title: Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863).
abstract: BACKGROUND
  Continuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance.
  
  
  METHODS
  Postmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS).
  
  
  RESULTS
  Of 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1-15.2), 8.0 (6.2-12.4) and 10.8 (7.1-16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1-21.1), 13.2 (8.8-19.8) and 24.0 (16.9-60.9) months, respectively (p<0.001), without translation in differences in survival times.
  
  
  CONCLUSIONS
  Intermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer. Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.
authors.affiliation: Department of Medical Oncology, 452 Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, and Department of Oncology, Lund University Hospital, Sweden. l.beex@onco.umcn.nl
authors.forename: L
authors.initials: L
authors.lastname: Beex
authors.forename: C
authors.initials: C
authors.lastname: Rose
authors.forename: H
authors.initials: H
authors.lastname: Mouridsen
authors.forename: J
authors.initials: J
authors.lastname: Jassem
authors.forename: M
authors.initials: M
authors.lastname: Nooij
authors.forename: J
authors.initials: J
authors.lastname: Estape
authors.forename: R
authors.initials: R
authors.lastname: Paridaens
authors.forename: M
authors.initials: M
authors.lastname: Piccart
authors.forename: T
authors.initials: T
authors.lastname: Gorlia
authors.forename: S
authors.initials: S
authors.lastname: Lardenoije
authors.forename: L
authors.initials: L
authors.lastname: Baila
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D013629:Tamoxifen; D017258:Medroxyprogesterone Acetate