title: Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.
abstract: BACKGROUND
  The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer.
  
  
  METHODS
  In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020.
  
  
  RESULTS
  3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4).
  
  
  CONCLUSIONS
  These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes.
  
  
  BACKGROUND
  Novartis Global and NIHR Cancer Research Network.
authors.affiliation: CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, University of Sheffield, Sheffield, UK. Electronic address: r.e.coleman@sheffield.ac.uk.
authors.forename: Robert
authors.initials: R
authors.lastname: Coleman
authors.affiliation: Edinburgh Cancer Research Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.affiliation: St James Institute of Oncology, University of Leeds, Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Dodwell
authors.affiliation: Andrew Love Cancer Centre, Geelong, VIC, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Bell
authors.affiliation: CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, University of Sheffield, Sheffield, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
authors.affiliation: CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, University of Sheffield, Sheffield, UK; St James Institute of Oncology, University of Leeds, Leeds, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Rathbone
authors.affiliation: University Hospital Galway, Galway, Ireland.
authors.forename: Maccon
authors.initials: M
authors.lastname: Keane
authors.affiliation: Institut Català d'Oncologia - IDIBELL. L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gil
authors.affiliation: CR-UK/YCR Sheffield Cancer Research Centre, Weston Park Hospital, University of Sheffield, Sheffield, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Burkinshaw
authors.affiliation: University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Grieve
authors.affiliation: Velindre Cancer Center, Whitchurch, Cardiff, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Barrett-Lee
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Ritchie
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Liversedge
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Samantha
authors.initials: S
authors.lastname: Hinsley
authors.affiliation: Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Marshall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D004164:Diphosphonates / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D055088:Early Detection of Cancer; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007391:International Cooperation; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid