Anthracycline-induced chronic cardiotoxicity and heart failure

Abstract

Anthracyclines are effective drugs used in a wide range of malignant diseases. The drugs have frequent, serious adverse effects including cardiotoxicity and resulting heart failure. Systematic reviews, meta-analyses and other relevant studies were identified using the Cochrane and the Medline databases. Chronic cardiotoxicity and heart failure may complicate anthracycline treatment often months to years after treatment has ended. Risk factors including diverse cardiac diseases increase the risk of chronic cardiotoxicity. Screening for impairment of left ventricular function with echocardiography or radionuclide ventriculography is recommended. Search for new sensitive methods has been prompted to predict development of heart failure at an early stage enabling to modify the chemotherapeutic regimen, to include cardiac protectants or to initiate treatment.

Anthracyclines such as epirubicin and doxorubicin (Figure 1) are effective anti-neoplastic drugs used in adults and children in a wide range of malignant diseases including breast cancer, childhood tumours, soft tissue sarcomas, lymphomas and leukaemias. The use of anthracyclines is limited by serious side effects, the major ones being myelosuppression and chronic cardiotoxicity with resulting heart failure. Other common side effects are alopecia and nausea. Heart failure may develop during therapy, but deterioration of the cardiac function can progress gradually and heart failure become evident years after treatment has ended [1], [2].

Figure 1.  Doxorubicin.

Methods

Databases were searched systematically using the keywords anthracycline, epirubicin, and doxorubicin combining with cardiotoxicity, cardiomyopathy or heart failure. Systematic reviews and meta-analyses were identified using the Cochrane Database of Systematic Reviews. Other studies were searched using the Medline database, preferring randomised trials.

Mechanism

The mechanism behind the development of anthracycline induced cardiomyopathy is complex and only partially understood. Oxidative damage seems to play a central part [3]. Through redox-cycling of anthracycline, superoxide and hydrogen peroxide are generated as well as free hydroxyl radicals. Studies indicate that a C-13 alcohol-metabolite may be important for the development of cardiotoxicity. The anthracyclines bind to phospholipids altering the structure of cellular membranes [4]. As a result lipid-protein interactions involved in signal transduction pathways are affected [4]. Increased calcium release from sarcoplasmatic reticulum leads to cytosolic calcium overload [5]. The treatment also results in mitochondrial dysfunction with abnormal calcium-ion handling and abnormal energy metabolism [6], [7].

Anthracyclines cause DNA-strand breaks by interaction with topoisomerase II, the primary target of their anti-tumor activity. Selective inhibition of a muscle gene expression is possibly responsible for the myofibrillar loss in anthracycline induced cardiotoxicity.

Combination treatment with doxorubicin or epirubicin and the taxan, paclitaxel seems to enhance the toxicity seen with anthracycline-therapy alone [8]. This is possibly due to increased concentration of the anthracycline and its alcohol-metabolite, caused by competition for excretory mechanisms. Besides, allosteric interactions between paclitaxel and cytoplasmic reductases result in increased formation of the alcohol-metabolite.

Apoptotic cell death is probably a prominent mechanism for the myocardial cell loss seen [9]. It can be triggered by apoptotic regulatory proteins (FAS, Bax) [9], transcription factors (GATA-4) [9] and mitochondrial dysfunction.

Incidence

The published incidences of heart failure during anthracycline therapy vary considerably in studies, reflecting the use of different definitions of heart failure, methods for cardiac evaluation, populations examined, anthracycline regimens, study design and follow-up. The incidence of anthracycline induced heart failure increases with cumulative doses, but low doses may as well result in decreasing left ventricular function and sub-clinical myocardial damage [10].

The incidence of heart failure rises dramatically at doxorubicin doses above 500 mg/m². At a cumulated dose of 400 mg/m² the incidence of CHF is reported as 3% and 18% at 700 mg/m². For epirubicin the incidence increases from 4% at 900 mg/m² to 15% at 1000 mg/m² and even more dramatic increases are reported [1], [2], [11].

Monitoring

ECG

ECG-changes resulting from anthracycline administration are non-specific [2]. They are of limited value as a method for monitoring chronic cardiotoxicity.

Pathological changes

Light and electron microscopy of right ventricular biopsies show progressive pathological changes, which have permitted the development of a semi-quantitative grading system well correlated to the cumulated dose of anthracycline [10]. The changes include cytoplasmic vacuolisation involving mitochondrial and sarco-tubular dilatation, myocardial swelling and myofibrillar loss. Though myocardial biopsy is believed to be among the most sensitive monitoring methods, the invasive nature of the procedure makes it unsuitable for routine monitoring

Hormones and markers of cardiac damage

The cardiac natriuretic peptides, atrial and brain natriuretic peptide (ANP and BNP), are synthesised, stored and secreted from cardiomyocytes in atria and ventricles, respectively. Stretch and wall tension in the heart are important in controlling the production and secretion of the hormones. They are well-established markers of heart failure but they are also increased during anthracycline treatment. Studies have indicated that natriuretic peptides might be useful as predictors for anthracycline induced heart failure even though a recent study failed to show early changes [12]. The exact role of natriuretic hormones in the monitoring of cardiotoxicity remains to be established.

