Oral clodronate for adjuvant treatment of operable breast cancer: Results of a randomized, double-blind, placebo-controlled multicenter trial

Abstract

528 Background: The bisphosphonate clodronate (Bonefos) may reduce the incidence of bone metastases by inhibiting tumor-induced osteoclastic resorption of bone. Methods: This randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of oral clodronate in 1,069 patients with primary operable stage I-III breast cancer from 1989–2000. Patients received oral clodronate (1600 mg/day) or placebo for 2 years, starting within 6 months of primary treatment (surgery, radiotherapy, and tamoxifen). Ad hoc analyses from this study have been published previously (Powles et al. JCO 2002), and the unpublished protocol-specified results and ad hoc analysis of stage II/III patients are reported here. The protocol-specified primary endpoint was time to first bone metastasis during the 5-year study period. The secondary endpoint was overall survival. These endpoints were analyzed by unstratified Log-rank test and hazard ratio (HR) with 95% CI. Results: Patient demographics were similar between treatment groups. Oral clodronate significantly reduced the risk of bone metastases by 45% in all patients during the medication period (2 years: HR = 0.546, P = 0.031), and by 31% during the study period (5 years: HR = 0.692, P = 0.043) compared to placebo. Similarly, clodronate significantly reduced the risk of bone metastases in patients with stage II/III disease during the medication (2 years: 50%, HR = 0.496, P = 0.020) and study (5 years: 41%, HR = 0.592, P = 0.009) periods. Oral clodronate vs. placebo significantly improved overall survival (23% reduction in risk of death: HR = 0.768, P = 0.048) and survival for stage II/III patients (26% reduction in risk of death: HR = 0.743, P = 0.041). Oral clodronate was well tolerated, with mild-to-moderate diarrhea being the most frequently reported adverse event. Conclusion: In patients with primary operable breast cancer, oral clodronate significantly reduced the risk of bone metastases and significantly improved survival rates during the medication and 5-year study periods compared to placebo. Similar results were seen in stage II/III patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering OY Schering AG Schering AG; Schering Oy Leiras Oy