Cochrane Review: Medical interventions for treating anthracycline‐induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer
Authors: Sieswerda Elske , van Dalen Elvira C , Postma Aleida , Cheuk Daniel KL , Caron Huib N , Kremer Leontien CM 
Published: November 2012

Background

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline‐induced cardiotoxicity.

Objectives

To compare the effect of medical interventions on anthracycline‐induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions or no treatment.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, issue 1), MEDLINE/PubMed (1949 to May 2011) and EMBASE/Ovid (1980 to May 2011) for potentially relevant articles. We additionally searched reference lists of relevant articles, conference proceedings and ongoing trial databases.

Selection criteria

Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline‐induced cardiotoxicity with either placebo, other medical interventions or no treatment.

Data collection and analysis

Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments which were checked by another review author.

Main results

We identified two RCTs. One trial (135 patients) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline induced cardiac dysfunction. The other trial (68 patients) compared a two‐week treatment of phosphocreatine with a control treatment (vitamin C, ATP, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline‐induced cardiotoxicity. Both studies had methodological limitations.

The RCT on enalapril showed no (statistically) significant differences in overall survival, mortality due to heart failure, development of clinical heart failure and quality of life between treatment and control group. A post‐hoc analysis showed a decrease (i.e. improvement) in one measure of cardiac function (left ventricular end systolic wall stress (LVESWS): ‐8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Patients treated with enalapril had a higher risk of dizziness or hypotension (RR 7.17, 95% CI 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).

The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function and adverse events between treatment and control group.

Authors' conclusions

For the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction, only one RCT is available. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side‐effects of enalapril in childhood cancer survivors with asymptomatic anthracycline‐induced cardiotoxicity.

For the effect of phosphocreatine in childhood cancer patients with anthracycline‐induced cardiotoxicity, only one RCT is available. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatment on echocardiographic function and clinical outcomes.

We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.

High‐quality studies should be performed.

Plain Language Summary

Treatment for cardiac problems caused by anthracycline chemotherapy for childhood cancer

Anthracyclines are anti‐cancer drugs that are used in the treatment of different types of childhood cancer. An important adverse effect of anthracyclines is damage to the heart that can lead to asymptomatic (without complaints) or symptomatic (with complaints) cardiac problems during and after cancer treatment. There are several drugs available to treat other types of cardiac problems in adults, but it is not known if these drugs are beneficial in treating cardiac problems caused by anthracyclines in childhood cancer patients and survivors. If a physician is confronted with a childhood cancer patient or survivor with anthracycline‐induced cardiac problems, he or she should be able to make an informed decision to treat this patient based on high‐quality evidence about the beneficial and adverse effects of the treatment options. We searched for and summarised studies that evaluated drugs for treating anthracycline‐induced cardiac problems in childhood cancer patients and survivors.

We identified two randomised studies evaluating two different drugs in two different types of patients. One of these drugs, an ACE‐inhibitor (enalapril), had a short‐term beneficial effect on heart function in survivors of childhood cancer with asymptomatic cardiac problems caused by anthracyclines compared with placebo. However, the drug had no significant beneficial effect on other important outcomes and was associated with side effects such as dizziness and fatigue. This study was of reasonable/good quality. The other study was of low quality and found no effect of a short treatment with phosphocreatine in childhood leukaemia patients with symptomatic or asymptomatic cardiac problems compared with a control treatment with vitamin C, ATP, vitamin E, and oral coenzyme Q10.

No definitive conclusions can be made about treatment options for anthracycline‐induced cardiac problems in childhood cancer patients and survivors. High‐quality studies are necessary to show if there are drugs that improve heart function in these patients.