Troponins (TnT and TnI) are sensitive and specific markers of myocardial damage in myocardial infarction and in myocarditis. During anthracycline treatment, troponins can be elevated. The release is prolonged and differs from the troponin release during myocardial infarction, indicating a continuous damage to the myofibrillar system rather than an acute cellular event [13]. Serial measurements of troponins during chemotherapy have shown promising potential as early markers of late myocardial impairment, but they are not currently part of routine monitoring [13].

Left ventricular function

Serial measurements of the left ventricular ejection fraction (LVEF) by radionuclide ventriculography or echo-cardiography should be performed before initiation and during the anthracycline treatment according to treatment guidelines for children [14], [15]. No guidelines for adults have systematically been adopted, but screening of the left ventricular function should probably follow same guidelines as for children. Earlier studies have found LVEF measurements to have predictive value for the development of heart failure [14]. A recent study, showed low sensitivity for later left ventricular impairment [1]. Diastolic ventricular function can be affected early in the course of several heart diseases. Reduced diastolic function has also been demonstrated during anthracycline therapy, but controversy exists about the value of the diastolic parameters [16]. New echo-cardiographic modalities including tissue Doppler imaging may offer increased sensitivity, but need to be examined further.

Prevention

Screening for risk factors

Several factors increasing the risk of cardiotoxicity have been identified, especially high cumulated dose of anthracycline but also ventricular dysfunction, ischemic heart disease, valvular heart disease, hypertension, advanced age and mediastinal radiotherapy increase the risk of cardiotoxicity. Females and children seem to be more susceptible than males when exposed to anthracyclines [1], [2].

Combination therapy including the taxan paclitaxel appears to increase the toxicity of simultaneous anthracycline-therapy [8]

Risk factors may result in modification of the anthracycline regimen, reduction of the cumulated anthracycline dose or avoidance of the drug [8].

Restriction of the cumulated anthracycline dose

Maximum doses of anthracyclines have been implemented. Maximum cumulated doses of 550 mg/m² of doxorubicin and 900 mg/m² of epirubicin are currently recommended [11].

Anthracycline regimens

A number of close analogs have been developed from the first anthracyclines, doxorubicin (Figure 1) and daunorubicin, but only few of these, like epirubicin and idarubicin, have reached clinical use. Epirubicin has similar mode of action and spectrum compared to doxorubicin, but it has increased volume of distribution and clearance reflected in lower plasma levels achieved after administration [17].

Epirubicin seems to carry similar risk of heart failure compared to doxorubicin [11]. Higher cumulated doses of epirubicin are used, and the maximum doses mentioned for doxorubicin and epirubicin reflect the level of equal cardiotoxicity, approximately 1:2 [17]. Idarubicin has been developed from daunorubicin and has a broader spectrum of activity than its parental drug, possibly due to increased lipophilicity and cellular uptake [18]. Controversy exists whether idarubicin has advantages over doxorubicin in regard to cardiac toxicity [18].

New preparations of liposomal doxorubicin have been developed in order to reduce the risk of toxicities. Liposomal doxorubicin and especially pegylated liposomal doxorubicin have proven reduced risk of toxicity and myocardial damage compared to conventional doxorubicin while maintaining anti-tumour efficacy [19], [20].

Anthracycline-induced cardiotoxicity seems related to peak plasma concentrations. In a recent metaanalyses converting bolus injections of anthracycline into prolonged infusions is reported to be less cardiotoxic [21].

Cardioprotectants

Dexrazoxane is a derivative of the metal-chelating agent edetic acid. The effect of dexrazoxane seems related to its iron chelating activity, preventing oxidative damage to the cardiac mitochondria. Proof of efficacy in protecting from cardiotoxicity has been demonstrated in randomised trials and in a recent meta-analysis [22]. No significant negative effect on the anti-tumour efficacy has been found [22]. Guidelines recommend that the use of dexrazoxane may be considered for patients with metastatic breast cancer or patients with other tumours, who have received more than 300 mg/m² of doxorubicin [23]. No guidelines exist regarding childhood malignancies or epirubicin treatment.

Treatment

Few recommendations exist on the treatment of anthracycline-induced heart failure as a consequence of a lack of studies addressing this aspect. If the left ventricular function deteriorates during treatment no further anthracycline therapy should be given [14], [15]. The treatment for heart failure should probably include an angiotensin converting enzyme inhibitor (ACE–inhibitor) and treatments shown effective for other types of heart failure: diuretic, ACE-inhibitor, β-receptor antagonist, aldosterone antagonist and digoxin according to current guidelines for heart failure [1], [24–26]. Heart transplantation remains a treatment of terminal heart failure in patients cured for their malignant disease.

Conclusion

Anthracyclines are effective drugs used in a wide range of malignant diseases. Anthracycline induced cardiotoxicity with heart failure is dose dependent and the risk is increased by a number of risk factors. Heart failure may develop months to years after treatment has ended.

Monitoring the systolic ventricular function using radionuclide ventriculography or echo-cardiography is recommended for all patients, but cardiac hormones, markers and new echocardiographic modalities may prove to have increased sensitivity. Prevention of chronic cardiotoxicity is difficult, but regimens for the administration of the anthracyclines using prolonged infusion, may carries lower risks. Also new liposomal preparations of doxorubicin offer less cardiotoxicity than traditional doxorubicin. The cardiac protectant dexrazoxane is effective in some clinical settings.

The treatment of anthracycline induced heart failure is not well studied; it should probably be treated like other types of heart failure.