Methodology for treatment evaluation in patients with cancer metastatic to bone

Background: Patients with cancer metastatic to bone experience several adverse and clinically important skeletal-related events, including pathologic fractures, vertebral compressions with fracture, the need for surgery to treat or prevent fractures, and the need for radiation therapy for the treatment of bone pain. We present appropriate methods for describing and modeling the clinical course of skeletal-related events and comparing treatments for such events. Methods: On the basis of data from a recently completed randomized, placebo-controlled trial involving 380 breast cancer patients with bone metastatases, we tested the validity of the "events-per-person-years" method, one of the most commonly used techniques, for the analysis of skeletal-related events. We then used more robust methods of analysis that are based on fewer assumptions, including a random-effects Poisson model, and contrasted the inferences about skeletal-related event rates and treatment effects for the different analytic methods. All statistical tests were two-sided. Results: The events-per-person-years analysis underestimated substantially the variation in the data and is not appropriate to summarize the incidence rate of skeletal-related events. A random-effects Poisson model did provide a valid basis for analyzing such data. Conclusions: The underestimation of variability in data associated with the use of the events-per-person-years analysis leads to unduly narrow confidence intervals for complication rates and inflated false-positive error rates in treatment comparisons. A random-effects Poisson model provides a valid, robust basis for describing the clinical course of bone complications and evaluating treatment effects.