Different anthracycline derivates for reducing cardiotoxicity in cancer patients

Abstract

Background

The use of anthracyclines is limited by the occurrence of cardiotoxicity. In an effort to prevent this cardiotoxicity, different anthracycline derivates have been studied.

Objectives

To determine the occurrence of cardiotoxicity with the use of different anthracycline derivates in cancer patients.

Search methods

We searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 to 29 May 2009) and EMBASE (1980 to 2 June 2009). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing‐trials‐databases.

Selection criteria

Randomised controlled trials (RCTs) in which different anthracycline derivates were compared in cancer patients (children and adults).

Data collection and analysis

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

Main results

We identified five RCTs of varying quality addressing epirubicin versus doxorubicin (1036 patients) with the same dose. The meta‐analysis showed no evidence for a significant difference in the occurrence of clinical heart failure between the treatment groups (RR = 0.36, 95% CI 0.12 to 1.11). However, there is some suggestion of a lower rate of clinical heart failure in patients treated with epirubicin.

We identified two RCTs with varying quality addressing liposomal‐encapsulated doxorubicin versus conventional doxorubicin (521 patients). The meta‐analysis showed a significantly lower rate of both clinical heart failure and clinical and subclinical heart failure combined in patients treated with liposomal‐encapsulated doxorubicin (RR = 0.20, 95% CI 0.05 to 0.75 and RR = 0.38, 95% CI 0.24 to 0.59 respectively). It should be noted that in one of the studies patients in the liposomal‐encapsulated doxorubicin group received a higher cumulative anthracycline dose than patients in the doxorubicin group.

For the other possible combinations of different anthracycline derivates only one RCT (epirubicin versus liposomal‐encapsulated doxorubicin) or no RCT was identified.

Authors' conclusions

We are not able to favour either epirubicin or doxorubicin when given with the same dose. Based on the currently available evidence on heart failure, we conclude that in adults with a solid tumour liposomal‐encapsulated doxorubicin should be favoured over doxorubicin. For both epirubicin versus doxorubicin and liposomal‐encapsulated doxorubicin versus conventional doxorubicin no conclusions can be made about the effects of treatment in children treated with anthracyclines and also not in patients diagnosed with leukaemia. More research is needed. For other combinations of anthracycline derivates not enough evidence was available to make definitive conclusions about the occurrence of cardiotoxicity in patients treated with anthracyclines.

Author(s)

Elvira C van Dalen, Erna MC Michiels, Huib N Caron, Leontien CM Kremer

Abstract

Plain language summary

Different anthracycline derivates for reducing cardiotoxicity in cancer patients

Anthracyclines are among the most effective chemotherapy treatments available for various types of cancer. However, there is a risk of damage to the heart depending on the cumulative dose. In an effort to prevent heart damage different anthracycline derivates (like doxorubicin, daunorubicin, and epirubicin) are being used.

The authors found that for the use of many different combinations of anthracycline derivates there was no high quality evidence available and it was impossible to draw conclusions.

For the use of epirubicin versus doxorubicin, there was some suggestion of a lower rate of clinical heart failure in patients treated with epirubicin. There is no evidence which suggests a difference in anti‐tumour response rate and survival between epirubicin and doxorubicin. No conclusions can be made regarding adverse effects. There are no data for children and patients with leukaemia. Further research is needed. For the use of doxorubicin versus liposomal‐encapsulated doxorubicin, the authors found a significantly lower rate of both clinical heart failure and subclinical heart failure (i.e. various cardiac abnormalities, diagnosed with different diagnostic methods like echocardiography in asymptomatic patients) in patients treated with liposomal‐encapsulated doxorubicin. There is no evidence which suggests a difference in anti‐tumour response rate and survival between doxorubicin and liposomal‐encapsulated doxorubicin. A lower rate of adverse effects was identified in patients treated with liposomal‐encapsulated doxorubicin. There are no data for children and patients with leukaemia. Further research is needed.

Author(s)

Elvira C van Dalen, Erna MC Michiels, Huib N Caron, Leontien CM Kremer

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Combinations of different anthracycline derivates for which no adequate RCTs were identified

For all combinations of different anthracycline derivates for which no adequate RCTs were identified, no conclusions can be made about possible differences in preventing anthracycline‐induced heart damage. Based on the current available evidence, we are not able to give recommendations for clinical practice.

