Different dosage schedules for reducing cardiotoxicity in people with cancer receiving anthracycline chemotherapy Edited (no change to conclusions)

Abstract

Abstract Background

This review update has been managed by both the Childhood Cancer and Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Groups.

The use of anthracycline chemotherapy is limited by the occurrence of cardiotoxicity. To prevent this cardiotoxicity, different anthracycline dosage schedules have been studied.

Objectives

To determine the occurrence of cardiotoxicity with the use of different anthracycline dosage schedules (that is peak doses and infusion durations) in people with cancer.

Search methods

We searched the databases of the Cochrane Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 11, 2015), MEDLINE (1966 to December 2015), and EMBASE (1980 to December 2015). We also searched reference lists of relevant articles, conference proceedings, experts in the field, and ongoing trials databases.

Selection criteria

Randomised controlled trials (RCTs) in which different anthracycline dosage schedules were compared in people with cancer (children and adults).

Data collection and analysis

Two review authors independently performed the study selection, the 'Risk of bias' assessment, and data extraction. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

We identified 11 studies: 7 evaluated different infusion durations (803 participants), and 4 evaluated different peak doses (5280 participants). Seven studies were RCTs addressing different anthracycline infusion durations; we identified long‐term follow‐up data for one of the trials in this update. The meta‐analysis showed a statistically significant lower rate of clinical heart failure with an infusion duration of six hours or longer as compared to a shorter infusion duration (risk ratio (RR) 0.27; 95% confidence interval 0.09 to 0.81; 5 studies; 557 participants). The majority of participants included in these studies were adults with different solid tumours. For different anthracycline peak doses, we identified two RCTs addressing a doxorubicin peak dose of less than 60 mg/m2 versus 60 mg/m2 or more, one RCT addressing a liposomal doxorubicin peak dose of 25 mg/m2 versus 50 mg/m2, and one RCT addressing an epirubicin peak dose of 83 mg/m2 versus 110 mg/m2. A significant difference in the occurrence of clinical heart failure was identified in none of the studies. The participants included in these studies were adults with different solid tumours. High or unclear 'Risk of bias' issues were present in all studies.

Authors' conclusions

An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.

We identified no significant difference in the occurrence of clinical heart failure in participants treated with a doxorubicin peak dose of less than 60 mg/m2 or 60 mg/m2 or more. Only one RCT was available for the other identified peak doses, so we can make no definitive conclusions about the occurrence of cardiotoxicity. More high‐quality research is needed, both in children and adults and in leukaemias and solid tumours.

Author(s)

Elvira C van Dalen, Helena JH van der Pal, Leontien CM Kremer

Abstract

Plain language summary

Different dosage schedules for reducing damage to the heart in people with cancer receiving anthracycline chemotherapy

Review question

We reviewed the evidence of different anthracycline dosage schedules to cause damage to the heart in people with cancer of all ages receiving anthracycline chemotherapy. We also looked at tumour response, participant survival, adverse effects other than damage to the heart, and quality of life.

Background

Anthracyclines are one of the most effective treatments for various types of cancer. Unfortunately, there is a risk of heart damage depending on the total dose a patient has received. In an effort to prevent heart damage, different anthracycline dosage schedules such as different infusion durations or different individual peak doses (the maximal dose received in one week) are being used.

Study characteristics

The evidence is current to December 2015.

We found 11 studies: 7 evaluated different infusion durations (803 participants), and 4 evaluated different peak doses (5280 participants). Participants had different types of cancer.

Key results

For the use of different anthracycline infusion durations, the authors found that an anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure (for example shortness of breath or leg oedema), and it seems to reduce the risk of subclinical heart failure (that is heart damage diagnosed for example by an echocardiography in people without symptoms). Only a small amount of data was available for children and individuals with leukaemia, since most studies evaluating different anthracycline infusion durations were performed in adults with solid tumours.

Based on the currently available evidence, we are not able to favour either a doxorubicin peak dose of less than 60 mg/m2 or 60 mg/m2 or more. There was not enough high‐quality evidence available for the use of other anthracycline peak doses to be able to draw conclusions. No data were available for children and individuals with leukaemia.

Further high‐quality research is needed.

