension [6]. Multivariate analysis of these factors by Torti and colleagues [30], based on histologic evidence of anthracycline cardiotoxicity, showed that only higher rates of anthracycline administration and previous cardiac irradiation were independent risk factors. An additional confounding factor in the identification of patients at highest risk for cardiotoxicity is the wide variation in individual sensitivity to anthracyclines [31-33]. Doses in excess of 1000 mg/m (2) body surface area can be well tolerated by some patients [31, 33]. In contrast, appreciable decreases in left ventricular ejection fraction have been documented by multigated nuclear scans at doses as low as 300 mg/m2 body surface area [26, 27]. Furthermore, endomyocardial biopsy specimens may show histopathologic changes characteristic of doxorubicin-induced cardiotoxicity (Figure 2) at doses as low as 183 mg/m2 body surface area [13]—less than one third of the conventional limiting dose. Thus, a substantial proportion of patients have anthracycline-induced cardiac damage while receiving standard treatment regimens, whereas others can tolerate cumulative doses twice as large as the conventional limiting dose.

    Figure 2. Light microscopy. Section of left ventricle from a 57-year-old woman with adriamycin-induced cardiomyopathy showing marked myofibril loss and vacuolar degeneration ( ). (Hematoxylin and eosin stain. Original magnification, × 400). Electron microscopy. Cardiac myocyte showing adriamycin-induced cardiotoxicity with extensive loss of myofilaments (large arrows). Unaffected myocytes are shown in lower left. Small arrow denotes normal myocyte. (Original magnification, × 2800).
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    Figure 2. Light microscopy. Section of left ventricle from a 57-year-old woman with adriamycin-induced cardiomyopathy showing marked myofibril loss and vacuolar degeneration ( ). (Hematoxylin and eosin stain. Original magnification, × 400). Electron microscopy. Cardiac myocyte showing adriamycin-induced cardiotoxicity with extensive loss of myofilaments (large arrows). Unaffected myocytes are shown in lower left. Small arrow denotes normal myocyte. (Original magnification, × 2800). Changes characteristic of adriamycin-induced cardiotoxicity. Top.arrowBottom.

    Late-Onset Cardiotoxicity

    Several recent studies have noted occult ventricular dysfunction, heart failure, and arrhythmias occurring in asymptomatic patients more than 1 year after anthracycline treatment [16-21, 34-36]. These initial findings suggest that survivors of cancer may have a previously unacknowledged increase in cardiac morbidity and mortality due to anthracycline therapy. Steinherz and associates [16], who studied 201 patients with solid tumors or leukemia, found an 18% incidence of reduced fractional shortening on resting echocardiograms in patients followed for 4 to 10 years after completion of anthracycline therapy. Even more troubling are the findings of Lipshultz and coworkers [17], who noted that cumulative doses of doxorubicin as low as 228 mg/m2 body surface area increased afterload or decreased contractility or both in 65% of patients with leukemia up to 15 years after treatment with anthracyclines. These abnormalities appear to be progressive and reflect future clinical decompensation.

    Lipshultz and coworkers [17] noted both early and late congestive heart failure in 5 of 115 patients within 11 years of the completion of anthracycline therapy. A similar incidence of late-onset heart failure, occurring in 9 of 201 patients, was reported by Steinherz and associates [16]. However, most patients in the study by Steinherz and associates were followed for fewer than 10 years after completion of therapy, and new-onset symptomatic ventricular dysfunction was not seen until 12 to 14 years after treatment in the study by Lipshultz and coworkers [17]. Additionally, the incidence of severe echocardiographic abnormalities increased with the duration of follow-up (Figure 3). These findings indicate that the full extent of the problem has yet to unfold in many asymptomatic patients after remote anthracycline treatment. In addition, late-onset arrhythmias and sudden death have been reported to have occurred in patients more than 15 years after anthracycline treatment [19-21]. Incidences of nonsustained ventricular tachycardia ranging between 3% and 5% in anthracycline-treated patients at long-term follow-up have been reported [17, 19]. The natural history of these arrhythmias and whether they occur independently of ventricular dysfunction [19] are issues that remain to be clarified.

