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Treatment for Asymptomatic Anthracycline-Induced Cardiac Dysfunction in Childhood Cancer Survivors: The Need for Evidence

Emma Children’s Hospital/Academic Medical Center, Amsterdam, the Netherlands

To the Editor: Cardiac damage after anthracycline chemotherapy is a considerable and serious problem among young childhood cancer survivors with long life expectancy after successful antineoplastic treatment.¹

Unfortunately, at present, the optimal management of a patient with asymptomatic cardiac dysfunction after anthracycline therapy for childhood cancer is not clear. In adult patients with asymptomatic cardiac dysfunction due to causes other than anthracyclines, angiotensin converting enzyme (ACE) inhibitors have been shown to reduce mortality and cardiac events.² However, extrapolation of these data to children with anthracycline-induced heart damage is risky. Pharmacokinetics of many drugs vary with age, and their beneficial and adverse effects are different in adults and children.³ Moreover, the etiology of the heart damage in the adult study was different.

The study by Lipshultz et al,⁴ published in the December 1, 2002, issue of the Journal of Clinical Oncology, is the first study to investigate the problem of the management of childhood cancer survivors with anthracycline-induced cardiotoxicity. This case series, with precise outcome measurements and a long-term follow-up, provides important new information. During the first 6 years of ACE inhibitor therapy, cardiac function seemed to improve, but in all patients, cardiac function eventually declined. However, we must realize that in this study not only asymptomatic patients were included, but also patients with symptomatic heart failure. Furthermore, the results have to be interpreted with caution because of the methodological limitations associated with case series, such as selection bias. Selection of a nonrandom subgroup of patients with cardiotoxicity could have led to a selection of worst cases, which may have influenced the results.

Before it is possible to make an evidence-based decision regarding lifelong therapy with ACE inhibitors for patients with asymptomatic anthracycline-induced cardiac dysfunction, a randomized, controlled trial should be undertaken. This trial should focus only on patients with asymptomatic cardiac dysfunction after anthracycline therapy for childhood cancer and on adverse effects of treatment. We are awaiting the results of the trial by Silber et al.⁵

The poor prognosis of anthracycline-induced cardiotoxicity in this patient group emphasizes the need for studies that investigate the optimal treatment options for anthracycline-induced asymptomatic cardiac dysfunction and cardioprotective interventions during anthracycline therapy.

REFERENCES

1. Kremer LCM, Van Dalen EC, Offringa M, et al: Anthracycline induced clinical heart failure in a cohort of 607 children: A long-term follow-up study. J Clin Oncol 19:191–196, 2001[Abstract/Free Full Text]

2. The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 327:685–691, 1992[Abstract]

3. Lipshultz SE: Ventricular dysfunction clinical research in infants, children and adolescents. Prog Pediatr Cardiol 12:1–28, 2000[CrossRef][Medline]

4. Lipshultz SE, Lipsitz SR, Sallan SE, et al: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20:4517–4522, 2002[Abstract/Free Full Text]

5. Silber JH, Cnaan A, Clark BJ, et al: Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors. Am Heart J 142:577–585, 2001[CrossRef][Medline]

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