Review question
We reviewed the evidence regarding the effectiveness of the medicine dexrazoxane to prevent or reduce heart damage in children and adults with cancer treated with anthracycline chemotherapy. We also looked at the possible effects of dexrazoxane on antitumour effectiveness (that is, survival and tumour response rate), quality of life and adverse effects (i.e. unwanted or harmful effects of a treatment) other than cardiac damage.
Background
Anthracyclines are 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 (total amount of treatment given over time). Cardiotoxicity may lead to subclinical myocardial dysfunction (when there is evidence from a test that heart function is limited, but the person does not have symptoms), which can progress to clinical heart failure (when the person has symptoms). Dexrazoxane is a medicine with the potential to prevent or reduce this damage.
This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents (medicines that protect the heart), was split and this review now focuses on dexrazoxane only.
Study characteristics
The evidence is current to May 2021.
We found 13 randomised studies (clinical studies where people are randomly put into one of two or more treatment groups) looking at dexrazoxane: 5 studies in children (1252 children with leukaemia, lymphoma or a solid tumour) and 8 studies in adults (1269 adults who were mostly diagnosed with breast cancer).
Key results
Our analyses showed that:
- in adults, dexrazoxane was able to prevent or reduce heart damage for those treated with anthracyclines;
- in children, there was a difference between treatment groups in favour of dexrazoxane for only one of the cardiac (heart-related) outcomes; namely, clinical heart failure and subclinical myocardial dysfunction combined;
- in adults, no evidence of a negative effect on survival or a lower tumour response rate was identified;
- in children, no evidence of a lower overall mortality or a lower tumour response rate was identified.
The results for adverse effects varied. Children treated with dexrazoxane might have a higher risk of secondary cancers (i.e. a new cancer). This outcome was not evaluated in adults.
None of the studies evaluated the quality of life of the people who participated.
Before definitive conclusions on the use of dexrazoxane can be made, especially in children, more high-quality research is needed. We conclude that if the risk of heart damage from anthracyclines is expected to be high, it might be justified to use dexrazoxane in children and adults with cancer who are treated with anthracyclines. However, clinicians and patients should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects, including secondary cancers, for each individual. For children, the International Late Effects of Childhood Cancer Guideline Harmonization Group has developed a clinical practice guideline (www.ighg.org).
Quality of the evidence
In children, we assessed the quality of the evidence as low for almost all evaluated outcomes and very low for two outcomes (one definition of clinical heart failure and subclinical myocardial dysfunction combined and one definition of tumour response rate); for the other definitions of these outcomes, we assessed the results as low quality. In adults, we assessed the quality of the evidence as moderate for almost all evaluated outcomes, and as low for two definitions of survival (for the other two definitions of survival as moderate).
The quality of the evidence was limited because of issues with the study design, the small numbers of participants in some studies, or for both reasons.
Our meta-analyses showed the efficacy of dexrazoxane in preventing or reducing cardiotoxicity in adults treated with anthracyclines. In children, there was a difference between treatment groups for one cardiac outcome (i.e. for one of the definitions used for clinical heart failure and subclinical myocardial dysfunction combined) in favour of dexrazoxane. In adults, no evidence of a negative effect on tumour response rate, OS and PFS was identified; and in children, no evidence of a negative effect on tumour response rate and overall mortality was identified. The results for adverse effects varied. In children, dexrazoxane may be associated with a higher risk of SMN; in adults this was not addressed. In adults, the quality of the evidence ranged between moderate and low; in children, it ranged between low and very low. Before definitive conclusions on the use of dexrazoxane can be made, especially in children, more high-quality research is needed.
We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in children and adults with cancer who are treated with anthracyclines. However, clinicians and patients should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects, including SMN, for each individual.
For children, the International Late Effects of Childhood Cancer Guideline Harmonization Group has developed a clinical practice guideline.
This review is the third update of a previously published Cochrane Review. The original review, looking at all possible cardioprotective agents, was split and this part now focuses on dexrazoxane only.
Anthracyclines are effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent or reduce this cardiotoxicity, different cardioprotective agents have been studied, including dexrazoxane.
