Survival-adjusted multiple-event analysis for the evaluation of treatment effects of zoledronic Acid in patients with bone metastases from solid tumors.

Bone metastasis causes significant pain and morbidity and is characterized by multiple skeletal-related events (SREs), including fractures, spinal cord compression, and the requirement for radiation or surgery to bone. Analysis of such a composite endpoint provides insight into the clinical impact of the disease. However, SREs typically occur in a complex pattern. Recently, zoledronic acid (4 mg) was approved for the treatment of bone metastases secondary to all solid tumors and primary bone lesions from multiple myeloma based on significant benefits from first-event and skeletal morbidity rate analyses. However, multiple-event methods can provide information about the risk of SREs over the entire course of follow-up and address interpatient variation in event rates and temporal trends. Moreover, multiple-event methodology can adjust for survival, which has an effect on SRE incidence. Herein we present a survival-adjusted multiple-event analysis of the cumulative incidence of radiation to bone (a homogenous endpoint) and SREs (a composite endpoint) in 3 large, randomized clinical trials of zoledronic acid (4 mg) in patients with prostate cancer, lung cancer and other solid tumors, or breast cancer. In patients with prostate cancer, zoledronic acid significantly reduced the cumulative incidence of SREs compared with placebo (P = 0.002) as it did among patients with lung cancer and other solid tumors (P = 0.025). In patients with breast cancer, zoledronic acid significantly reduced the cumulative incidence of SREs compared with pamidronate 90 mg over 25 months (P = 0.050). These results are consistent with those obtained using established methods, supporting the validity of the survival-adjusted cumulative mean function for assessing benefits during bisphosphonate therapy.