title: 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: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.
authors.affiliation: University of Miami, Leonard M Miller School of Medicine, Miami, FL, USA. slipshultz@med.miami.edu
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Scully
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Lipsitz
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Miller
authors.forename: Elly V
authors.initials: EV
authors.lastname: Barry
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Asselin
authors.forename: Uma
authors.initials: U
authors.lastname: Athale
authors.forename: Luis A
authors.initials: LA
authors.lastname: Clavell
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.forename: Albert
authors.initials: A
authors.lastname: Moghrabi
authors.forename: Yvan
authors.initials: Y
authors.lastname: Samson
authors.forename: Bruno
authors.initials: B
authors.lastname: Michon
authors.forename: Marshall A
authors.initials: MA
authors.lastname: Schorin
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Cohen
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: E John
authors.initials: EJ
authors.lastname: Orav
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D002170:Canada; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D011446:Prospective Studies; D011647:Puerto Rico; D011929:Razoxane / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors; D013997:Time Factors; D016896:Treatment Outcome; D020107:Troponin T / Q000097:blood; D014463:Ultrasonography; D014481:United States; D016277:Ventricular Function, Left / Q000187:drug effects; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D002317:Cardiovascular Agents; D020107:Troponin T; D011929:Razoxane; D004317:Doxorubicin