Daunorubicin and doxorubicin share many common indications for cancer therapy, but they differ in that doxorubicin is used in solid tumors such as breast carcinoma, and daunorubicin is used in hematogenous malignancies, such as acute myelogenous leukemia and acute lymphocytic leukemia. The clinical toxicity of the older anthracyclines is limited by the use of less toxic structural analogs (eg, epirubicin, idarubicin) and liposome-encapsulated formulations (pegylated liposomal doxorubicin).
The chemotherapeutics derived from the bacterium Streptomyces are dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, and plicamycin. Only plicamycin crosses the blood–brain barrier. Doxorubicin has a protein binding of 75% to 80%, a volume of distribution of 28.0 ± 3.3 L/kg, and a terminal elimination half-life of approximately 30 hours.43 The liposome encapsulated formulation of doxorubicin has a prolonged terminal half-life of 50 hours because of a slower clearance compared with the nonencapsulated formulation. Doxorubicin and daunorubicin are both eliminated by the liver, and their dosages are decreased in patients with hepatic insufficiency. Delayed drug elimination contributes to increased area under the concentration versus time curve and peak concentration, both of which are associated with myelosuppression and cardiac toxicity, respectively.66 The mechanism of therapeutic action of the anthracyclines is attributed to DNA intercalation101 and inactivation of topoisomerase II.117 These xenobiotics are metabolized to active metabolites, which have lesser degrees of activity than their parent compounds. The liposomal-encapsulated formulation of doxorubicin has limited selective activity at the tumor compared to nontumor sites in the body, such as the heart and bone marrow because of its particle size (100 A°).86,98 A typical dose schedule for daunorubicin is 30 to 60 mg/m2 daily for 3 days; for doxorubicin, 45 to 60 mg/m2 every 18 to 21 days; and for pegylated liposomal doxorubicin, 50 mg/m2 every 28 days.
The red anthracycline antibiotics—dactinomycin and doxorubicin—are associated with cardiotoxicity, which limits their therapeutic use. The associated toxicity is caused by a different mechanism than the therapeutic effects.117 The purported mechanism of cardiac toxicity is from the formation of free radicals and impaired intracellular calcium.84,91 Doxorubicin and dactinomycin are quinone derivatives and can be reduced to free radicals. These metabolites are extremely cytotoxic through the promotion of lipid peroxidation in a manner similar to paraquat and bleomycin. The limited efficacy of free radical scavengers (α-tocopherol, N-acetylcysteine) for anthracycline cardiotoxicity led to an understanding of the importance of iron as a cofactor for these free radical-producing reactions.85 The anthracyclines have a high affinity for metal ions. Doxorubicin has an iron (Fe3+) binding constant of 1041, which is comparable to deferoxamine.41 The heart’s increased susceptibility to free radicals is attributed to its lack of sufficient enzyme activity responsible for free radical scavenging.29
The cardiotoxic manifestations can be divided into those occurring acutely or those of late onset. Acute toxicity is characterized by dysrhythmias, ST and T-wave changes on the electrocardiogram (ECG), diminished ejection fraction that usually resolves over 24 hours, or sudden death.12,113 Abnormal findings on ECG are present in 41% of patients receiving doxorubicin.103,113 These abnormalities are neither dose related nor associated with the development of cardiomyopathy. Acute pericarditis and myocarditis resulting in conduction defects and congestive heart failure (CHF) are also reported.13 Animal studies with doxorubicin demonstrate beneficial effects of adrenergic antagonists for toxicity because of elevated concentrations of catecholamines.13
Significant cardiotoxicity results from elevated peak serum concentrations and led to therapeutic decisions based on continuous or periodic infusion delivery. The anthracycline antibiotics can cause a congestive cardiomyopathy with systolic dysfunction that typically presents at 1 to 4 months after exposure.53 The condition is irreversible and is associated with a 48% mortality.94 This drug induced CHF is associated with pathognomonic changes on electron microscopy that can distinguish this type of cardiomyopathy from that of infectious and ischemic etiologies. These histologic changes include reduced numbers of myocardial fibrils, and mitochondrial and cellular degeneration.10 The incidence of late onset cardiotoxicity for doxorubicin is between 1% and 10% when the cumulative dose is less than 450 mg/m2, and this incidence becomes greater than 20% when more than 550 mg/m2 (comparable to dactinomycin, 950 mg/m2, and epirubicin, 720 mg/m2) is administered.79,127 Daunorubicin and mitoxantrone are associated with a 2% incidence at the cumulative doses of 600 mg/m2 and 140 mg/m2, respectively.
