Elsevier

European Journal of Cancer

Volume 42, Issue 18, December 2006, Pages 3191-3198
European Journal of Cancer

Clinical heart failure in a cohort of children treated with anthracyclines: A long-term follow-up study

https://doi.org/10.1016/j.ejca.2006.08.005Get rights and content

Abstract

The cumulative incidence of anthracycline-induced clinical heart failure (A-CHF) in a large cohort of 830 children treated with a mean cumulative anthracycline dose of 288 mg/m2 (median 280 mg/m2; range 15–900 mg/m2) with a very long and complete follow-up after the start of anthracycline therapy (mean 8.5 years; median 7.1 years; range 0.01–28.4 years) was 2.5%. A cumulative anthracycline dose of 300 mg/m2 or more was the only independent risk factor (relative risk (RR) = 8). The estimated risk of A-CHF increased with time to 5.5% at 20 years after the start of anthracycline therapy; 9.8% if treated with 300 mg/m2 or more.

In conclusion, 1 in every 10 children treated with a cumulative anthracycline dose of 300 mg/m2 or more will eventually develop A-CHF. This is an extremely high risk and it reinforces the need of re-evaluating the cumulative anthracycline dose used in different treatment protocols and to define strategies to prevent A-CHF which could be implemented in treatment protocols.

Introduction

Anthracyclines have gained widespread use in the treatment of numerous childhood malignancies: nearly 60% of children diagnosed with a malignancy receive anthracyclines. The introduction of anthracyclines has contributed to the improvement in the survival rates of childhood cancer: from 30% in the 1960s to 70% nowadays.1, 2 As a result, a rapidly growing number of children will have survived childhood cancer. In the Netherlands, nowadays, approximately 1 out of every 750–800 young adults has survived childhood cancer.3

Unfortunately, the use of anthracyclines is limited by the occurrence of cardiotoxicity. It can become manifest as either clinical heart failure4 or asymptomatic cardiac dysfunction,5 which can not only develop during anthracycline therapy, but also years after the cessation of treatment.6 Several studies have evaluated the incidence and risk factors for the anthracycline-induced clinical heart failure (A-CHF) in children,7, 8, 9 but the majority of these studies have serious methodological limitations: small study populations, only subgroups were described, and/or a short follow-up period. The reported incidence of A-CHF varies widely between 0% and 16%. Several risk factors, like a higher cumulative anthracycline dose, different anthracycline derivates, peak dose (i.e. maximal dose received in one week), radiation therapy involving the heart region, female sex, younger age at diagnosis, black race, additional treatment with amsacrine, cyclophosphamide, ifosfamide or mitoxantrone and the presence of trisomy 21, have been identified, although not univocal in all studies.7, 10 The risk of developing anthracycline-induced cardiotoxicity remains a lifelong threat. In one of our earlier studies, the estimated risk of A-CHF increased with time to 2% at 2 years and 5% at 15 years after the start of treatment.9 Other studies also reported that the incidence of cardiac abnormalities increased with time.8, 11

The consequences of A-CHF are extensive. It impairs the quality of life in childhood cancer survivors, it involves long-term treatment and thus high medical costs and it causes premature death. The excess mortality due to cardiac disease is 8-fold higher than that expected for long-term survivors of childhood cancer compared to the normal population.11 In order to establish adequate follow-up protocols for these patients, who should have a long life expectancy after a successful antineoplastic treatment, it is important to estimate the risk and risk factors of A-CHF in those patients.

In this study, we evaluated the cumulative incidence of A-CHF and associated risk factors in a large cohort of patients with childhood cancer treated with anthracyclines between 1976 and 2001.

The patients treated with anthracyclines between 1976 and 1996 have been evaluated before,9 so for this subgroup we are able to give the results of a 5-year additional follow-up.

Section snippets

Patients

All children who where treated with anthracyclines in the Emma Children’s Hospital/Academic Medical Center (EKZ/AMC) for childhood cancer between 1st January 1976 and 31st December 2000 were eligible for this study. The patients were identified using the Registry of Childhood Cancer of the EKZ/AMC. This registry was established in 1966 and contains data on all children treated for childhood cancer in the EKZ/AMC with regard to diagnosis, treatment and follow-up. We decided to include only

Study population

The study population consisted of 830 out of 831 eligible patients. The data of 817 of 831 children were collected directly from the medical records. For 13 patients whose medical records were missing, we obtained information by means of the registry charts kept by the Registry of Childhood Cancer. No data were available for 1 child. We succeeded in obtaining information on the clinical status up to at least January 2002 (or date of death) for 795 patients (95.8% of the cohort) including

Discussion

This study in a large cohort of patients with a very long and complete follow-up demonstrates that the risk of A-CHF increased over time and that it was strongly dose-dependent. The estimated risk of A-CHF increased from 2% at 2 years after the start of anthracycline therapy to 5.5% at 20 years. For patients treated with a cumulative anthracycline dose of 300 mg/m2 or more, the estimated risk at 20 years after the start of anthracycline therapy was nearly 10%. This means that 1 in every 10

Conflict of interest statement

None of the authors have competing interests.

Acknowledgements

The authors thank M.C. Cardous-Ubbink and J.H. van der Lee for their statistical advice, R.C. Heinen for helping in identifying all eligible patients, F.G. Hakvoort-Cammel (of the Late Effects Outpatient Clinic (LATER), Sophia Children’s Hospital/Erasmus MC, Rotterdam) and D. Bresters (of the Late Effects Outpatient Clinic (KLEP) of the Leiden University Medical Center, Leiden) for the provision of additional and follow-up data on patients who went to other hospitals for their follow-up, and

References (19)

  • L.C. Kremer et al.

    Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review

    Ann Oncol

    (2002)
  • H.S. Heymans et al.

    Childhood cancers in the Netherlands (1989–1997)

    Ned Tijdschr Geneesk

    (2001)
  • G. Gatta et al.

    Childhood cancer survival in Europe and the United States

    Cancer

    (2002)
  • Heikens J. Childhood cancer and the price of cure: studies on late effects of childhood cancer treatment. Thesis,...
  • D.D. Von Hoff et al.

    Risk factors for doxorubicin-induced congestive heart failure

    Ann Intern Med

    (1979)
  • S.E. Lipshultz et al.

    Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia

    J Clin Oncol

    (2005)
  • K. Shan et al.

    Anthracycline-induced cardiotoxicity

    Ann Intern Med

    (1996)
  • D.M. Green et al.

    Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group

    J Clin Oncol

    (2001)
  • L.C. Kremer et al.

    Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study

    J Clin Oncol

    (2001)
There are more references available in the full text version of this article.

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