title: Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial.
abstract: BACKGROUND
  The most appropriate timing of chemotherapy and hormone therapy administration is a critical issue in early breast cancer patients. The purpose of our study was to compare the efficacy of concurrent vs sequential administration of adjuvant chemotherapy and tamoxifen.
  
  
  METHODS
  Women with node-positive primary breast cancer were randomly assigned to receive tamoxifen (20 mg/d for 5 years) during (concurrent arm) or after (sequential arm) adjuvant chemotherapy. Chemotherapy consisted of alternating regimens of cyclophosphamide, epidoxorubicin, and 5-fluorouracil and cyclophosphamide, methotrexate, and 5-fluorouracil every 21 days for a total of 12 cycles. The primary endpoint was overall survival (OS), and secondary endpoints were toxic effects and disease-free survival (DFS). No provision for interim analyses was made in the original study protocol. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models, adjusted for age, menopausal status, tumor stage, and lymph node and hormone receptor status, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
  
  
  RESULTS
  From 1985 to 1992, 431 patients were randomly assigned and studied according to the intention-to-treat principle. After a maximum of 15.4 years of follow-up (median 12.3 years), the estimated actuarial 10-year OS was equivalent for the two study arms (concurrent arm: 111 patients, 66%, 95% CI = 59% to 72%; sequential arm: 114 patients, 65%, 95% CI = 59% to 72%, P = .86). No differences in DFS and toxic effects were evident. Four interim analyses were performed, but no alpha error adjustment was necessary because of the largely negative results of this final analysis (sequential vs concurrent arm: HR of death = 1.06, 95% CI = 0.78 to 1.44, P = .76; HR of relapse = 1.16, 95% CI = 0.88 to 1.52, P = .36).
  
  
  CONCLUSIONS
  No statistically significant differences in OS, DFS, and toxic effects between concurrent and sequential adjuvant chemo- and hormone therapies were observed. Our study does not support the superiority of one schedule of chemo- and hormone-therapy administration over the other. However, because of the limited statistical power of the study, these results must be considered with caution.
authors.affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. bedodav@yahoo.it
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.forename: Mario Roberto
authors.initials: MR
authors.lastname: Sertoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Pronzato
authors.forename: Lucia
authors.initials: L
authors.lastname: Del Mastro
authors.forename: Marco
authors.initials: M
authors.lastname: Venturini
authors.forename: Paola
authors.initials: P
authors.lastname: Taveggia
authors.forename: Elisa
authors.initials: E
authors.lastname: Zanardi
authors.forename: Guido
authors.initials: G
authors.lastname: Siffredi
authors.forename: Simona
authors.initials: S
authors.lastname: Pastorino
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gardin
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Clara
authors.initials: C
authors.lastname: Monzeglio
authors.forename: Francesco
authors.initials: F
authors.lastname: Boccardo
authors.forename: Paolo
authors.initials: P
authors.lastname: Bruzzi
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001365:Axilla; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D015986:Confounding Factors, Epidemiologic; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D005965:Glucuronates / Q000008:administration & dosage; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D015412:Mastectomy, Segmental; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012307:Risk Factors; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005965:Glucuronates; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C074868:epidoxorubicin glucuronide; D013629:Tamoxifen; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate