title: Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873).
abstract: BACKGROUND
  The most frequent site of metastases from prostate cancer is bone. Adjuvant bisphosphonate treatment improves outcomes of patients with bone metastasis-negative breast cancer, but the effects of bisphosphonates on bone metastases in prostate cancer are not known.
  
  
  METHODS
  We performed a randomized double-blind placebo-controlled trial to determine whether a first-generation bisphosphonate could improve symptomatic bone metastasis-free survival (time to symptomatic bone metastases or death from prostate cancer) in men with nonmetastatic prostate cancer who were at high risk of developing bone metastases. Between June 1, 1994, and December 31, 1997, 508 men from 26 UK sites and one New Zealand site who were within 3 years of initial prostate cancer diagnosis with no evidence of metastases from current bone scanning were randomly assigned to daily oral sodium clodronate (2080 mg/day, n = 254) or placebo (n = 254) for a maximum of 5 years. Estimates of outcome risks were compared using Kaplan-Meier analyses.
  
  
  RESULTS
  The groups allocated to each treatment were well balanced. After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of bone metastases-free survival (clodronate versus placebo, 80 events versus 68 events; hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.88 to 1.68) or overall survival (clodronate versus placebo, 130 deaths versus 127 deaths; HR = 1.02; 95% CI = 0.80 to 1.30). Adverse events, notably gastrointestinal problems and increased lactate dehydrogenase levels, were more frequent in the clodronate group than in the placebo group; otherwise, clodronate was well tolerated. Modification of trial drug dose was more frequent in the clodronate group than the placebo group (HR = 1.63, 95% CI = 1.21 to 2.19).
  
  
  CONCLUSIONS
  Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer.
authors.affiliation: Velindre Hospital, Department of Oncology & Palliative Medicine, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Mason
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.forename: John
authors.initials: J
authors.lastname: Glaholm
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Langley
authors.forename: Robert A
authors.initials: RA
authors.lastname: Huddart
authors.forename: Michael
authors.initials: M
authors.lastname: Sokal
authors.forename: Mark
authors.initials: M
authors.lastname: Stott
authors.forename: Anne C
authors.initials: AC
authors.lastname: Robinson
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: James
authors.forename: Mahesh K B
authors.initials: MK
authors.lastname: Parmar
authors.forename: David P
authors.initials: DP
authors.lastname: Dearnaley
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004002:Clodronic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy; D018450:Disease Progression; D004311:Double-Blind Method; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011878:Radiotherapy
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004002:Clodronic Acid