title: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide.
abstract: OBJECTIVE
  We reviewed follow-up of patients treated in 19 randomized trials of adjuvant epirubicin in early breast cancer to determine incidence, risk, and risk factors for subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
  
  
  METHODS
  The patients (N = 9,796) were observed from the start of adjuvant treatment (53,080 patient-years). Cases of AML or MDS (AML/MDS) were reported, with disease characteristics. Incidence and cumulative risk were compared for possible risk factors, for assigned regimens, and for administered cumulative doses of epirubicin and cyclophosphamide.
  
  
  RESULTS
  In 7,110 patients treated with epirubicin-containing regimens (92% of whom also received cyclophosphamide), 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose-intensity, and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (</= 720 mg/m(2) and </= 6,300 mg/m(2), respectively) had an 8-year cumulative probability of developing AML/MDS of 0.37% (95% CI, 0.13% to 0.61%) compared with 4.97% (95% CI, 2.06% to 7.87%) for patients administered higher cumulative doses of both epirubicin and cyclophosphamide.
  
  
  CONCLUSIONS
  Patients treated with standard cumulative doses of adjuvant epirubicin (</= 720 mg/m(2)) and cyclophosphamide (</= 6,300 mg/m(2)) for early breast cancer have a lower probability of secondary leukemia than patients treated with higher cumulative doses. Increased risk of secondary leukemia must be considered when assessing the potential benefit to risk ratio of higher than standard doses.
authors.affiliation: Centre Oscar Lambret, Lille, France.
authors.forename: Claudio
authors.initials: C
authors.lastname: Praga
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.forename: Judith
authors.initials: J
authors.lastname: Bliss
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonneterre
authors.forename: Bruno
authors.initials: B
authors.lastname: Cesana
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Pierre
authors.initials: P
authors.lastname: Fargeot
authors.forename: Annika
authors.initials: A
authors.lastname: Folin
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Rosa
authors.initials: R
authors.lastname: Giuliani
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerbrat
authors.forename: Michel
authors.initials: M
authors.lastname: Hery
authors.forename: Jonas
authors.initials: J
authors.lastname: Nilsson
authors.forename: Francesco
authors.initials: F
authors.lastname: Onida
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Lois
authors.initials: L
authors.lastname: Shepherd
authors.forename: Patrick
authors.initials: P
authors.lastname: Therasse
authors.forename: Jacques
authors.initials: J
authors.lastname: Wils
authors.forename: David
authors.initials: D
authors.lastname: Rogers
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000627:therapeutic use; D003627:Data Interpretation, Statistical; D015251:Epirubicin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000139:chemically induced*; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D015251:Epirubicin; D003520:Cyclophosphamide