    Figure 3. Percentage of patients with abnormal fractional shortening at long-term follow-up over time after completion of therapy. Adapted from Steinherz and colleagues with permission of The Journal of the American Medical Association. White bars = mild reduction in fractional shortening (25% to 28%); striped bars = moderate reduction in fractional shortening (21% to 24%); black bars = severe reduction in fractional shortening (≤ 20%).
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    Figure 3. Percentage of patients with abnormal fractional shortening at long-term follow-up over time after completion of therapy. Adapted from Steinherz and colleagues with permission of The Journal of the American Medical Association. White bars = mild reduction in fractional shortening (25% to 28%); striped bars = moderate reduction in fractional shortening (21% to 24%); black bars = severe reduction in fractional shortening (≤ 20%). Late-onset ventricular dysfunction over time.[16]

    As with the form of anthracycline cardiotoxicity that manifests earlier, the incidence of late-onset cardiac decompensation increases with larger cumulative doses [16, 17], higher rates of anthracycline administration [37], and mediastinal radiotherapy [16]. Young age [16] at the time of treatment and female sex [38] may be risk factors for late-onset anthracycline cardiotoxicity, but this is still controversial [17, 39]. However, recent evidence appears to support both characteristics as independent risk factors for late-onset ventricular dysfunction [37].

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    Pathogenesis

    Chronic Cardiomyopathy

    Anthracyclines cause the selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase in vivo [40], which may explain the myofibrillar loss (Figure 2, bottom) associated with anthracycline-induced cardiomyopathy. Hypotheses at the cellular level include free-radical-mediated myocardial injury [41-48], myocyte damage from calcium overload [49-53], disturbances in myocardial adrenergic function [54-56], release of vasoactive amines [57, 58], and cellular toxicity from metabolites of doxorubicin [59, 60]. Finally, elaboration of pro-inflammatory cytokines, which have been consistently identified in other forms of ventricular dysfunction [61-64], may be directly relevant to anthracycline-induced cardiac injury.

    Although the cause of anthracycline-induced cardiotoxicity is probably multifactorial, a large body of evidence points to free-radical-mediated myocyte damage [41-44]. Increased oxygen radical activity generated through the semiquinone moiety of the doxorubicin molecule can cause lipid peroxidation and cell injury [41, 42]. Anthracycline-induced intracellular calcium overload may also lead to myocyte death [49-53]. Doxorubicin activates the calcium-release channel across the sarcoplasmic reticulum [52] and causes calcium influx into the myocyte [50, 51, 53]. Free-radical-induced cell membrane damage has also been seen with calcium influx [65, 66], suggesting that these two putative anthracycline-induced cardiotoxic pathways may be linked. Adrenergic dysfunction, including downregulation of myocardial β-adrenergic receptors [67, 68], may be present in evolving [69, 70] as well as established anthracycline-induced ventricular dysfunction [71, 72].

    Recent reports [61-64] that circulating pro-inflammatory cytokines may be intimately linked to the evolution of ventricular dysfunction and dilated cardiomyopathies may provide further insight into the process by which anthracyclines produce cardiac injury. Doxorubicin induces the release of tumor necrosis factor-α from macrophages and of interleukin-2 from monocytes [73-75]. Interleukin-2 and tumor necrosis factor-α, which has functional myocardial receptors [76], have documented cardiotoxicity that can result in dilated cardiomyopathy [77, 78]. Varying degrees of cytokine liberation from different tumors [79-81] during anthracycline treatment may provide another explanation for the discrepancy in the incidence of cardiotoxicity in different populations with cancer [82, 83].

    Late-Onset Cardiotoxicity

    Progressive ventricular dysfunction after an initial myocardial insult probably underlies late-onset decompensation. Reductions in left ventricular mass, mass index, and compliance have been reported in anthracycline-treated survivors of childhood cancer followed for more than 7 years after completion of chemotherapy [34, 84]. These patients appear to have a thin-walled left ventricle working against high systolic wall stress [34]. Such a pattern of cardiac injury is concordant with the theory that occult late-onset anthracycline cardiac dysfunction manifests clinically in patients who remain in a compensated state for many years. Acute viral infection [85] and cardiovascular stressors, such as weight lifting [20], pregnancy, and surgery, are possible triggers of late-onset anthracycline-induced cardiac dysfunction.

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    Monitoring

    The lifelong cardiotoxic effects of conventional anthracycline therapy highlight the need for monitoring methods that are highly sensitive and capable of predicting cardiac dysfunction. In addition, the specificity of any test should allow for an accurate risk–benefit analysis in balancing the likelihood of cardiac dysfunction with greater drug doses against the harm that may result from withholding antitumor therapy.

    Detection of Chronic Anthracycline-Induced Cardiomyopathy

    Billingham and colleagues [86] have developed a semiquantitative histologic scoring system for endomyocardial biopsy specimens that correlates well with cumulative anthracycline dose. Biopsy grade is predictive of the rate of early progression around the time of therapy and is currently considered the most sensitive indicator of chronic anthracycline-induced cardiotoxicity [87]. Underestimation of cardiac damage with right ventricular biopsy may occur because of scattered cardiomyopathic changes [88] or the predominance of left ventricular injury [89]. Also, expertise in obtaining and interpreting biopsy specimens is not widely available, and concerns remain about the safety of repeated testing, particularly in children [90]. Thus, the use of endomyocardial biopsy for the routine monitoring of early anthracycline-induced cardiotoxicity has been limited.

    Radionuclide angiocardiography is extensively used in monitoring for early anthracycline-induced cardiotoxicity on the basis of its proven value in reducing the incidence of cardiac failure from early anthracycline cardiotoxicity [91-93]. Having used data on serial left ventricular ejection fraction in patients with doxorubicin-induced cardiomyopathy, Alexander and colleagues [91] suggested that a 15% decline in left ventricular ejection fraction or a baseline left ventricular ejection fraction less than 40% identifies patients at high risk for cardiac decompensation. Similar findings by others [92, 93] have led to the proposal of broad guidelines for basing administration of anthracycline therapy on RNA findings [94]. Unfortunately, resting left ventricular ejection fraction measurements obtained through RNA findings are relatively insensitive in detecting early anthracycline cardiotoxicity. This is largely because no appreciable change in left ventricular ejection fraction occurs until a critical amount of morphologic damage has been done. After this point, functional deterioration proceeds rapidly. Exercise radionuclide studies may increase the chances of detecting subclinical early anthracycline cardiotoxicity [26, 95]. McKillop and coworkers [96] have suggested that the failure to increase ejection fraction by 5% over the resting value, as measured by stress radionuclide angiocardiography, is a marker of high risk for the development of early anthracycline-induced ventricular dysfunction. However, the specificity of exercise radionuclide angiocardiography is low without serial testing, and maximal exercise may be difficult for debilitated patients with cancer.

    Two-dimensional echocardiography is the other primary noninvasive technique used to monitor anthracycline cardiotoxicity, particularly in children [97-100]. Resting left ventricular ejection fraction and fractional shortening are the most commonly used echocardiographic parameters. However, as with radionuclide measurements, cardiac compensation in the face of substantial anthracycline-induced cardiac injury often maintains normal left ventricular ejection fraction until the cardiomyopathic changes are relatively well established.

    Parameters of diastolic function have also been examined for their usefulness in detecting early anthracycline-induced cardiac injury [101-108]. Chronic anthracycline cardiotoxicity can present with substantial fibrous thickening of the endocardium [89], suggesting that diastolic dysfunction is probably an impairment co-existing with the disease. Marchandise and coworkers [101], in an echocardiographic study, found a prolongation of the isovolumic relaxation period of 32% (from 65 ms to 86 ms) and a reduction in early peak flow velocity of 18% (from 60 ms to 49 ms) in anthracycline-treated adults before detectable decreases in left ventricular shortening fraction, which remained at about 40% [101]. In addition, Stoddard and colleagues [103] have reported an increase in the mean isovolumic relaxation time from 66 to 84 ms after cumulative doxorubicin doses as low as 100 mg/m2 body surface area in a prospective study of 26 anthracycline-treated adults. These authors have suggested that an increase in the isovolumic relaxation time of more than 37% reliably predicts anthracycline-induced systolic dysfunction (defined as a decrease in ejection fraction of less than equals 10% to less than 55%). Other echocardiographic diastolic parameters, such as rapid and slow filling velocities [103], have also been reported to precede anthracycline-induced systolic dysfunction in adults. Reductions in peak filling rate, a diastolic parameter measured by multigated angiocardiography in adults, occur before anthracycline-induced decrements in left ventricular ejection fraction [104]. However, a recent report on anthracycline-treated adults [107] suggests that reductions in peak filling rate and ejection fraction measured by radionuclide studies appear simultaneously. The utility of diastolic filling abnormalities to unmask early anthracycline cardiotoxicity in children also needs to be confirmed [105-108]. Fractional shortening has been reported to be more sensitive than diastolic parameters in children with early anthracycline-induced cardiomyopathy [106]. In contrast, a recent smaller prospective study has shown the value of diastolic indices in detecting early anthracycline-induced cardiomyopathy in asymptomatic children [108]. Table 1 summarizes studies examining diastolic and systolic abnormalities in early anthracycline-induced cardiotoxicity. Despite inherent limitations in sensitivity, resting left ventricular ejection fraction based on radionuclide angiocardiography or echocardiography remains the most widely used monitoring method for early anthracycline-induced cardiotoxicity. The limited sizes of these studies (the largest of which involved 60 patients) underscore the need for larger prospective studies to establish the value of diastolic abnormalities in the detection of early anthracycline-induced cardiotoxicity.

