title: Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy.
abstract: OBJECTIVE
  In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC).
  
  
  METHODS
  Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants.
  
  
  RESULTS
  Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10(-3.17)) relative to single-agent thalidomide (log g = 10(-2.08)) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration.
  
  
  CONCLUSIONS
  Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials.
authors.affiliation: Medical Oncology Branch and Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. tfojo@helix.nih.gov
authors.forename: Wilfred D
authors.initials: WD
authors.lastname: Stein
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.forename: Jeff
authors.initials: J
authors.lastname: Schlom
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Madan
authors.forename: William
authors.initials: W
authors.lastname: Dahut
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Yang-Min
authors.initials: YM
authors.lastname: Ning
authors.forename: Phil M
authors.initials: PM
authors.lastname: Arlen
authors.forename: Doug
authors.initials: D
authors.lastname: Price
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D054547:National Cancer Institute (U.S.); D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D016896:Treatment Outcome; D047368:Tumor Burden; D014481:United States
chemical_list: D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen