title: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.
abstract: OBJECTIVE
  In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results.
  
  
  METHODS
  Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival.
  
  
  RESULTS
  No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups.
  
  
  CONCLUSIONS
  Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA 15212-5234, USA. bernard.fisher@nsabp.org
authors.forename: B
authors.initials: B
authors.lastname: Fisher
authors.forename: S
authors.initials: S
authors.lastname: Anderson
authors.forename: A
authors.initials: A
authors.lastname: DeCillis
authors.forename: N
authors.initials: N
authors.lastname: Dimitrov
authors.forename: J N
authors.initials: JN
authors.lastname: Atkins
authors.forename: L
authors.initials: L
authors.lastname: Fehrenbacher
authors.forename: P H
authors.initials: PH
authors.lastname: Henry
authors.forename: E H
authors.initials: EH
authors.lastname: Romond
authors.forename: K S
authors.initials: KS
authors.lastname: Lanier
authors.forename: E
authors.initials: E
authors.lastname: Davila
authors.forename: C G
authors.initials: CG
authors.lastname: Kardinal
authors.forename: L
authors.initials: L
authors.lastname: Laufman
authors.forename: H I
authors.initials: HI
authors.lastname: Pierce
authors.forename: N
authors.initials: N
authors.lastname: Abramson
authors.forename: A M
authors.initials: AM
authors.lastname: Keller
authors.forename: J T
authors.initials: JT
authors.lastname: Hamm
authors.forename: D L
authors.initials: DL
authors.lastname: Wickerham
authors.forename: M
authors.initials: M
authors.lastname: Begovic
authors.forename: E
authors.initials: E
authors.lastname: Tan-Chiu
authors.forename: W
authors.initials: W
authors.lastname: Tian
authors.forename: N
authors.initials: N
authors.lastname: Wolmark
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D015993:Life Tables; D015409:Mastectomy, Radical; D008875:Middle Aged; D017211:Treatment Failure
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D003520:Cyclophosphamide