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    Table 1. Abnormalities in Diastolic and Systolic Ventricular Function for the Early Detection of Anthracycline-Induced Cardiotoxicity*

    Detection of Late-Onset Anthracycline-Induced Cardiotoxicity

    Recognition of late-onset cardiac dysfunction and failure has highlighted the need for monitoring methods that will help detect and predict long-term cardiac impairment in asymptomatic patients. Currently, there are few universally accepted guidelines on which tests of ventricular function should directly influence long-term monitoring for late-onset cardiotoxicity in asymptomatic adults, although the issue has been extensively debated in children [97-99]. Lipshultz and coworkers [17] have reported that fractional shortening as assessed by echocardiography has a sensitivity of 64% and a specificity of 81% for either abnormal contractility or abnormal afterload at long-term follow-up [17]. Congruent with these findings are the results of Steinherz and colleagues [16]. In a study of 201 children treated with anthracycline, they found that only 29% of patients with mildly abnormal or worse fractional shortening (≤ 28%) on an “end-therapy” echocardiogram had normal fractional shortening (≥ 29%) at late follow-up. Thus, abnormal fractional shortening after therapy may help predict long-term cardiac dysfunction. In contrast, 87% of patients with normal fractional shortening during the first year after therapy have maintained normal fractional shortening at late follow-up [16]. However, most late-onset clinical decompensations occur after more than 10 years of follow-up, and data from beyond that time point are limited. Echocardiographically determined left ventricular end-systolic wall stress (a more load-independent measure of systolic function than fractional shortening) has also been used to assess late-onset anthracycline-induced cardiotoxicity. Lipshultz and coworkers [17] have reported that left ventricular end-systolic wall stress is substantially increased to a mean of 64 g/cm2 (normal mean, 47.5 g/cm2) in anthracycline-induced late-onset ventricular dysfunction, although correlation with symptoms was poor.

    Resting left ventricular ejection fraction and fractional shortening are often absent despite substantial decreases in functional capacity associated with late-onset cardiotoxicity [109-111]. Dobutamine [109], exercise echocardiography [110], and exercise radionuclide angiography [111] have all been shown to unmask late-onset cardiac dysfunction in small series of patients with normal resting systolic function. Using dobutamine echocardiography in a group of patients treated with anthracycline, Klewer and coworkers [109] found significant reductions in shortening fraction and end-systolic wall stress that were only detectable during inotropic stimulation a mean of 6.1 years after therapy. Yeung and colleagues [18] tested 29 children, 19 of whom had received anthracyclines up to 6 years earlier with exercise echocardiography. The children treated with anthracycline had an average increase in fractional shortening of 3% compared with an average increase of 23% in the control group, although fractional shortening at rest was normal (mean, 38%) in all participants [18].

    Diastolic dysfunction can also be seen with late-onset anthracycline-induced systolic impairment, particularly in patients who have received high doses of anthracyclines with radiotherapy [112]. Concordant with these findings, preliminary data from anthracycline-treated survivors of leukemia suggest that features of restrictive cardiomyopathy may appear on long-term follow-up [84]. Table 2 summarizes studies evaluating ventricular function during long-term (> 1 year) follow-up after anthracycline treatment.

