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.
ABSTRACT 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 ClinicalTrials.gov, 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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ABSTRACT: The success achieved in advances in cancer therapy has been marred by development of cardiotoxicity, which causes significant morbidity and mortality. This has led to the development of surveillance protocols for cardiotoxicity utilizing multimodality imaging techniques and investigation of various drugs to treat and prevent cardiotoxicity in this subset of patients. Cardiac biomarkers hold important diagnostic and prognostic value in various cardiac diseases. In this review, we discuss the use of biomarkers in patients receiving chemotherapy, highlighting data behind the use of troponin, B-type natriuretic peptide, and myeloperoxidase. We also discuss the use of dexrazoxane, angiotensin-converting enzyme inhibitors, and beta blockers in the treatment and prevention of chemotherapy-induced cardiotoxicity. Cardiac biomarkers may serve an important role in selecting patients that are at high risk of cardiotoxicity and can potentially be used to guide the administration of drugs to treat and prevent cardiotoxicity.Current Heart Failure Reports 04/2015; 12(3). DOI:10.1007/s11897-015-0258-4
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ABSTRACT: Preservation of ovarian function following chemotherapy for non-ovarian cancers is a formidable challenge. For prepubescent girls, the only option to prevent chemotherapy damage to the ovary is ovarian tissue cryopreservation, an experimental procedure requiring invasive surgeries to harvest and re-implant tissue, which carries the risk of cancer re-introduction. Drugs that block the primary mechanism of chemotherapy insult, such as dexrazoxane (Dexra) in the context of anthracycline chemotherapy, provide a novel approach for ovarian protection and have the potential to overcome current limitations to oncofertility treatment. Dexra is a catalytic topoisomerase 2 inhibitor that protects the mouse ovary from acute doxorubicin (DXR) chemotherapy toxicity in vitro by preventing DXR-induced DNA damage and subsequent gamaH2AX activation. To translate acute DXR ovarian insult and Dexra protection from mouse to nonhuman primate, freshly obtained marmoset ovarian tissue was cultured in vitro and treated with vehicle or 20 μM Dexra 1 hour prior to 50 nM DXR. Cultured ovarian tissue was harvested at 2, 4, or 24 hours post-DXR treatment. Dexra prevented DXR-induced DNA double-strand breaks (DSBs) as quantified by the neutral comet assay. DXR treatment for 24 hours increased gammaH2AX phosphorylation, predominantly in granulosa cells of antral follicles, while Dexra pretreatment inhibited DXR-induced gammaH2AX phosphorylation. Additionally, Dexra pretreatment trended towards attenuating DXR-induced AKT1 phosphorylation and caspase-9 activation assayed on Western blots of ovarian tissue lysates. The combined findings suggest Dexra prevents primary DXR-induced DNA damage, the early cellular response to DNA damage, and may diminish early apoptotic signaling in marmoset ovarian tissue. This study provides initial translation of Dexra protection against acute ovarian DXR toxicity from mice to marmoset monkey tissue. Copyright 2015 by The Society for the Study of Reproduction.Biology of Reproduction 01/2015; 92(3). DOI:10.1095/biolreprod.114.119495 · 3.45 Impact Factor
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ABSTRACT: To review the evidence for the use of various biomarkers in the detection of chemotherapy associated cardiac damage.Design and methodsPubmed.gov was queried using the search words chemotherapy and cardiac biomarkers with the filters of past 10 years, humans, and English language. An emphasis was placed in obtaining primary research articles looking at the utility of biomarkers for the detection of chemotherapy-mediated cardiac injury.ResultsBiomarkers may help identify patients undergoing treatment who are at high risk for cardiotoxicity and may assist in identification of a low risk cohort that does not necessitate continued intensive screening. cTn assays are the best studied biomarkers in this context and may represent a promising and potentially valuable modality for detecting cardiac toxicity in patients undergoing chemotherapy. Monitoring cTnI levels may provide information regarding the development of cardiac toxicity before left ventricular dysfunction becomes apparent on echocardiography or via clinical symptoms. A host of other biomarkers have been evaluated for their utility in the field of chemotherapy related cardiac toxicity with intermittent success; further trials are necessary to determine what role they may end up playing for prediction and prognostication in this setting.Conclusions Biomarkers represent an exciting potential complement or replacement for echocardiographic monitoring of chemotherapy related cardiac toxicity which may allow for earlier realization of the degree of cardiac damage occurring during therapy, creating the opportunity for more timely modulation of therapy.Clinical Biochemistry 11/2014; 48(4-5). DOI:10.1016/j.clinbiochem.2014.10.013 · 2.23 Impact Factor