To assess the efficacy of dexrazoxane to prevent or reduce cardiotoxicity and determine possible effects of dexrazoxane on antitumour efficacy, quality of life and toxicities other than cardiac damage in adults and children with cancer receiving anthracyclines when compared to placebo or no additional treatment.
We searched CENTRAL, MEDLINE and Embase to May 2021. We also handsearched reference lists, the proceedings of relevant conferences and ongoing trials registers.
Randomised controlled trials (RCTs) in which dexrazoxane was compared to no additional therapy or placebo in adults and children with cancer receiving anthracyclines.
Two review authors independently performed study selection, data extraction, risk of bias and GRADE assessment of included studies. We analysed results in adults and children separately. We performed analyses according to the Cochrane Handbook for Systematic Reviews of Interventions.
For this update, we identified 548 unique records. We included three additional RCTs: two paediatric and one adult. Therefore, we included a total of 13 eligible RCTs (five paediatric and eight adult). The studies enrolled 1252 children with leukaemia, lymphoma or a solid tumour and 1269 participants, who were mostly diagnosed with breast cancer.
In adults, moderate-quality evidence showed that there was less clinical heart failure with the use of dexrazoxane (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.43; 7 studies, 1221 adults). In children, we identified no difference in clinical heart failure risk between treatment groups (RR 0.20, 95% CI 0.01 to 4.19; 3 studies, 885 children; low-quality evidence). In three paediatric studies assessing cardiomyopathy/heart failure as the primary cause of death, none of the children had this outcome (1008 children, low-quality evidence). In the adult studies, different definitions for subclinical myocardial dysfunction and clinical heart failure combined were used, but pooled analyses were possible: there was a benefit in favour of the use of dexrazoxane (RR 0.37, 95% CI 0.24 to 0.56; 3 studies, 417 adults and RR 0.46, 95% CI 0.33 to 0.66; 2 studies, 534 adults, respectively, moderate-quality evidence). In the paediatric studies, definitions of subclinical myocardial dysfunction and clinical heart failure combined were incomparable, making pooling impossible. One paediatric study showed a benefit in favour of dexrazoxane (RR 0.33, 95% CI 0.13 to 0.85; 33 children; low-quality evidence), whereas another study showed no difference between treatment groups (Fischer exact P = 0.12; 537 children; very low-quality evidence).
Overall survival (OS) was reported in adults and overall mortality in children. The meta-analyses of both outcomes showed no difference between treatment groups (hazard ratio (HR) 1.04, 95% 0.88 to 1.23; 4 studies; moderate-quality evidence; and HR 1.01, 95% CI 0.72 to 1.42; 3 studies, 1008 children; low-quality evidence, respectively). Progression-free survival (PFS) was only reported in adults. We subdivided PFS into three analyses based on the comparability of definitions, and identified a longer PFS in favour of dexrazoxane in one study (HR 0.62, 95% CI 0.43 to 0.90; 164 adults; low-quality evidence). There was no difference between treatment groups in the other two analyses (HR 0.95, 95% CI 0.64 to 1.40; 1 study; low-quality evidence; and HR 1.18, 95% CI 0.97 to 1.43; 2 studies; moderate-quality evidence, respectively). In adults, there was no difference in tumour response rate between treatment groups (RR 0.91, 95% CI 0.79 to 1.04; 6 studies, 956 adults; moderate-quality evidence). We subdivided tumour response rate in children into two analyses based on the comparability of definitions, and identified no difference between treatment groups (RR 1.01, 95% CI 0.95 to 1.07; 1 study, 206 children; very low-quality evidence; and RR 0.92, 95% CI 0.84 to 1.01; 1 study, 200 children; low-quality evidence, respectively). The occurrence of secondary malignant neoplasms (SMN) was only assessed in children. The available and worst-case analyses were identical and showed a difference in favour of the control group (RR 3.08, 95% CI 1.13 to 8.38; 3 studies, 1015 children; low-quality evidence). In the best-case analysis, the direction of effect was the same, but there was no difference between treatment groups (RR 2.51, 95% CI 0.96 to 6.53; 4 studies, 1220 children; low-quality evidence). For other adverse effects, results also varied. None of the studies evaluated quality of life.
If not reported, the number of participants for an analysis was unclear.