- Email: [email protected]
Should anthracyclines and dexrazoxane be used for children with cancer?
Correspondence
Colin Cuthbert/Science Photo Library
Should anthracyclines and dexrazoxane be used for children with cancer? Anthracyclines are widely used to treat childhood malignancies; however, one in 10 children who are treated with a cumulative anthracycline dose of 300 mg/m² or more will eventually develop clinical heart failure.1 The consequences of anthracycline-induced cardiotoxicity are extensive; excess mortality due to cardiac disease is eight-times higher than expected for long-term childhood cancer survivors than for the normal population.2 The risk of developing anthracycline-induced cardiotoxicity is life-long, which is especially important for children who have a long life expectancy after successful treatment. Despite their widespread use, a systematic review has shown that there is no—or only very sparse— evidence from randomised trials, which underscores the use of anthracyclines for different childhood malignancies.3 Randomised trials were identified for only five malignancies. For acute lymphoblastic leukaemia (three randomised trials; 912 children; one trial assessed standard risk; stages were not mentioned for the other two trials), no significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better efficacy in patients who were treated with anthracyclines. For rhabdomyosarcoma and undifferentiated sarcoma (one study; 413 children; clinical group III–IV), and for non-Hodgkin lymphoma (one study; 285 children; stage I–IV), no difference in antitumour efficacy between treatment groups was identified. However, for Wilms’ tumour (one study; 316 children; stage II–IV), and for non-metastatic Ewing’s sarcoma (one study; 94 children), a significant difference in survival was identified in favour of 12
anthracycline treatment. The hazard ratios for overall survival and for event-free survival in Wilms’ tumour were 1·85 (95% CI 1·09–3·15; p=0·02) and 2·21 (1·44–3·40; p=0·003). For patients with Ewing’s sarcoma, only descriptive results were available (p=0·02 for overall survival; p=0·01 for event-free survival).3 Long-term followup of the Wilms’ tumour trial has since become available; with long-term follow-up (16 years in some of the patients), the significant difference in overall survival disappears,4 possibly resulting from mortality caused by different late effects.2 Furthermore, in a randomised trial of anthracyclines for standard-risk hepatoblastoma, there was no difference in antitumour efficacy between treatment groups.5 If treatment with anthracyclines has no added value regarding antitumour efficacy compared with treatment without them, they should not be used at all, and anthracycline-related cardiotoxicity will not be an issue. However, if treatment with anthracyclines is necessary, it is extremely important to prevent cardiotoxicity. Dexrazoxane is one of the most important cardioprotective interventions. It significantly reduces anthracycline-related cardiotoxicity in adults with different solid tumours and in children with acute lymphoblastic leukaemia and Ewing’s sarcoma.6,7 With the exception of Hodgkin’s disease (long-term cardiac data not yet available; no difference in antitumour efficacy),8 no results relating to dexrazoxane use in other childhood malignancies have yet been published. That dexrazoxane is not routinely used in clinical practice might be explained by the suspicion of interference with antitumour efficacy and by the occurrence of secondary malignancies. However, meta-analyses of antitumour efficacy showed no significant difference between patients who were treated with or without dexrazoxane.6 Furthermore, a meta-analysis including three of
the four randomised trials available about secondary malignancies after dexrazoxane,9,10 did not show a significant difference in the occurrence of secondary malignancies between children treated with or without dexrazoxane (relative risk 1·16, 95% CI 0·06–22·17, p=0·92; eight secondary malignancies in the dexrazoxane group and four in the control group). One other trial did not provide enough information to be included in the meta-analysis, but showed no statistically significant difference in 5-year and 10-year cumulative incidence of secondary malignancies between treatment groups.11 In conclusion, only very sparse evidence is available supporting the use of anthracyclines in children. Evidence about dexrazoxane shows a strong cardioprotective effect in adults with different solid malignancies and in children with acute lymphoblastic leukaemia and Ewing’s sarcoma, while the risk of interference with antitumour efficacy and the occurrence of secondary malignancies are not substantiated. More research is needed to establish the exact role of anthracyclines in childhood malignancies. If treatment with anthracyclines is necessary, then treatment with dexrazoxane should be considered. The Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KIKA), the Netherlands. The authors declared no conflicts of interest.
Elvira C van Dalen*, Henk van den Berg, Martine F Raphaël, Huib N Caron, Leontien C Kremer [email protected] Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Amsterdam, Netherlands (ECvD, HvdB, HNC, LCK); Cochrane Childhood Cancer Group, Amsterdam, Netherlands (ECvD, HNC, LCK); and Department of Pediatric Hematology and Oncology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands (MFR) 1
Van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 2006; 42: 3191–98.
www.thelancet.com/oncology Vol 12 January 2011
Correspondence
2
3
4
5
Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001; 19: 3163–72. Van Dalen EC, Raphaël MF, Caron HN, Kremer LC. Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst Rev 2009; 1: CD006647. Green DM. The treatment of stages I–IV favorable histology Wilms’ tumor. J Clin Oncol 2004; 22: 1366–72. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 2009; 361: 1662–70.
www.thelancet.com/oncology Vol 12 January 2011
6
7
8
Van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2008; 2: CD003917. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010; 11: 950–61. Schwartz CL, Constine LS, Villaluna D, et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 2009; 114: 2051–59.
9
10
11
Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 2007; 25: 493–500. Barry EV, Vrooman LM, Dahlberg SE, et al. Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 2008; 26: 1106–11. Salzer WL, Devidas M, Carroll WL, et al. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children’s oncology group. Leukemia 2010; 24: 355–70.