Quality of the evidence

All studies had problems relating to quality of the evidence.

Author(s)

Elvira C van Dalen, Helena JH van der Pal, Leontien CM Kremer

Reviewer's Conclusions

Authors' conclusions

Implications for practice Different anthracycline infusion durations

For different anthracycline infusion durations, our meta‐analysis clearly showed that an anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure, and in individual studies it seems to reduce the risk of subclinical heart failure. There is no evidence suggesting a difference in response rate and survival between the treatment groups. We can make no conclusions regarding adverse effects other than cardiac damage and QoL. It should be emphasised that the majority of the participants included in these studies were adults with advanced solid tumours. We found no new studies since the last version of this review.

We conclude that if the risk of cardiac damage is expected to be high or if it is necessary to administer a higher cumulative anthracycline dose, it might be justified to use an infusion duration of six hours or longer in people with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of a longer infusion duration against the uncertain risk of a reduced antitumour efficacy and adverse effects other than cardiac damage for each individual patient. We found no new studies since the last version of this review.

Different anthracycline peak doses

For different doxorubicin peak doses (that is less than 60 mg/m2 versus 60 mg/m2 or more), our meta‐analysis showed no significant difference in the occurrence of clinical heart failure between the treatment groups. There is no evidence suggesting a difference in overall survival between the treatment groups. We could not pool the results of adverse effects other than cardiac damage, but they were not unambiguous in the individual studies. No information on subclinical heart failure, response rate, PFS and QoL was provided. It should be emphasised that all participants included in these studies were adults with solid tumours. Based on the currently available evidence, we are not able to favour a doxorubicin peak dose of either less than 60 mg/m2 or 60 mg/m2 or more.

Since we identified only one RCT evaluating a liposomal doxorubicin (Caelyx) peak dose of 25 mg/m2 versus 50 mg/m2, we can make no definitive conclusions regarding this peak dose. No significant differences between the treatment groups for both clinical and subclinical heart failure were identified. There was a borderline‐significant difference in response rate in favour of participants treated with a peak dose of 50 mg/m2. No significant difference between the treatment groups for QoL was shown. However, these findings should be confirmed in other RCTs. The results of adverse effects other than cardiac damage were not unambiguous. No information on PFS and OS was provided. It should be emphasised that the all participants included in these studies were adults with solid tumours. Based on the currently available evidence, we are not able to make recommendations for clinical practice.

Since we identified only one RCT evaluating an epirubicin peak dose of 83 mg/m2 versus 110 mg/m2, we can make no definitive conclusions regarding this peak dose. No significant difference between the treatment groups for clinical heart failure was identified. However, this finding should be confirmed in other RCTs. The results of adverse effects other than cardiac damage were not unambiguous. No information on subclinical heart failure, response rate, PFS and QoL was provided. It should be emphasised that all the participants included in these studies were adults with solid tumours. Based on the currently available evidence, we are not able to make recommendations for clinical practice.

As no high‐quality evidence was available for other combinations of anthracycline peak doses, we can make no conclusions about the efficacy of different peak doses in preventing heart damage in people treated with anthracyclines. Based on the currently available evidence, we are not able to make recommendations for clinical practice.

Implications for research Different anthracycline infusion durations

Since there is only a small amount of data for children and also because data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children. Future RCTs should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour using valid outcome definitions (including cardiotoxicity, response rate, survival, and adverse effects other than cardiac damage). The follow‐up should be long enough to identify late‐onset cardiotoxic effects. The number of included participants should be sufficient to obtain the power needed for the results to be reliable. Also, it will be very interesting to examine long‐term follow‐up data from the already performed RCTs.

Different anthracycline peak doses

Future RCTs should be performed in homogeneous study populations treated for either a haematological malignancy or a solid tumour using valid outcome definitions (including cardiotoxicity, response rate, survival, and adverse effects other than cardiac damage). The follow‐up should be long enough to identify late‐onset cardiotoxic effects. The number of included participants should be sufficient to obtain the power needed for the results to be reliable. Since no data for children are available and data obtained in adults cannot be extrapolated to children, different anthracycline peak doses should also be evaluated in children. Also, it will be very interesting to examine long‐term follow‐up data from the already performed RCTs.

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