A Double-Blind, Placebo-Controlled, Randomized Trial of Oral Sodium Clodronate for Metastatic Prostate Cancer (MRC PR05 Trial)

• Published in: JNCI : Journal of the National Cancer Institute 2003-09, Vol.95 (17), p.1300-1311
• Main Authors: Dearnaley, David P., Sydes, Matthew R., Mason, Malcolm D., Stott, Mark, Powell, Christopher S., Robinson, Anne C. R., Thompson, Peter M., Moffat, Leslie E., Naylor, Sharon L., Parmar, Mahesh K. B.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aged; Analgesics, Non-Narcotic - administration & dosage; Analgesics, Non-Narcotic - adverse effects; Androgen Antagonists - administration & dosage; Antineoplastic Agents, Hormonal - administration & dosage; Biological and medical sciences; Bone Neoplasms - complications; Bone Neoplasms - drug therapy; Bone Neoplasms - secondary; Clinical trials; Clodronic Acid - administration & dosage; Clodronic Acid - adverse effects; Digestive System - drug effects; Diphosphonates - administration & dosage; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; General and cellular metabolism. Vitamins; Humans; Imidazoles - administration & dosage; Male; Medical research; Medical sciences; Middle Aged; Odds Ratio; Pain - etiology; Pain - prevention & control; Pharmacology. Drug treatments; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - mortality; Prostatic Neoplasms - pathology; Research Design; Survival Analysis; Treatment Outcome; United Kingdom; Zoledronic Acid
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djg038

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.