Perspectives on Chemotherapy-related Cardiotoxicity

MS EWER, J-B DURAND, MT VOOLETICH
THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER, HOUSTON, TEXAS 77030, USA

Introduction

The anthracyclines are a group of antibiotics with significant anticancer activity.¹ The group contains a number of different agents that are effective in the treatment of a wide variety of haematologic and solid tumours. Treatment with anthracyclines, however, is accompanied by a cumulative dose-related cardiotoxicity that places limits on the extent that these agents can safely be used.²

Doxorubicin

Initial studies performed on doxorubicin, the agent that has undergone the most intensive scrutiny, showed that clinical cardiotoxicity was unusual at cumulative doses below 550 mg/m², and then significantly increased.³ Later, it became clear that doxorubicin was more cardiotoxic than had previously been thought, and now most clinicians limit the use of doxorubicin to cumulative dosages of approximately 400 mg/m² to 450 mg/m². Treatment to this level carries a likelihood of congestive heart failure of approximately 5%, defined either by the identification of new symptoms or by decreases in ejection fractions consistent with cardiac dysfunction. The 5% threshold for congestive heart failure is generally considered to be the upper level of acceptability for cardiotoxicity.⁴

Clinically, patients show little or no evidence of cardiac dysfunction at low doses; they are generally asymptomatic and usually have normal ejection fraction values. Studies utilising cardiac biopsy, however, have clearly established that morphologic changes detected by electronmicroscopy occur much earlier than can be appreciated using non-invasive clinical measurements of left ventricular function such as cardiac ultrasound or nuclear multi-gated cardiac blood scans.⁵ The heart has considerable reserves, and the circulatory system can, and does, compensate for losses of cardiac muscle mass up to a point. This fact probably explains, at least in part, the hyperbolic relationship between the cumulative dose and the likelihood of demonstrating congestive heart failure. Biopsy changes, however, can be seen much earlier than is the case with ejection fractions, and the biopsy changes progress in a more linear fashion.

Monitoring changes in systolic function, although extensively undertaken and described in the literature, has not achieved the desired goal of early detection of subclinical cardiac damage, thereby allowing a modification of treatment strategies to protect the vulnerable myocardium. The tests are associated with 2 characteristics that are problematic. First, they are influenced by many biologic changes in addition to the direct cardiac effects of the drugs that are being monitored. Second, the tests themselves are suboptimal false positive and false negative results frequently occur, even in the absence of biologic change.

Not infrequently, one or both of these factors may result in changes in ejection fraction that are either real or artifactual, but that are unrelated to the drug under scrutiny.⁶ Acting upon such changes may place patients at risk from premature termination of potentially life-saving treatment regimens. Recent trends have been to reduce the number of non-invasive tests ordered because of their suboptimal predictive value.

Other strategies have evolved in an attempt to protect the heart from anthracycline toxicity. Limiting the total cumulative dose creates a dilemma of having to balance the risk of cardiotoxicity against that of suboptimal treatment. Continuous infusion regimens are effective, but they require infusion pumps and are associated with increased mucositis. Liposomal delivery systems offer considerable cardioprotection, but have not been adequately studied for many diseases for which anthracyclines are widely used. Pharmacological protectors in the form of iron chelators or free-radical scavengers have been studied and one agent, dexrazoxane, is approved for use in the USA for the treatment of breast cancer patients who have previously received doxorubicin 300 mg/m² without pharmacological protection. At least 1 report has raised concern that there may be a loss of efficacy with the use of this agent,^7,8 while others suggest that tumour response is not significantly altered. Finally, toxicity can be reduced when less toxic anthracyclines or anthracycline analogues are used.

Epirubicin

Epirubicin is the 4' epimer of doxorubicin with a chemical structure and clinical spectrum similar to that of the parent compound. This agent has a broad spectrum of activity for a variety of malignancies. Epirubicin has enjoyed wide clinical use in many countries and has been the subject of a large number of clinical investigations. The structural difference between doxorubicin and epirubicin is responsible for the decreased pKa for epirubicin, as well as for increased lipophilicity allowing more effective cellular penetration. The structure also allows for an altered metabolic breakdown to form epirubicin glucuronide, either directly or from the intermediate epirubicinol.⁹

These metabolic pathways to glucuronide do not exist to the same extent that they do for doxorubicin and some investigators have found that this allows for a more rapid plasma clearance, and a shorter terminal half-life for epirubicin (approximately 30 versus 45 hours).¹⁰ Epirubicin has been shown to be at least as effective as doxorubicin for the treatment of breast cancer, and sequential use of taxanes carries an acceptable risk profile. It is now clearly established that anthracycline-containing regimens have a documented advantage over therapeutic strategies that do not include an anthracycline in the treatment of breast cancer,¹¹ and are widely used. Cardioprotection is therefore a very important consideration. While epirubicin has a side effect profile suggesting less toxicity than doxorubicin with regard to haematologic and non-haematologic toxicity, it is the decreased cardiotoxicity that offers a definite, albeit small, advantage when compared with the parent compound (Figure 1).

	Figure 1. Bar graphs depicting estimated myelosuppression (left) and estimated cardiotoxicity of doxorubicin and epirubicin. These graphs make the assumption that 400 mg/m2 of doxorubicin is about as myelosupressive as is 600 mg/m2 of epirubicin. The scale for the epirubicin bars has been compressed according to this estimated ratio. Using cardiotoxicity as a limiting factor, it would be possible to offer 2 to 3 additional cycles of epirubicin over what could be safely given with respect to doxorubicin. Some investigators suggest a ratio of myelosuppression closer to unity, which would substantially increase the relative advantage as well as the margin of safety of epirubicin with regard to cardiotoxicity as depicted on the graph.

Whereas cumulative dosages of doxorubicin are limited to approximately 400 mg/m² to 450 mg/m², epirubicin is associated with the same degree of cardiotoxicity at cumulative dosages of approximately 900 mg/m². While the cardiotoxicity of various anthracyclines is relatively easy to compare using cardiac biopsy grading, other characteristics are more difficult to equate. Some myelosuppression studies have suggested that 90 mg/m² of epirubicin causes similar myelosuppression as 60 mg/m² of doxorubicin, while others have suggested a higher value.

Even myelosuppression will not reveal the entire story, as oncologic efficacy may not correlate with either cardiotoxicity or with immunosuppression. Epirubicin clearly has a cardioprotective advantage, since it allows at least 2 additional cycles of anthracycline to be used compared with regimens that use rapidly infused doxorubicin at equi-myelosuppressive doses. It is this characteristic that makes epirubicin an attractive consideration.

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