Prevention of anthracycline-induced cardiotoxicity in children: The evidence

Abstract

Anthracycline-induced cardiotoxicity after treatment for childhood cancer is a considerable and serious problem. In this review, important insight into the current state of the evidence on the use of different cardioprotective agents, different anthracycline analogues, and different anthracycline infusion durations to reduce or prevent cardiotoxicity in children treated with anthracyclines is provided. It has become clear that, at the present time, there is not enough reliable evidence for many aspects of the prevention of anthracycline-induced cardiotoxicity in children. More high quality research is necessary. Suggestions for future research have been presented. As the results of these new studies become available, it will hopefully be possible to develop evidence-based recommendations for preventing anthracycline-induced cardiotoxicity in children. Until then, we can only advise care providers to carefully monitor the cardiac function of children treated with anthracyclines. With regard to the use of the cardioprotectant dexrazoxane, it might be justified to use dexrazoxane in children if the risk of cardiac damage is expected to be high. However, for each individual patient, care providers should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects including a lower response rate. We recommend its use in the context of well-designed studies.

Introduction

Anthracyclines have gained widespread use in the treatment of both solid tumours and haematological malignancies in children. Almost 60% of children diagnosed with cancer receive anthracyclines as part of their treatment; the most used types are doxorubicin, daunorubicin and epirubicin.

The introduction of anthracyclines, together with other improvements in childhood cancer treatment, has contributed to the improved survival of many different childhood cancers.¹ As a result, a rapidly growing number of children will have survived childhood cancer. In the Netherlands, at the present time, approximately one out of every 750–800 young adults has survived childhood cancer.²

Unfortunately, an important side effect of anthracyclines is heart damage (cardiotoxicity). It can become manifest in patients as either clinical heart failure (i.e. with symptoms)³ or as asymptomatic heart damage (i.e. without symptoms, but on, for example, an ultrasound of the heart, abnormalities in heart function can be seen).⁴ Heart damage caused by anthracyclines cannot only occur during treatment, but also years after the end of treatment.⁵

Anthracycline-induced cardiotoxicity is a widely prevalent problem. In one of our earlier studies, the estimated risk of anthracycline-induced clinical heart failure increased with time to 5.5% at 20 years after the start of anthracycline therapy. In patients treated with a cumulative anthracycline dose of 300 mg/m² or more the risk was even higher, almost 10%.⁶ The incidence of anthracycline-induced asymptomatic cardiac dysfunction has been reported to be more than 57% at a median of 6.4 years after treatment.⁷ The incidence of anthracycline-induced cardiotoxicity, both clinical and asymptomatic, seems to increase with a longer follow-up period.6, 8, 9 With the current improved cancer survival rates, the problem of late-onset cardiotoxicity is increasing.

The consequences of heart damage caused by anthracyclines are extensive. First, it can cause a reduction in the amount of anthracyclines that a patient was supposed to receive and as a result, the chance of survival of that patient can be reduced.¹⁰ Also, cardiotoxicity can lead to long-term side effects, causing severe morbidity and reduced quality of life. 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 expected for long-term survivors of childhood cancer compared to the normal population.¹¹

Extensive research has been devoted to the identification of methods or agents capable of ameliorating anthracycline-induced cardiotoxicity. This review provides a compilation of evidence from multiple Cochrane systematic reviews, the quality of which is higher than that of reviews published in paper journals.¹² It covers the existing evidence on (1) the use of cardioprotective agents, (2) the use of possibly less cardiotoxic anthracycline analogues, and (3) the use of different anthracycline dosage schedules to reduce or prevent cardiotoxicity in children treated with anthracyclines.