Oral sodium clodronate for non-metastatic prostate cancer - results of a randomized double-blind placebo-controlled trial: Medical Research Council PRO4 (ISRCTN61384873)

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 [Cl] = 0.88 to 1.68) or overall survival (clodronate versus placebo, 130 deaths versus 127 deaths; HR = 1.02; 95% Cl = 0.80 to 1.30). Adverse events, notably gastrointestinal problems and increased lactate clehydrogenase 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% Cl = 1.21 to 2.19). Conclusion Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer.