title: Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients.
abstract: BACKGROUND
  Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce.
  
  
  METHODS
  This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin-cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer.
  
  
  RESULTS
  At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% [95% confidence interval (CI) 1.5% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05).
  
  
  CONCLUSIONS
  HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of four to six cycles is not recommended in clinical practice.
authors.affiliation: Jules Bordet Institute, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Bernard-Marty
authors.forename: M
authors.initials: M
authors.lastname: Mano
authors.forename: M
authors.initials: M
authors.lastname: Paesmans
authors.forename: C
authors.initials: C
authors.lastname: Accettura
authors.forename: R
authors.initials: R
authors.lastname: Munoz-Bermeo
authors.forename: T
authors.initials: T
authors.lastname: Richard
authors.forename: K
authors.initials: K
authors.lastname: Kleiber
authors.forename: F
authors.initials: F
authors.lastname: Cardoso
authors.forename: J P
authors.initials: JP
authors.lastname: Lobelle
authors.forename: D
authors.initials: D
authors.lastname: Larsimont
authors.forename: M J
authors.initials: MJ
authors.lastname: Piccart
authors.forename: A
authors.initials: A
authors.lastname: Di Leo
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001530:Belgium; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005500:Follow-Up Studies; D006801:Humans; D007951:Leukemia, Myeloid / Q000139:chemically induced / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000175:diagnosis; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000139:chemically induced; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012189:Retrospective Studies
chemical_list: D000903:Antibiotics, Antineoplastic; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate