Anthracyclines and related compounds

Cardiomyopathy

Anthracyclines can cause the late complication of a cardiomyopathy, which can be irreversible and can proceed to congestive cardiac failure, ventricular dysfunction, conduction disturbances, or dysrhythmias several months or years after the end of treatment [ , ]. Doxorubicin can cause abnormalities of right ventricular wall motion [ ]. A significant number of patients receiving anthracyclines develop cardiac autonomic dysfunction [ ].

Dose-relatedness : The development of anthracycline-induced cardiomyopathy is closely related to the cumulative lifetime dose of the anthracycline. The recommended maximum cumulative lifetime dose of doxorubicin is 450–550 mg/m ² [ ] and of daunorubicin 400–550 mg/m ² intravenously in adults [ , ]. About 5% of doxorubicin-treated patients develop congestive cardiac failure at this dose; however, the incidence approaches 50% at cumulative doses of 1000 mg/m ² [ ]. These figures are derived from experience with doxorubicin administered as a bolus or by infusion of very short duration (under 30 minutes). The incidence of clinical cardiotoxicity falls dramatically with other schedules of administration (that is weekly doses or continuous infusion for more than 24 hours).

In a randomized study of adjuvant chemotherapy comparing bolus against continuous intravenous infusion of doxorubicin 60 mg/m ² , cardiotoxicity, defined as a 10% or greater reduction in left ventricular ejection fraction, occurred in 61% of patients on a bolus median dose equal to 420 mg/m ² compared with 42% on the continuous infusion schedule with a median dose of 540 mg/m ² ; the rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm [ ].

In 11 patients with anthracycline cardiotoxicity studied by heart catheterization and endomyocardial biopsy, myocytic damage correlated linearly with cumulative dose [ ]. There was a non-linear relation between electron microscopic changes and the extent of hemodynamic impairment. There was pronounced fibrous thickening of the endocardium in most patients, especially in the left ventricle. Endocardial fibrosis may be the first morphological sign of cardiotoxicity.

Susceptibility factors : The risk of cardiotoxicity is greater in children and patients with pre-existing cardiac disease or concomitant or prior mediastinal or chest wall irradiation [ , ].

Of 682 patients, 144 who were over 65 years of age all had doses up to but not exceeding the usual cumulative dose for doxorubicin [ ]. The authors concluded that older patients without cardiovascular co-morbidity are at no greater risk of congestive heart failure.

The use of doxorubicin in childhood impairs myocardial growth, resulting in a progressive increase in left ventricular afterload, sometimes associated with impaired myocardial contractility [ ]. Of 201 children who received doxorubicin and/or daunorubicin 200–1275 mg/m ² , 23% had abnormal cardiac function 4–20 years afterwards. Of those who were followed for more than 10 years, 38% had abnormal cardiac function compared with 18% in those who were followed for less than 10 years [ , ]. In another study, more than half of the children studied by serial echocardiography after doxorubicin therapy for acute lymphoblastic leukemia developed increased left ventricular wall stress due to reduced wall thickness. This stress progressed with time [ ].

Predisposing factors to mitoxantrone cardiotoxicity include increasing age, prior anthracycline therapy, previous cardiovascular disease, mediastinal radiotherapy, and a cumulative dose of the drug exceeding 120 mg/m ² . In 801 patients treated with mitoxantrone, prior treatment with doxorubicin and mitoxantrone was significantly associated with risk of cardiotoxicity; however, age, sex, and prior mediastinal radiotherapy were not useful predictors [ ].

Anesthesia is difficult in patients with cumulative anthracycline-induced cardiotoxicity, and it has proved fatal on occasions [ ].

Comparative studies of anthracyclines : All anthracyclines have cardiotoxic potential. However, because only a few cycles of treatment are administered in most regimens, few patients reach the cardiotoxic threshold of cumulative anthracycline dose. There is therefore limited information about the comparative cardiotoxic potential of these agents.

Epirubicin is considered to cause substantially less cardiotoxicity than doxorubicin on a molar basis [ , ]. This has been attributed to its more rapid clearance rather than a different action [ ]. In a randomized, double-blind comparison of epirubicin and doxorubicin, there was a significant reduction in left ventricle ejection fraction with doxorubicin but not with epirubicin [ ]. However, data from large clinical series and from morphological examination of endomyocardial biopsies in smaller series of patients suggest that the incidence and severity of cumulative cardiac toxicity associated with epirubicin 900 mg/m ² is similar to that associated with doxorubicin 450–550 mg/m ² [ ]. In 29 patients treated with epirubicin in cumulative doses ranging from 147 to 888 mg/m ² the ultrastructural myocardial lesions were similar to those produced by doxorubicin (partial and total myofibrillar loss in individual myocytes) [ ]. With both drugs, severe lesions were associated with replacement fibrosis. None of the patients who received epirubicin in the study developed congestive cardiac failure.

Both mitoxantrone and the oral formulation of idarubicin have been thought to be less cardiotoxic than doxorubicin [ , ]. The South West Oncology Group reported on 801 patients treated with mitoxantrone; 1.5% developed congestive cardiac failure, an additional 1.5% had a reduced left ventricular ejection fraction (LVEF), and 0.25% developed acute myocardial infarction [ ]. Idarubicin has been reported to cause short-term cardiac toxicity when used in high doses in leukemia, and there is no doubt that it causes cumulative dose-related toxicity as well [ ]. Electrocardiographic changes occurred in 7% of adults with acute leukemia receiving aclarubicin [ ].

