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. 2022 Sep 27;9(9):CD014638.
doi: 10.1002/14651858.CD014638.pub2.

Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines

Esmée C de Baat  1 , Renée L Mulder  1 , Saro Armenian  2 , Elizabeth Am Feijen  1 , Heynric Grotenhuis  3 , Melissa M Hudson  4 , Annelies Mc Mavinkurve-Groothuis  1 , Leontien Cm Kremer  1 , Elvira C van Dalen  1
Affiliations

Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines

Esmée C de Baat et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: We searched CENTRAL, MEDLINE and Embase to May 2021. We also handsearched reference lists, the proceedings of relevant conferences and ongoing trials registers.

Selection criteria: Randomised controlled trials (RCTs) in which dexrazoxane was compared to no additional therapy or placebo in adults and children with cancer receiving anthracyclines.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

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Conflict of interest statement

ECdB: none known RLM: none known SA: contributed to the P9404 study included in this review; however, he was not involved in data extraction, risk of bias or GRADE assessment EAMF: none known HBG: none known MMH: none known AMCMG: none known LCMK: none known ECvD: none known

Figures

1
1
Flow diagram of selection of studies
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (+ = low risk of bias, ‐ = high risk of bias, ? = unclear risk of bias)
3
3
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.1 Clinical heart failure available‐case.
4
4
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.5 Heart failure (i.e. clinical and subclinical heart failure combined) available‐case.
5
5
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.8 Overall survival.
6
6
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.9 Overall mortality.
7
7
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.10 Progression‐free survival.
8
8
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.11 Response rate available‐case.
9
9
Forest plot of comparison: 1 Dexrazoxane versus no dexrazoxane or placebo, outcome: 1.14 Adverse effects: Secondary malignant neoplasms (Children).
1.1
1.1. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 1: Clinical heart failure available‐case
1.2
1.2. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 2: Clinical heart failure best‐case
1.3
1.3. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 3: Clinical heart failure worst‐case
1.4
1.4. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 4: Cardiomyopathy/heart failure primary cause of death available‐case (best‐case and worst‐case identical results)
1.5
1.5. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 5: Heart failure (i.e. clinical heart failure and subclinical myocardial dysfunction combined) available‐case
1.6
1.6. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 6: Heart failure (i.e. clinical heart failure and subclinical myocardial dysfunction combined) best‐case
1.7
1.7. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 7: Heart failure (i.e. clinical heart failure and subclinical myocardial dysfunction combined) worst‐case
1.8
1.8. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 8: Overall survival
1.9
1.9. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 9: Overall mortality
1.10
1.10. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 10: Progression‐free survival
1.11
1.11. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 11: Response rate available‐case
1.12
1.12. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 12: Response rate best‐case
1.13
1.13. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 13: Response rate worst‐case
1.14
1.14. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 14: Adverse effects: Secondary malignant neoplasms (Children)
1.15
1.15. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 15: Adverse effects: Haematological effects (Adults)
1.16
1.16. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 16: Adverse effects: Haematological effects (Children)
1.17
1.17. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 17: Adverse effects: Immune system/infectious effects (Adults)
1.18
1.18. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 18: Adverse effects: Immune system/infectious effects (Children)
1.19
1.19. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 19: Adverse effects: Gastrointestinal effects (Adults)
1.20
1.20. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 20: Adverse effects: Gastrointestinal effects (Children)
1.21
1.21. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 21: Adverse effects: Neurological effects (Adults)
1.22
1.22. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 22: Adverse effects: Neurological (Children)
1.23
1.23. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 23: Adverse effects: Other (Adults)
1.24
1.24. Analysis
Comparison 1: Dexrazoxane versus no dexrazoxane or placebo, Outcome 24: Adverse effects: Other (Children)
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD014638

References

References to studies included in this review

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P9404 {published data only}
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P9426 {published data only}
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References to studies excluded from this review

Getz 2019 {published data only}
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References to studies awaiting assessment

Aggarwal 2018 {published data only}
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Cardenas 2003 {published data only}
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Chow 2016 {published data only}
    1. Chow EJ, Doody DR, Armenian SH, Aggarwal S, Baker KS, Bhatia S, et al. Effect of dexrazoxane on heart function among long-term survivors of childhood leukemia and lymphoma: a report from the children's oncology Group (COG) (Abstract ASH Annual Meeting). Blood 2016;128(22):696.
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De Berranger 2006 {published data only}
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Feldmann 1992 {published data only}
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Jackowska 2003 {published data only}
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Liu 2013 {published data only}
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References to ongoing studies

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References to other published versions of this review

Van Dalen 2002
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