This Article Full Text (PDF) Supplemental Data All Versions of this Article: theoncologist.2008-0016v1 13/10/1055    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stein, W. D. Articles by Fojo, T. Search for Related Content PubMed PubMed Citation Articles by Stein, W. D. Articles by Fojo, T.

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: 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.

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.

This article has been cited by other articles:

				J. D. Patel, T. A. Hensing, A. Rademaker, E. M. Hart, M. G. Blum, D. T. Milton, and P. D. Bonomi Phase II Study of Pemetrexed and Carboplatin Plus Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer J. Clin. Oncol., July 10, 2009; 27(20): 3284 - 3289. [Abstract] [Full Text] [PDF]

				W. D. Stein, W. D. Figg, W. Dahut, A. D. Stein, M. B. Hoshen, D. Price, S. E. Bates, and T. Fojo Tumor Growth Rates Derived from Data for Patients in a Clinical Trial Correlate Strongly with Patient Survival: A Novel Strategy for Evaluation of Clinical Trial Data Oncologist, October 1, 2008; 13(10): 1046 - 1054. [Abstract] [Full Text] [PDF]