Presentation : The main effects of anthracycline-induced cardiotoxicity are reduced left ventricular function and chronic congestive heart failure. Other cardiotoxic events occur only rarely. Occasionally, acute transient electrocardiographic changes (ST–T wave changes, prolongation of the QT interval) and dysrhythmias can occur. Acute conduction disturbances, acute myopericarditis, and acute cardiac failure are also rare. In a study of the effects of anthracyclines on myocardial function in 50 long-term survivors of childhood cancer, there was cardiac failure in one patient and electrocardiographic abnormalities (non-specific ST segment and T wave changes) in two [ ]. In one patient with a VVI pacemaker, who received the combination of vincristine, doxorubicin, and dexamethasone, the pacemaker had to be reset after each cycle of treatment, as the pacing threshold had increased, resulting in bradycardia [ ].

Hypokinetic heart wall motion abnormalities and early signs of chronic cardiomyopathy have been identified as a significant toxic effect of mitoxantrone in patients who received cumulative doses of 32–174 mg [ ]. Electrocardiographic T wave inversion and cardiac complications have been described from intensive therapy with mitoxantrone 40 mg/m ² over 5 days and cyclophosphamide 1550 mg/m ² for 4 days, given before bone marrow transplantation for metastatic breast cancer. All the patients had had previous exposure to doxorubicin in cumulative doses that did not exceed 442 mg/m ² [ ].

The authors of a study of the use of MRI scans to assess the subclinical effects of the anthracyclines concluded that increased MRI enhancement equal to or greater than 5 on day 3 compared with the baseline predicted significant reduction in ejection fraction at day 28 [ ]. In 1000 patients given doxorubicin chemotherapy and irradiation there were six cases of congestive heart failure and three cases of myocardial infarction; there was a cumulative cardiac mortality of 0.4% in all anthracycline-exposed patients [ ].

Diagnosis : The diagnosis of anthracycline cardiomyopathy is based on the clinical presentation and investigations such as radionuclide cardiac angiography, which can show a reduced ejection fraction [ ], and echocardiography, which can show reduced or abnormal ventricular function [ , ]. Dysrhythmias can be detected by electrocardiography, and QT _c interval prolongation may offer an easy, non-invasive test to predict patients who are at special risk of late cardiac decompensation after anthracycline treatment for childhood cancer [ ]. Radioimmunoscintigraphy can be used to highlight damaged myocytes, and changes such as myocardial fibrosis are characteristic on endomyocardial biopsy [ , , ].

The subtle chronic abnormalities in myocardial function that occur 10–20 years after anthracycline exposure in childhood are best detected by exercise echocardiography, since these patients may have normal resting cardiac function [ ].

It has been suggested that monitoring B type natriuretic peptide concentrations after anthracycline administration can reflect cardiac tolerance, and through serial monitoring allow a picture of the degree of left ventricular dysfunction to be established [ ].

Mechanisms : Several mechanisms contribute to anthracycline cardiotoxicity. The principal mechanism is thought to be oxidative stresses placed on cardiac myocytes by reactive oxygen species. Amelioration of this toxicity is possible using dexrazoxane, an intracellular metal-chelating agent of the dioxopiperazine class [ ]. Dexrazoxane acts by depleting intracellular iron, thus reducing the formation of cardiotoxic hydroxyl anions and radicals. In patients without heart failure, in vivo measurements of myocardial oxidative metabolism and blood flow did not change in patients with cancer receiving doxorubicin [ ].

Anthracyclines have the ability inherent in their quinone structure to form free-radical semiquinones which result in very reactive oxygen species, causing peroxidation of the lipid membranes of the heart. However, this reaction has not been demonstrated with mitoxantrone, and the mechanism of its cardiotoxicity is unknown.

Abnormalities of left ventricular ejection fraction have been described in 46% of patients (n = 14) treated with mitoxantrone (14 mg/m ² ) and with vincristine and prednisolone [ ]. A history of cardiac disease or of previous anthracycline exposure was excluded. Only one patient developed clinically overt congestive cardiac failure. Other reports have described less cardiotoxicity compared with the parent compound, doxorubicin [ , ].

Management : Anthracycline cardiomyopathy, although reportedly difficult to treat, often responds to current methods used to manage congestive cardiac failure.

Severe anthracycline-induced cardiotoxicity is generally considered irreversible, and it is associated with a poor prognosis and high mortality. However, in four cases the advanced cardiac dysfunction associated with doxorubicin recovered completely after withdrawal [ ]. Of 19 patients with anthracycline-induced congestive cardiac failure, 12 recovered after withdrawal, although reversal was modest [ ].

The prolongation of the QT interval that occurs in patients who have recently finished doxorubicin therapy is slowly reversible over at least 3 years and the degree of prolongation is related to the cumulative dose [ ].

Heart transplantation has been successful in patients with late, progressive cardiomyopathy without recurrence of the underlying malignant disease [ ].

Cardiac dysrhythmias

Cardiac dysrhythmias have been reported after amsacrine therapy in association with hypokalemia. Pre-existing supraventricular dysrhythmias or ventricular extra beats are not absolute contraindications to its use [ ]. Of 5430 patients treated with amsacrine, 65 developed cardiotoxicity, including prolongation of the QT interval, non-specific ST–T wave changes, ventricular tachycardia, and ventricular fibrillation [ ]. There were serious ventricular dysrhythmias resulting in cardiopulmonary arrest in 31 patients; 14 died as a result. The dysrhythmias occurred within minutes to several hours after drug administration. The cardiotoxicity was not related to total cumulative dose, and hypokalemia was possibly a risk factor for dysrhythmias.