Epirubicin versus doxorubicin

Based on the current available evidence, we are not able to favour either epirubicin or doxorubicin when given in equimolar doses. No conclusions can be made regarding treatment with epirubicin and doxorubicin with different cumulative doses.

It should be emphasised that all patients included in these studies were adults with advanced solid tumours. As a result no conclusions can be made about the effects of treatment with epirubicin and doxorubicin in children treated with anthracyclines and also not in patients diagnosed with leukaemia.

Liposomal‐encapsulated doxorubicin versus conventional doxorubicin

Based on our meta‐analysis which clearly shows that treatment with liposomal‐encapsulated doxorubicin reduces the risk of both clinical and subclinical heart failure as compared to treatment with doxorubicin despite the fact that patients treated with liposomal‐encapsulated doxorubicin received a higher cumulative anthracycline dose than patients treated with doxorubicin, we conclude that in adults with a solid tumour liposomal‐encapsulated doxorubicin should be favoured over doxorubicin. However, until more evidence becomes available on tumour response and survival in patients treated with liposomal‐encapsulated doxorubicin or doxorubicin in equimolar doses, we recommend the use of a higher cumulative liposomal‐encapsulated doxorubicin dose as compared to the standard cumulative doxorubicin dose. Despite the higher cumulative anthracycline dose received in the liposomal‐encapsulated doxorubicin group, patients treated with liposomal‐encapsulated doxorubicin suffered from less side effects than patients treated with doxorubicin.

It should be emphasised that all patients included in these studies were adults with advanced breast cancer. As a result no conclusions can be made about the effects of treatment with liposomal‐encapsulated doxorubicin and doxorubicin in children treated with anthracyclines and also not in patients diagnosed with leukaemia.

Liposomal‐encapsulated doxorubicin versus epirubicin

Since pooling of results was not possible for the comparison of epirubicin versus liposomal‐encapsulated doxorubicin, no definitive conclusions can be made about the occurrence of anthracycline‐induced heart damage with the use of these anthracycline derivates. Based on the currently available evidence, we are not able to give recommendations for clinical practice.

Implications for research 

Combinations of different anthracycline derivates for which no adequate RCTs were identified

Before any conclusions can be made about the occurrence of anthracycline‐induced heart damage with the use of the anthracycline derivates for which no adequate RCTs were identified, 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. 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 and also, there should be adequate reporting of the occurrence of cardiotoxicity in relation to follow‐up time. We are awaiting results of the trial currently awaiting assessment which compares liposomal‐encapsulated doxocrubicin with liposomal daunorubicin.

Epirubicin versus doxorubicin

Future trials in adults on epirubicin versus doxorubicin in equimolar doses should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour. Also, since data obtained in adults cannot be extrapolated to children, epirubicin and doxorubicin in equimolar doses should be evaluated in children. Epirubicin and doxorubicin with different cumulative doses could also be evaluated in high quality RCTs. The number of included patients in all RCTs should be sufficient to obtain the power needed for the results to be reliable and also, there should be adequate reporting of the occurrence of cardiotoxicity in relation to follow‐up time. We are awaiting results of the three trials currently awaiting assessment.

Liposomal‐encapsulated doxorubicin versus conventional doxorubicin

Future trials in adults on doxorubicin versus liposomal‐encapsulated doxorubicin should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour. Also, since data obtained in adults cannot be extrapolated to children, doxorubicin and liposomal‐encapsulated doxorubicin should be evaluated in children. The number of included patients in all RCTs should be sufficient to obtain the power needed for the results to be reliable and also, there should be adequate reporting of the occurrence of cardiotoxicity in relation to follow‐up time. We are awaiting the results of the currently ongoing study and also results of the two trials currently awaiting assessment.

Liposomal‐encapsulated doxorubicin versus epirubicin

Before any definitive conclusions can be made about the possible difference between epirubicin and liposomal‐encapsulated doxorubicin in preventing anthracycline‐induced heart damage, more 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. 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 and also, there should be adequate reporting of the occurrence of cardiotoxicity in relation to follow‐up time. We are awaiting results of the two trials currently awaiting assessment.

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