The best way of monitoring cardiac function during therapy is to measure the left ventricular ejection fraction (LVEF) by radionuclide cineradiography or echocardiography.4 However, the radionuclide method is more sensitive to small decreases in the LVEF than the method using sonography.36 Therapy should be discontinued when the ejection fraction falls below 50%. Two dimensional echocardiography can demonstrate left ventricular wall thickening and fractional shortening from anthracycline overexposure. Newer approaches used to determine early or subclinical signs of cardiac dysfunction include the evaluation of cardiac specific contractile protein, troponin, cardiacnatriuretic peptide, and radionuclide tagged monoclonal antibody imaging.37,65,71
Factors associated with an increased risk of cardiotoxicity include mediastinal irradiation, preexisting cardiac disease in children, age older than 70 years, and the concomitant use of cyclophosphamide, paclitaxel, and other anthracyclines.13 The recent therapeutic use of the monoclonal antibody to human epidermal growth factor receptor 2 (HER2), trastuzumab, with anthracyclines appears to enhance cardiac toxicity.26 Children are at risk for developing increased left ventricular afterload from doxorubicin toxicity because of the ability of the drug to inhibit myocardial growth, which can lead to a disproportionate ratio of left ventricular wall thickness to left ventricular chamber size.69 Fatalities are reported with minimum doses of 150 to 333 mg/m2 and occur within 1 to 16 days following exposure.24
Myelosuppression and mucositis from the use of the anthracyclines typically occur in 1 to 2 weeks.7 The white cells are affected more than either the red cells or platelets. Patients with diminished drug clearance due to hepatic failure are at risk for the development of these findings.
Mitoxantrone is less toxic than doxorubicin and daunorubicin. Major organs of toxicity remain the heart, bone marrow, and gut. Gastrointestinal effects are less severe and less frequent with mitoxantrone than with doxorubicin.110 Four cases of mitoxantrone overdose are reported in the literature.45,110 Common to these events is a 10-fold error in dosing (100 mg/m2 instead of 10 mg/m2), early onset of nausea with vomiting, and myelosuppression with fever. Acute decreased cardiac contractility was observed by echocardiography in an asymptomatic patient.45 No patients developed dysrhythmias, congestive heart failure, ECG changes, or elevated creatine phosphokinase concentrations. Unfortunately, three patients developed fatal CHF from 1 to 4 months later.110
Patients receiving anthracyclines require monitoring for cardiotoxicity and pancytopenia. A baseline chest radiograph, ECG, and echocardiography to determine LVEF (at rest and/or with stress) are necessary. Endomyocardial biopsy and cardiac catheterization can assist in distinguishing other causes of cardiac dysfunction. Left ventricular function is the best predictor for cardiomyopathy.34,104 A 10% absolute decrease in the LVEF or a decrease in LVEF of 50% from baseline is an indication to discontinue anthracycline therapy.104 Treatment is largely supportive and includes the use of dexrazoxane, which is a specific antidote for doxorubicin toxicity. Dexrazoxane is a cardioprotectant that limits the adverse cardiac effects of doxorubicin by chelating intracellular iron, which mediates the formation of free radical cellular damage.
In clinical trials, patients receiving dexrazoxane had smaller decreases in LVEF per dose of doxorubicin or epirubicin, had fewer histologic changes on cardiac biopsy, were better able to tolerate doxorubicin doses greater than 600 mg/m2, and had a lower occurrence of CHF than did patients who were not pretreated with dexrazoxane.40,71,72,112,115,116,123 The current role of this chelator is to limit cardiotoxicity in patients receiving more than 300 mg/m2 of doxorubicin.106 It is administered 30 minutes before doxorubicin in a ratio not greater than 10:1 to limit dexrazoxane-induced granulocytopenia and thrombocytopenia.112,115,116 The early institution of β-adrenergic antagonists (carvedilol) or angiotensin-converting enzyme inhibitors can reduce cardiac dysfunction from anthracycline therapy, but they are less effective than dexrazoxane.42,58,70 Further investigations are required to determine the optimal use of dexrazoxane in patients with unintentional excessive exposures.
The anthracyclines are highly protein bound and have a large volume of distribution, which limits the use of hemodialysis. However, the early institution of hemoperfusion may enhance elimination. In an animal model, serum doxorubicin clearance could be enhanced up to 20 fold with hemoperfusion.129 Factors determining this were duration of therapy, rate of flow, and the use of a 2% acrylic hydrogel coated cartridge. Three patients with a doxorubicin overdose were treated with hemoperfusion, one with an Amberlite cartridge, and all had a rapid reduction in their serum concentrations.24 One survived a 10 fold error in dosing. In a patient with an intravenous mitoxantrone overdose of 98 mg, hemoperfusion was begun within hours, but in two sessions, only 0.287 and 0.236 mg of drug were removed.45 The role of double-filtration plasmapheresis to enhance the elimination of liposomal encapsulated doxorubicin in the overdosed patient remains exploratory.95