13
Colin Cuthbert/Science Photo Library
Should anthracyclines and dexrazoxane be used for children with cancer? Anthracyclines are widely used to treat childhood malignancies; however, one in 10 children who are treated with a cumulative anthracycline dose of 300 mg/m² or more will eventually develop clinical heart failure.1 The consequences of anthracycline-induced cardiotoxicity are extensive; excess mortality due to cardiac disease is eight-times higher than expected for long-term childhood cancer survivors than for the normal population.2 The risk of developing anthracycline-induced cardiotoxicity is life-long, which is especially important for children who have a long life expectancy after successful treatment. Despite their widespread use, a systematic review has shown that there is no—or only very sparse— evidence from randomised trials, which underscores the use of anthracyclines for different childhood malignancies.3 Randomised trials were identified for only five malignancies. For acute lymphoblastic leukaemia (three randomised trials; 912 children; one trial assessed standard risk; stages were not mentioned for the other two trials), no significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better efficacy in patients who were treated with anthracyclines. For rhabdomyosarcoma and undifferentiated sarcoma (one study; 413 children; clinical group III–IV), and for non-Hodgkin lymphoma (one study; 285 children; stage I–IV), no difference in antitumour efficacy between treatment groups was identified. However, for Wilms’ tumour (one study; 316 children; stage II–IV), and for non-metastatic Ewing’s sarcoma (one study; 94 children), a significant difference in survival was identified in favour of 12
anthracycline treatment. The hazard ratios for overall survival and for event-free survival in Wilms’ tumour were 1·85 (95% CI 1·09–3·15; p=0·02) and 2·21 (1·44–3·40; p=0·003). For patients with Ewing’s sarcoma, only descriptive results were available (p=0·02 for overall survival; p=0·01 for event-free survival).3 Long-term followup of the Wilms’ tumour trial has since become available; with long-term follow-up (16 years in some of the patients), the significant difference in overall survival disappears,4 possibly resulting from mortality caused by different late effects.2 Furthermore, in a randomised trial of anthracyclines for standard-risk hepatoblastoma, there was no difference in antitumour efficacy between treatment groups.5 If treatment with anthracyclines has no added value regarding antitumour efficacy compared with treatment without them, they should not be used at all, and anthracycline-related cardiotoxicity will not be an issue. However, if treatment with anthracyclines is necessary, it is extremely important to prevent cardiotoxicity. Dexrazoxane is one of the most important cardioprotective interventions. It significantly reduces anthracycline-related cardiotoxicity in adults with different solid tumours and in children with acute lymphoblastic leukaemia and Ewing’s sarcoma.6,7 With the exception of Hodgkin’s disease (long-term cardiac data not yet available; no difference in antitumour efficacy),8 no results relating to dexrazoxane use in other childhood malignancies have yet been published. That dexrazoxane is not routinely used in clinical practice might be explained by the suspicion of interference with antitumour efficacy and by the occurrence of secondary malignancies. However, meta-analyses of antitumour efficacy showed no significant difference between patients who were treated with or without dexrazoxane.6 Furthermore, a meta-analysis including three of
the four randomised trials available about secondary malignancies after dexrazoxane,9,10 did not show a significant difference in the occurrence of secondary malignancies between children treated with or without dexrazoxane (relative risk 1·16, 95% CI 0·06–22·17, p=0·92; eight secondary malignancies in the dexrazoxane group and four in the control group). One other trial did not provide enough information to be included in the meta-analysis, but showed no statistically significant difference in 5-year and 10-year cumulative incidence of secondary malignancies between treatment groups.11 In conclusion, only very sparse evidence is available supporting the use of anthracyclines in children. Evidence about dexrazoxane shows a strong cardioprotective effect in adults with different solid malignancies and in children with acute lymphoblastic leukaemia and Ewing’s sarcoma, while the risk of interference with antitumour efficacy and the occurrence of secondary malignancies are not substantiated. More research is needed to establish the exact role of anthracyclines in childhood malignancies. If treatment with anthracyclines is necessary, then treatment with dexrazoxane should be considered. The Cochrane Childhood Cancer Group is funded by Stichting Kinderen Kankervrij (KIKA), the Netherlands. The authors declared no conflicts of interest.
Elvira C van Dalen*, Henk van den Berg, Martine F Raphaël, Huib N Caron, Leontien C Kremer [email protected] Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical Center, Amsterdam, Netherlands (ECvD, HvdB, HNC, LCK); Cochrane Childhood Cancer Group, Amsterdam, Netherlands (ECvD, HNC, LCK); and Department of Pediatric Hematology and Oncology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands (MFR) 1
Van Dalen EC, van der Pal HJ, Kok WE, Caron HN, Kremer LC. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 2006; 42: 3191–98.
www.thelancet.com/oncology Vol 12 January 2011
Correspondence
2
3
4
5
Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 2001; 19: 3163–72. Van Dalen EC, Raphaël MF, Caron HN, Kremer LC. Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst Rev 2009; 1: CD006647. Green DM. The treatment of stages I–IV favorable histology Wilms’ tumor. J Clin Oncol 2004; 22: 1366–72. Perilongo G, Maibach R, Shafford E, et al. Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma. N Engl J Med 2009; 361: 1662–70.
www.thelancet.com/oncology Vol 12 January 2011
6
7
8
Van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2008; 2: CD003917. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010; 11: 950–61. Schwartz CL, Constine LS, Villaluna D, et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 2009; 114: 2051–59.
9
10
11
Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 2007; 25: 493–500. Barry EV, Vrooman LM, Dahlberg SE, et al. Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 2008; 26: 1106–11. Salzer WL, Devidas M, Carroll WL, et al. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children’s oncology group. Leukemia 2010; 24: 355–70.
13