title: Bevacizumab reduces the growth rate constants of renal carcinomas: a novel algorithm suggests early discontinuation of bevacizumab resulted in a lack of survival advantage.
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 microg/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 microg/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.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wilfred D
authors.initials: WD
authors.lastname: Stein
authors.forename: James
authors.initials: J
authors.lastname: Yang
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D003627:Data Interpretation, Statistical; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008954:Models, Biological; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab