Anthracyclines

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Summary

Anthracyclines

Anthracyclines are widely used to treat a variety of haematological, soft- tissue and solid malignancies. Cardiac toxicity has been recognised as a complication of treatment since the 1970s,^15,16 with presentations ranging from subclinical ventricular dysfunction to severe cardiomyopathy and overt HF. Classically, cardiac dysfunction is related to anthracycline therapy in an exponentially dose-dependent manner. The early incidence of HF and LVSD ranges from 1 to 16 %, with increasing incidence as time post treatment progresses.^17–19 Consequently, childhood cancer survivors have a high risk of experiencing symptomatic cardiac events at an early age, and this risk remains high for at least 30 years, when almost one in eight will experience severe heart disease.²

Pathophysiology of Anthracycline-related Cardiomyopathy

The cardiotoxic effects of the anthracyclines are not completely understood. Several mechanisms have been proposed, with the most widely accepted theory being the formation of anthracycline–iron complexes and stimulation of free-radical formation.^2,20–23 In support of this is the finding that iron-chelating compounds inhibit this toxic effect.²⁴ Despite this being the preferred theory, it is by no means the only mechanism by which the anthracyclines are thought to cause myocardial damage. More recently, Zhang et al.²⁵ have demonstrated that, in mouse studies, deletion of the enzyme Top2b (encoding topoisomerase-II ) in cardiac myocytes was protective against the doxorubicin-induced DNA double-strand breaks and transcription changes that are responsible for defective mitochondrial biogenesis and the formation of reactive oxygen species. Furthermore, this deletion protected against the development of doxorubicin-induced HF, suggesting that doxorubicin-induced cardiotoxicity may be mediated by topoisomerase-II in mammalian cardiomyocytes.

Other proposed cardiotoxic actions of anthracyclines include: decreased adenosine triphosphate production; formation of toxic metabolites; inhibition of nucleic acid and protein synthesis; release of vasoactive amines; impairment of mitochondrial membrane binding, assembly and creatine kinase activity; induction of apoptosis; disturbances in intracellular calcium homeostasis; induction of nitric oxide synthetase; increased cytochrome C release from mitochondria; and increases in immune functions.^14,26,27

Risk Factors for Anthracycline Related Cardiomyopathy

Perhaps the most predictive measure of the development of anthracycline-related cardiotoxicity is the total cumulative dose.^28,29 In a review of three prospective trials assessing the effect of doxorubicin, Swain et al. demonstrated an incidence of HF of 3 % at a cumulative dose of 400 mg/m2, increasing to 7 % and 18 % at cumulative doses of 550 mg/m2 and 700 mg/m2, respectively.²⁸ Combined with other treatment-related risk factors, such as additional cardiotoxic chemotherapeutic agents and radiotherapy, the incidence of HF is substantially increased.¹⁰

Several patient-related factors have also been identified as markers of risk in the anthracycline-treated population. These range from genetic predisposition (female sex, Trisomy 21, African-American ancestry,^28,30–32 and carriers of the haemochromatosis C282Y HFE gene mutation³³), to recognised pre-existing cardiac risk factors such as extremes of age, prior ischaemic heart disease, valvular heart disease and, in particular, hypertension.³⁴

Prevention of Anthracycline-related Cardiomyopathy

A number of strategies and agents have been examined for potential use in preventing HF or LVSD related to anthracycline therapy, with varying levels of success.^26,35–61 Such strategies include attempts to reduce peak plasma concentrations, prevention of iron-dependent free-radical formation52 and the use of evidence-based HF medications.

Limitation of Peak Plasma Concentrations

Several strategies have been examined to limit peak plasma concentrations, including the use of liposomal anthracycline preparations, novel synthetic anthracyclines and infusion versus bolus administration. Despite promising results in terms of maintained anti-cancer therapy,^35–37 many strategies to limit peak plasma concentrations have either been limited by side effects⁴⁴ or have not been associated with significant reductions in long-term risk of cardiomyopathy.^{45,46,50,51,62,63} Most promising results have been with the use of liposomal preparations, with rates of cardiotoxicity being significantly lower compared with conventional preparations.^36,37,64

Iron Binding

Dexrazoxane binds intracellular iron and prevents iron-dependent free-radical formation.⁵² Although initial results led to the approval of its use to prevent long-term cardiotoxicity in patients receiving doxorubicin or epirubicin,^53,54 subsequent clinical trials reported cases of secondary leukaemia in children and adults.^55,56

Angiotensin Converting Enzyme Inhibitors, Beta-Blockers and Mineralocorticoid Receptor Antagonists

Angiotensin converting enzyme inhibitors (ACE-I) and beta (ß)-blocker therapy have both been shown to have protective effects against chemotherapy-induced HF or LVSD in both animal models and in adult patients with early toxicity.^57–59 More recently, the results of the preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies (OVERCOME) trial⁶⁰ have demonstrated that, compared with those in the treatment arm, those in the control group had a significantly higher reduction in LVEF, incidence of death or HF at six-months follow-up (p=0.02). Less evidence exists for the use of mineralocorticoid receptor antagonists (MRAs). In one recently published small randomised controlled trial, Akpek et al.⁶¹ demonstrated preservation of LV systolic and diastolic function in the group treated with spironolactone prior to the initiation of chemotherapy at 6-months follow-up. Further studies are needed to corroborate these findings.