title: Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS).
abstract: BACKGROUND
  Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo.
  
  
  OBJECTIVE
  To investigate ZA for the prevention of BMs in high-risk localised PCa.
  
  
  METHODS
  Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10.
  
  
  METHODS
  Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for ≤4 yr.
  
  
  METHODS
  BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups.
  
  
  CONCLUSIONS
  A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4±0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients.
  
  
  CONCLUSIONS
  ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr.
  
  
  RESULTS
  Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr.
  
  
  BACKGROUND
  The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762.
authors.affiliation: University Clinic Carl Gustav Carus, Urology, Dresden, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Tampere University Hospital and University of Tampere, Urology, Tampere, Finland.
authors.forename: Teuvo
authors.initials: T
authors.lastname: Tammela
authors.affiliation: Azienda Ospedaliera "S. Giuseppe Moscati", Urology, Avellino, Italy.
authors.forename: Virgilio
authors.initials: V
authors.lastname: Cicalese
authors.affiliation: A Coruña University Hospital, Urology, A Coruña, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gomez Veiga
authors.affiliation: Atrium Medisch Centrum, Urology, Heerlen, The Netherlands.
authors.forename: Karl
authors.initials: K
authors.lastname: Delaere
authors.affiliation: Charité, Universitätsmedizin, Urology, Berlin, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.affiliation: "Sant'Andrea Hospital", Urology, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tubaro
authors.affiliation: Private Practice Schulze, Markkleeberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schulze
authors.affiliation: Andros Clinic, Urology, Arnhem, The Netherlands.
authors.forename: Frans
authors.initials: F
authors.lastname: Debruyne
authors.affiliation: University Krankenhaus Eppendorf, Urology, Hamburg, Germany.
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.affiliation: European Association of Urology, Research Foundation, Arnhem, The Netherlands.
authors.forename: Anup
authors.initials: A
authors.lastname: Patel
authors.affiliation: Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Radiology, Brussels, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Lecouvet
authors.affiliation: European Association of Urology, Research Foundation, Arnhem, The Netherlands.
authors.forename: Christien
authors.initials: C
authors.lastname: Caris
authors.affiliation: European Association of Urology, Research Foundation, Arnhem, The Netherlands. Electronic address: w.witjes@curatrial.com.
authors.forename: Wim
authors.initials: W
authors.lastname: Witjes
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D016009:Chi-Square Distribution; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005060:Europe; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D012307:Risk Factors; D013997:Time Factors; D017211:Treatment Failure; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Androgen deprivation therapy; Anticancer agents; Bisphosphonates; Bone metastases; Prostate cancer; Skeletal-related events; Zoledronic acid