Bevacizumab Reduces the Growth Rate Constants of Renal Carcinomas: A Novel Algorithm Suggests Early Discontinuation of Bevacizumab Resulted in a Lack of Survival Advantage

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Abstract
Background.: To hasten cancer drug development, new paradigms are needed to assess therapeutic efficacy. In a randomized phase II study in patients with renal cell carcinoma, 10 μg/kg bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA) administered every 2 weeks resulted in a longer time to progression but a statistically significant difference in overall survival could not be demonstrated. Methods.: We developed a novel two-phase equation to estimate concomitant rates of tumor regression (regression rate constant) and tumor growth (growth rate constant). This method allows us to assess therapeutic efficacy using tumor measurements gathered while a patient receives therapy in a clinical trial. Results.: The growth rate constants of renal cell carcinomas were significantly lower during therapy with 10 μg/kg bevacizumab than those of tumors in patients receiving placebo. In all cohorts the tumor growth rate constants were correlated with survival. That a survival advantage was not demonstrated with bevacizumab appears to have been a result of early discontinuation of bevacizumab. Conclusions.: Single-agent bevacizumab significantly affects the growth rate constants of renal cell carcinoma. Extrapolating from the growth rate constants, we conclude that the failure to demonstrate a survival advantage in the original study was a result of premature discontinuation of bevacizumab. The mathematical model described herein has applications to many tumor types and should aid in evaluating the relative efficacies of different therapies. Quantitating tumor growth rate constants using data gathered while patients are enrolled in a clinical trial, as in the present study, may streamline and assist in drug development.