Abstract

Background

Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose‐dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied.

Objectives

The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010) and EMBASE (1980 to November 2010) databases. In addition, we handsearched reference lists, conference proceedings of the International Society of Paediatric Oncology (SIOP) and American Society of Clinical Oncology (ASCO) meetings (1998 to 2010) and ongoing trials registers.

Selection criteria

Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional therapy or placebo in cancer patients (children and adults) receiving anthracyclines.

Data collection and analysis

Two review authors independently performed the study selection, risk of bias assessment and data extraction including adverse effects.

Main results

We identified RCTs for the eight cardioprotective agents N‐acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N‐acetylcysteine, L‐carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta‐analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified.

Authors' conclusions

No definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient.

Author(s)

Elvira C van Dalen, Huib N Caron, Heather O Dickinson, Leontien CM Kremer

Abstract

Plain language summary

Drugs to prevent heart damage in cancer patients receiving anthracyclines

Anthracyclines are among the most effective chemotherapy treatments available for various types of cancer. However, there is a risk of damage to the heart (cardiotoxicity) depending on the cumulative dose. Certain drugs might prevent this damage, but for many of these drugs, the review authors found no high quality evidence about whether they were effective in protecting the heart and they were unable to draw conclusions. For dexrazoxane, the review authors found 10 studies enrolling over 1600 patients. These studies provided evidence that dexrazoxane prevented heart damage without interfering with the anti‐tumour effects of anthracycline treatment. Patients who got dexrazoxane with their anthracycline treatment had about one third of the risk of heart failure compared to patients who got anthracyclines without dexrazoxane. Dexrazoxane had no effect on survival. We can't be sure about whether it had any undesirable side effects.

Author(s)

Elvira C van Dalen, Huib N Caron, Heather O Dickinson, Leontien CM Kremer

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Probucol, vitamin E alone, vitamin C alone, ACE‐inhibitors, EDTA, deferoxamine, vitamin A, superoxide dismutase, monohydroxyethylrutoside, guanidines, cytochromes, selenium, sildenafil, trimetazidine, digoxin, valsartan and glutathione

For these cardioprotective interventions no RCTs were identified and so no conclusions can be made about their efficacy in preventing heart damage in patients treated with anthracyclines. Based on the currently available evidence, we are not able to give recommendations for clinical practice.

N‐acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamin E, vitamin C and N‐acetylcysteine, L‐carnitine, carvedilol and amifostine

For these cardioprotective interventions pooling was not possible, so no high quality evidence was available and therefore no definitive conclusions can be made about their efficacy in preventing heart damage in patients treated with anthracyclines. Based on the currently available evidence, we are not able to give recommendations for clinical practice.

Dexrazoxane

Our meta‐analysis clearly showed the efficacy of dexrazoxane in preventing heart damage in patients treated with anthracyclines. No evidence of a lower response rate or a negative effect on PFS and OS was identified. The results for adverse effects are ambiguous. No significant difference in the occurrence of secondary malignant disease was identified. It should be emphasised that the majority of the patients included in these studies were adults with advanced breast cancer.

We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects including secondary malignancies for each individual patient.

Implications for research 

Probucol, vitamin E alone, vitamin C alone, ACE‐inhibitors, EDTA, deferoxamine, vitamin A, superoxide dismutase, monohydroxyethylrutoside, guanidines, cytochromes, selenium, sildenafil, trimetazidine, digoxin, valsartan and glutathione

No RCTs were identified for these cardioprotective interventions. Therefore, before definitive conclusions can be made about their efficacy in preventing heart damage in patients treated with anthracyclines, high quality RCTs need to be undertaken. These RCTs should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour, with a long‐term follow up using valid outcome definitions (including cardiotoxicity, anti‐tumour efficacy, survival and adverse effects). Also, since data obtained in adults cannot be extrapolated to children, they should be evaluated in children. The number of included patients should be sufficient to obtain the power needed for the results to be reliable.

N‐acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamin E, vitamin C and N‐acetylcysteine, L‐carnitine, carvedilol and amifostine

Few RCTs were identified for these cardioprotective interventions. Therefore, before definitive conclusions can be made about their efficacy in preventing heart damage in patients treated with anthracyclines, high quality RCTs need to be undertaken. These RCTs should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour, with a long‐term follow up using valid outcome definitions (including cardiotoxicity, anti‐tumour efficacy, survival and adverse effects). Also, since data obtained in adults cannot be extrapolated to children, they should be evaluated (further) in children. The number of included patients should be sufficient to obtain the power needed for the results to be reliable.

Dexrazoxane

Future trials on dexrazoxane should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour, with a long‐term follow up using valid outcome definitions (including cardiotoxicity, anti‐tumour efficacy, survival and adverse effects). Since there is only a small amount of data for children, and also because data obtained in adults cannot be extrapolated to children, dexrazoxane should be further evaluated in children. The number of included patients should be sufficient to obtain the power needed for the results to be reliable. We are awaiting the results of the ongoing studies currently being performed in children. The performance of an individual patient data analysis is another possibility to assess the effect of dexrazoxane on survival.

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