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    Table 2. Late-Onset Ventricular Function Abnormalities with Anthracycline Treatment*

    From the standpoint of the clinician, it is unclear how much information in addition to that on resting systolic parameters is derived from the use of diastolic and stress systolic indices during screening for either early or late anthracycline-induced cardiotoxicity. Larger prospective studies are needed to provide more conclusive data on the correlation between these noninvasive parameters and 1) the overall frequency of early- and late-onset anthracycline-induced cardiotoxicity, 2) clinically important functional impairment, and 3) mortality from anthracycline-induced heart failure. Also, the value of early abnormalities in determining the need for long-term monitoring of late-onset cardiotoxicity needs to be clarified. The advantages and limitations of noninvasive assessment of ventricular function have been well reviewed [113, 114].

    Although the full clinical importance of systolic and diastolic dysfunction in anthracycline-induced cardiomyopathy is unclear, it may be useful to consider the clinical relevance of diastolic and systolic abnormalities in patients with idiopathic dilated cardiomyopathy [115-117]. In addition to decreased left ventricular ejection fraction [115], such diastolic abnormalities as shortened deceleration time [115, 116] and increased peak early velocity [116] have been reported as further markers of poor prognosis. Diastolic dysfunction strongly correlates with congestive symptoms in patients with dilated cardiomyopathy [115, 117]. Confirmation of such findings in patients with anthracycline-induced cardiomyopathy would be valuable in the assessment of prognosis and the rationalization of monitoring for anthracycline-induced cardiotoxicity.

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    Prevention

    Any method designed to minimize the cardiotoxic effects of anthracyclines must maintain antineoplastic efficacy. Strategies (other than cardiac monitoring) for the prevention of anthracycline-induced cardiotoxicity have focused on three main areas.

    First, the method of drug delivery [25, 118, 119] may influence cardiotoxicity. In adults, less clinical cardiotoxicity has been noted with prolonged infusions of doxorubicin over 48 or 96 hours than with shorter infusion times of 15 to 20 minutes [25]. However, concern about whether antineoplastic activity is preserved with this regimen remains [118], and the value of this approach has not been proven in children. An alternative way to deliver drug with potentially less cardiotoxicity is to use liposomal anthracyclines, which are now in Phase II clinical trials [119]. Second, the use of such anthracycline structural analogues as mitoxantrone and idarubicin is of undetermined benefit in the balance between cardiotoxicity and antineoplastic effect [31].

    Third, cardioprotectants are used to attenuate the effects of anthracyclines on the heart. Randomized, placebo-controlled studies in patients with breast cancer have shown that cardioprotection occurs with dexrazoxane (ICRF-187), an iron-chelating agent that appears to reduce free-radical generation by anthracyclines [120-123]. This agent has also shown the promise of cardioprotection in children [124]. Dexrazoxane is currently clinically approved only for use in women with metastatic breast cancer after a cumulative doxorubicin dose of 300 mg/m2 body surface area. However, substantial myocardial damage can be expected at much lower doses. In addition, concerns that dexrazoxane interferes with the antitumor efficacy of anthracyclines have been raised [125]; lower response rates and faster tumor progression times have been seen in patients with early breast cancer [122].

    Recent animal studies indicate that probucol, a lipid-lowering agent similar in structure to vitamin E, provides cardioprotection against doxorubicin-induced cardiomyopathy [46, 48]. Siveski-Iliskovic and associates [46] have reported that probucol enhances antioxidants in the rat myocardium by increasing myocardial glutathione peroxidase and superoxide dismutase activities. A reduction in anthracycline-induced lipid peroxidation occurred concomitantly with this improvement in myocardial antioxidant status [46]. Furthermore, probucol does not interfere with the antitumor effects of doxorubicin in this animal model [47]. Studies in humans are needed to determine whether these findings can be extrapolated to clinical practice.

