title: Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer.
abstract: The hormonal manipulation 5-Fluoro-uracil Epirubicin Cyclophosphamide (HMFEC) trial was developed at a time of uncertainty around the dose intensity of chemotherapy given to premenopausal patients with node positive breast cancer and to the benefits of tailored endocrine therapy in such patients.
  
  
  
  HMFEC was a multi-centre, phase III, open label, randomised controlled trial with a 2 × 2 factorial design. Eligible patients were premenopausal with node positive early breast cancer; significant cardiac disease or uncontrolled hypertension was exclusion criterion. Patients were allocated to receive either eight cycles of FE50C or FE75C (given 3 weekly) with or without hormone manipulation (HM; tamoxifen or luteinising hormone releasing hormone (LHRH) agonists according to residual hormone levels at the end of chemotherapy) irrespective of ER status. The primary end-point was disease free survival (DFS). Principal analyses were by intention to treat (ITT); however, to reflect contemporary practice, subgroup analyses according to ER status were also conducted. The mature follow-up now available from this modest sized trial enables presentation of definitive results.
  
  
  
  Between 1992 and 2000 a total of 785 patients were randomised into the HMFEC trial (203 FE50C-HM, 191 FE50C+HM, 198 FE75C-HM, 193 FE75C+HM). At a median follow-up of 7.4 years, 245 DFS events have been reported (92 ER-, 153 ER+/unknown). The effects on DFS were not statistically significantly different according to epirubicin dose (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.63-1.06; p = 0.13 FE75C versus FE50C); however, FE75C appeared to induce more alopecia and neutropenia. No statistically significant evidence was observed to support an improvement in DFS in patients allocated HM either overall (HR = 0.88, 95% CI 0.68-1.13; p = 0.32) or in patients with ER+/unknown disease (HR = 0.85, 95% CI 0.62-1.17; p = 0.32) although effect sizes are consistent with worthwhile clinical effects. Overall, there was no evidence of a difference in survival between any of the four treatment groups of the trial.
  
  
  
  Higher doses of epirubicin cause more adverse events in the absence of clear improvement in overall survival. Endocrine therapy with either tamoxifen or goserelin provided no significant added benefit to cytotoxic chemotherapy in this group of patients.
  
  
  
  ISRCTN98335268.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK. Electronic address: c.coombes@imperial.ac.uk.
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
authors.forename: L S
authors.initials: LS
authors.lastname: Kilburn
authors.affiliation: Department of Medical Oncology and Radiotherapy, Limoges University Hospital, Limoges, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Tubiana-Mathieu
authors.affiliation: Medical Oncology Department, Instituto Valenciano de Oncologia (IVO), Valencia, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Olmos
authors.affiliation: Department of Internal Medicine, Zaans Medical Centre, Zaandam, Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Van Bochove
authors.affiliation: Faculty of Medicine, University of Zaragoza and Lozano-Blesa University Hospital, Zaragoza, Spain.
authors.forename: F R
authors.initials: FR
authors.lastname: Perez-Lopez
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: C
authors.initials: C
authors.lastname: Palmieri
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Bliss
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D017697:Premenopause / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil
keywords: Adjuvant; Breast cancer; Chemotherapy; Clinical trial; Disease outcome; Hormone manipulation