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Clinical Pharmacology

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

^aMedical Oncology Branch and ^bSurgical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; ^cDepartment of Biological Chemistry, Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel

Key Words. Bevacizumab • Chemotherapy efficacy • Clear-cell carcinoma • Drug efficacy • Growth rate constant • Premature discontinuation • RECIST • Renal cell carcinoma • Tumor assessment • Tumor measurements

Correspondence: Tito Fojo, M.D., Ph.D., Medical Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Building 10, Room 12N226, 9000 Rockville Pike, Bethesda, Maryland 20892, USA. Telephone: 301-402-1357; Fax: 301-402-1608; e-mail: tfojo{at}helix.nih.gov

Received March 27, 2008; accepted for publication August 13, 2008; first published online in THE ONCOLOGIST Express on September 30, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, or staff managers.

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.

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