    The prevention of intracellular calcium overload caused by anthracyclines has also been targeted as a cardioprotective maneuver. Animal models have suggested that calcium antagonists both enhance and reduce anthracycline cardiotoxicity with calcium antagonists [126-129]; pilot data indicate that the calcium antagonist prenylamine may confer some cardioprotection in humans [130]. β-adrenergic blocking agents have been shown to prevent anthracycline-induced intracellular calcium overload [131] and reduce anthracycline-induced cardiotoxicity, possibly by blunting the cardiotoxic effect of catecholamines [126]. Lipophilic β-blockers, such as propranolol, can also prevent free-radical-mediated lipid peroxidation [132-134]. The safe and efficacious use of metoprolol in established anthracycline-induced cardiomyopathy [135], idiopathic dilated cardiomyopathy [136], and ischemic heart failure [137] have all been reported. However, the cardioprotective effects of β-blockers against anthracycline-induced cardiotoxicity remain untested in prospective studies.

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    Conclusions

    The morbidity and mortality rates related to anthracycline-induced cardiotoxicity will continue to increase because of several factors: significant cardiac injury, which occurs even with low-dose therapy and commonly occurs with therapeutic doses; the use of monitoring techniques that are often insensitive to subclinical cardiac damage; lack of effective cardioprotection; and late-onset ventricular impairment occurring in asymptomatic patients years after uncomplicated anthracycline treatment. Within the next 5 years, given the present survival trends, 1 in 900 young adults (15 to 45 years of age) in the United States will have survived cancer, and the total number of survivors of cancer may approach one quarter of a million by the year 2000 [138]. Many of these persons will have been exposed to anthracyclines. For example, acute lymphocytic leukemia, the most common childhood cancer, has a 5-year survival rate of more than 70%, and anthracycline chemotherapy is a crucial part of therapy for this condition [139]. Thus, it is important for the general internist to be aware of the increasing numbers of asymptomatic cancer survivors at risk for cardiac dysfunction in later life. A clinical history suggestive of such risk factors as high cumulative doses of anthracycline treatment, mediastinal radiotherapy, or young age at the time of anthracycline treatment may help identify high-risk subgroups and prompt closer evaluation of ventricular function. Early treatment of subclinical anthracycline-induced systolic dysfunction with angiotensin-converting enzyme inhibitors [140] and possibly β-blockers [136] would be reasonable ways to reduce mortality rates in these patients. Diastolic dysfunction seen in late-onset anthracycline cardiotoxicity may also have important therapeutic implications [141] in certain survivors of cancer, particularly those who have received both high doses of anthracyclines and radiotherapy [112]. Unfortunately, the mainstay of treatment for established anthracycline-induced ventricular dysfunction, as for other types of cardiomyopathy, is limited to conventional therapy for heart failure, including angiotensin-converting enzyme inhibitors, diuretics, digoxin, and vasodilators. As with other forms of clinical heart failure, the overall prognosis for patients with anthracycline-induced ventricular failure (both early- and late-onset) is poor. Heart transplantation may be a viable alternative for a few select persons [142-144]. Thus, prevention continues to be the primary way to stem the mortality rate related to anthracycline-induced cardiotoxicity.

    This review is limited by the relatively small numbers of patients and the retrospective data included in some studies; these factors may confound the accuracy of clinical predictions [145, 146]. Concurrent occult disease, including subclinical coronary artery disease, silent infarction, and hypertensive heart disease, may have affected the interpretation of the overall effect of anthracycline-induced cardiotoxicity. Consideration of studies involving anthracycline-treated children and adults together may also make global inferences from these studies more difficult, particularly with regard to ventricular function tests and the effects of cardiovascular risk factors. In addition, the heterogeneity of the types of cancer among the various study populations may also influence the observed incidence of heart failure because of different treatment regimens, adjunctive radiotherapies, and hydration regimens. Finally, many of the studies that address the efficacy of monitoring are limited by a lack of prospective clinical data on prognosis and functional class.

    Long-term follow-up shows that overt heart failure occurs in 4.5% to 7% of patients treated with anthracycline and that the incidence of cardiac function abnormalities increases with time. However, the lack of information about the cardiac status of patients more than 15 years after the completion of anthracycline therapy is troubling. As we await more extended cardiac follow-up, the grave prognosis for patients with anthracycline-induced cardiomyopathy is ominous [6]. Despite the qualified success of dexrazoxane, the need for widely applicable cardioprotection against anthracyclines is increasingly pressing.

    Acknowledgments: The authors thank Kathleen D. Saneto for assistance in manuscript preparation and Dr. Jocelyn F. Caple for providing (Figure 2).

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    1. Ann Intern Med July 1, 1996 vol. 125 no. 1 47-58
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