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

University of Miami, Leonard M Miller School of Medicine, Miami, FL, USA.
The Lancet Oncology (Impact Factor: 24.69). 10/2010; 11(10):950-61. DOI: 10.1016/S1470-2045(10)70204-7
Source: PubMed


Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment.
Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with, number NCT00165087.
100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99).
Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys.
US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.

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    • "While cardiotoxicity can develop at no specific time once the treatment has begun, identifying cardioprotective strategies to minimize the long-term damage caused by anthracyclines is imperative. In this context, many alternatives have been investigated either in experimental models or in clinical trials in order to prevent or diminish cardiac dysfunction, such as dexrazoxane (Lipshultz et al., 2010), carvedilol (Machado et al., 2008), plant extracts (Du and Lou, 2008) and stem cell therapy (Chen et al., 2010). Nevertheless, none of those are really established in routine medical practice to date. "
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    Toxicology Letters 11/2013; 224(3). DOI:10.1016/j.toxlet.2013.11.023 · 3.26 Impact Factor
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    • "Dexrazoxane is currently used in combination with doxorubicin for cardioprotection [25]. However, there is a need for better cardioprotectants because dexrazoxane does not eliminate the potential for cardiomyopathy by anthracyclines and newer anticancer agents that cause cardiotoxicity, such as trastuzumab, interleukin-2, and tyrosine kinase inhibitors, which are not known to elicit cardiotoxicity through iron-mediated oxidative stress [26]–[28]. "
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    PLoS ONE 08/2013; 8(8):e70575. DOI:10.1371/journal.pone.0070575 · 3.23 Impact Factor
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    • "While data again are mostly based on adult breast cancer patients, at least 2 RCTs in children suggest that DRZ may be effective in ameliorating cardiotoxicity [24–26]. In both trials, there were no statistical differences in cancer recurrence rates or overall survival between the study arms [25, 26]. Concerns regarding a possible association between DRZ and an increased risk of second cancers in children with Hodgkin lymphoma have hindered its more widespread use among children [27]. "
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