© 2003 by Oxford University Press
© 2003 Oxford University Press
ARTICLE |
A Double-Blind, Placebo-Controlled, Randomized Trial of Oral Sodium Clodronate for Metastatic Prostate Cancer (MRC PR05 Trial)
Affiliations of authors: D. P. Dearnaley, Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK; M. R. Sydes, S. L. Naylor, M. K. B. Parmar, Cancer Division, Medical Research Council (MRC) Clinical Trials Unit, London, UK; M. D. Mason, Section of Oncology and Palliative Medicine, University of Wales College of Medicine, Velindre Hospital, Cardiff, UK; M. Stott, Department of Urology, Royal Devon and Exeter Hospital, Exeter, UK; C. S. Powell, Department of Urology, Countess of Chester Hospital, Chester, UK; A. C. R. Robinson, Department of Oncology, Southend General Hospital, Southend, UK; P. M. Thompson, Department of Urology, Dartford and Gravesham National Health Service Trust, Dartford, Kent, UK; L. E. Moffat, Department of Urology, Aberdeen Royal Infirmary, Aberdeen, UK.
Correspondence to: Matthew R. Sydes, MSc, Cancer Division, MRC Clinical Trials Unit, London, NW1 2DA, UK (e-mail: pr05{at}ctu.mrc.ac.uk).
Background: The most frequent site of metastases from prostate cancer is bone. Bisphosphonates reduce excessive bone turnover while preserving bone structure and mineralization in patients with other tumor types. We conducted a double-blind, placebo-controlled, randomized trial to determine whether the first-generation bisphosphonate sodium clodronate could improve bone progression–free survival (BPFS) times among men with bone metastases from prostate cancer. Methods: Between June 1994 and July 1998, 311 men who were starting or responding to first-line hormone therapy for bone metastases were randomly assigned to receive oral sodium clodronate (2080 mg/day) or placebo for a maximum of 3 years. The primary endpoint of the trial was symptomatic BPFS. Secondary endpoints included overall survival, treatment toxicity, and change in World Health Organization (WHO) performance status. Time-to-event data were analyzed using the log-rank chi-square test and Kaplan–Meier curves. All statistical tests were two-sided. Results: Baseline characteristics were balanced across the two groups. After a median follow-up of 59 months, the sodium clodronate group showed statistically nonsignificant better symptomatic BPFS (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.61 to 1.02; P = .066) and overall survival (HR = 0.80, 95% CI = 0.62 to 1.03; P = .082) than the control group. Patients in the clodronate group were less likely to have a worsened WHO performance status (HR = 0.71, 95% CI = 0.56 to 0.92; P = .008). However, the clodronate group reported more gastrointestinal problems and increased lactate dehydrogenase levels and required more frequent modification of the trial drug dose (HR for any adverse event = 1.71, 95% CI = 1.21 to 2.41; P = .002). Results of subgroup analyses suggested that clodronate might be more effective the sooner after diagnosis of metastatic bone disease it is started. Conclusion: These results suggest that further studies of the effect of newer generation bisphosphonates on BPFS in men with metastatic prostate cancer are warranted.
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