title: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial.
abstract: BACKGROUND
  Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy.
  
  
  METHODS
  We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591.
  
  
  RESULTS
  Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group.
  
  
  CONCLUSIONS
  Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes.
  
  
  BACKGROUND
  National Cancer Institute (US National Institutes of Health).
authors.affiliation: Loyola University Stritch School of Medicine, Maywood, IL, USA. Electronic address: kalbain@lumc.edu.
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.affiliation: Southwest Oncology Group Statistical Center, Seattle, WA, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Barlow
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ravdin
authors.affiliation: Ohio State University Health Center, Columbus, OH, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Farrar
authors.affiliation: Louisiana State University, Shreveport, LA, USA.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Burton
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Ketchel
authors.affiliation: Flower Memorial Hospital, Sylvania, OH, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Cobau
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Ellis G
authors.initials: EG
authors.lastname: Levine
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: Toronto Sunnybrook Regional Cancer Centre, Toronto, ON, USA.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Allen S
authors.initials: AS
authors.lastname: Lichter
authors.affiliation: Loyola University Stritch School of Medicine, Maywood, IL, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schneider
authors.affiliation: Johns Hopkins Medical Center, Baltimore, MD, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Abeloff
authors.affiliation: University of California, San Francisco, San Francisco, CA, USA.
authors.forename: I Craig
authors.initials: IC
authors.lastname: Henderson
authors.affiliation: Vermont Cancer Center and University of Vermont, Burlington, VT, USA.
authors.forename: Hyman B
authors.initials: HB
authors.lastname: Muss
authors.affiliation: Southwest Oncology Group Statistical Center, Seattle, WA, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Green
authors.affiliation: Southwest Oncology Group Statistical Center, Seattle, WA, USA.
authors.forename: Danika
authors.initials: D
authors.lastname: Lew
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.affiliation: The Angeles Clinic and Research Institute, Santa Monica, CA, USA.
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil