Correspondence Department of Pediatrics, Miller School of Medicine, University of Miami, Medical Campus–MCCD–D820, 9th Floor, 1601 NW 12th Avenue, Miami, FL 33136, USA

Email slipshultz@med.miami.edu

Original article

van Dalen EC et al. (2006) Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42: 3191–3198   PubMed

Synopsis

Background

Survival rates of children with cancer have improved, in part because of the introduction of anthracyclines. This has led to an increase in the number of adult survivors of childhood cancer, but, unfortunately, anthracycline therapy is cardiotoxic, so these individuals have a risk of clinically significant cardiotoxicity during or after therapy. Late clinical heart failure and asymptomatic cardiac dysfunction have been reported. Previous studies of anthracycline-induced clinical heart failure (A-CHF) have been small, subgroup-based and performed over a short follow-up period; further study is, therefore, required.

Objective

To evaluate the risk factors for and cumulative incidence of A-CHF in a large group of adult survivors of childhood cancer who had received anthracyclines between 1976 and 2000.

Design and intervention

All children treated with anthracyclines between 1 January 1976 and 31 December 2000 were identified from the registry of a teaching hospital in the Netherlands. Data on diagnosis, treatment and follow-up were collected from the medical records or from the registry charts. A-CHF was defined as congestive heart failure that could not be attributed to renal failure, direct effects of the tumor, septic shock or valvular disease.

Outcome measure

The primary end point was occurrence of A-CHF.

Results

In total, data were collated for 831 patients. Mean follow-up time after the first dose of anthracycline treatment was 8.5 years (range 0.01–28.4 years), during which time the cumulative incidence of A-CHF was 2.5% (95% CI 1.6–3.8%; 21 patients). Early A-CHF (during or within the first year of therapy) occurred in 16 cases. The mean age at which anthracycline treatment was initiated was 8.8 years (range 0.1–18 years) and the mean cumulative anthracycline dose was 288 mg/m² (range 15–900 mg/m²). During follow-up, five individuals died from A-CHF and one from pericarditis with cardiac tamponade. In a multivariate regression analysis, a cumulative anthracycline dose of 300 mg/m² or higher was the only independent risk factor for developing A-CHF. For patients who had received a cumulative anthracycline dose <300 mg/m², the risk of A-CHF within 2 years of the first dose was estimated at 0.5% (95% CI 0–1.23%), and this risk did not increase over time. For patients who had received a cumulative anthracycline dose of 300 mg/m², the estimated risk for A-CHF was 3.3% (95% CI 1.4–5.1%), 4.1% (95% CI 1.9–6.2%), 4.5% (95% CI 2.2–6.8%), 6.2% (95% CI 3–9.4%) and 9.8% (95% CI 2.2–17.4%) at 2, 5, 10, 15 and 20 years after the first dose, respectively.

Conclusion

In this large cohort of patients, risk of A-CHF was highly dose-dependent and increased over time. Even in this young patient population the estimated risk of A-CHF was high following a cumulative anthracycline dose of 300 mg/m².

Commentary

van Dalen and colleagues confirm that clinically significant cardiovascular disease occurs in survivors of childhood cancer. Prior studies have demonstrated that 20-year survivors show eightfold higher rates of cardiac death and fourfold higher rates of sudden, presumed cardiovascular, death. In 30-year survivors, 15% have heart failure, 10% have other clinically significant cardiovascular disease, and another 10% have had a stroke.¹ Studies evaluating the risk of heart failure in survivors of childhood cancer have been difficult to perform due to a lack of heart failure definitions or standardized cardiac specialist evaluations, tautological relationships between heart failure and indices of ventricular function, and informative censoring for survivors.

Nevertheless, several studies examining cardiovascular morbidity and mortality in survivors have been carried out, producing a number of important findings. Over half of survivors have been treated with anthracycline, and such treatment is associated with progressive cardiotoxicity.¹ Risk factors for anthracycline cardiotoxicity in survivors include younger treatment age, longer follow-up, female sex, higher cumulative doses, and higher dose rates.^{2, 3, 4} Dilated cardiomyopathy is observed immediately following high-dose anthracycline treatment.⁵ With longer follow-up, restrictive cardiomyopathy (diastolic dysfunction) develops in many survivors, placing them at risk for heart failure with preserved systolic ventricular function.⁵ Anthracycline-associated left ventricular dysfunction in survivors develops via two mechanisms—depressed contractility (unhealthy heart muscle) and elevated afterload (increased stress on the heart wall).^{2, 3, 5} There is no dose of anthracycline that is free of cardiotoxicity.⁵

Anthracycline cardiotoxicity in survivors is progressive.⁵ We have demonstrated that enalapril treatment could delay but not completely prevent the progression of cardiotoxicity in survivors with asymptomatic left ventricular dysfunction.¹ Growth hormone replacement therapy did not delay or prevent cardiotoxicity in survivors.¹ Primary prevention of anthracycline cardiotoxicity is essential.⁴ Pretreatment with dexrazoxane reduces anthracycline-associated myocardial injury—reflected by elevations in serum cardiac troponin T.⁴ Following anthracycline exposure, sequential stress from viruses, pregnancy, arrhythmias, anemia, or other chemotherapy following may precipitate heart failure.¹ In addition, thyroid, growth, and sex hormone deficiencies are treatable risk factors for heart failure in survivors.¹ Individual susceptibility varies by patient, suggesting a genetic predisposition.^{2, 3, 5} Many patients treated with anthracycline experience early cardiotoxicity that may be a harbinger of later heart failure.^{2, 3, 5} The ability to individualize potentially cardiotoxic treatments and cardioprotective treatments to avoid late heart failure in survivors is limited by inadequate understanding of the absolute risk–benefit ratio and long-term history of cardiotoxicity.¹ Comprehensive multispecialty survivor follow-up programs facilitate clinical care and research for this specialized population of first-generation survivors.¹ Cardiotoxicity resulting in cardiomyopathy-associated heart failure is only one cause of cardiovascular morbidity and mortality in survivors.^{1, 5} Assessment of global cardiovascular risk in this population is important since accelerated atherosclerosis, hypertension, diabetes, smoking, drug and alcohol use might be present and represent incremental risks.¹ There is evidence to indicate that treatment with conventional anticongestive therapy may not be appropriate for survivors with heart failure.^{1, 5} Notably, there is no accepted therapy for heart failure with preserved systolic function. Restrictive cardiomyopathy in survivors warrants an early diagnostic cardiac catheterization, and early cardiac transplantation may be beneficial for affected patients.⁵ Preventive strategies in at-risk survivors, such as physical activity interventions and reduction in global cardiac risk, might reduce subsequent cardiovascular morbidity and mortality.¹

Acknowledgments

This paper has been supported in part by grants from the National Cancer Institute (CA68484, CA34183, CA79060, CA06516), National Heart, Lung, and Blood Institute (HL69800, HL53392, HL59837, HL53392), the Lance Armstrong Foundation, and the Children's Cardiomyopathy Foundation. The synopsis was written by Petra Roberts, Associate Editor, Nature Clinical Practice.

References

1. Alvarez JA et al. (2007) Long-term effects of treatments for childhood cancers. Curr Opin Pediat 19: 23–31
2. Lipshultz SE et al. (1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324: 808–815 | PubMed | ISI | ChemPort |
3. Lipshultz SE et al. (1995) Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332: 1738–1743 | Article | PubMed | ISI | ChemPort |
4. Lipshultz SE et al. (2004) The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351: 145–153 | Article | PubMed | ISI | ChemPort |
5. Lipshultz SE et al. (2005) Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23: 2629–2636 | PubMed | ISI | ChemPort |

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Subject areas under which this article appears: Pediatric Oncology