title: Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16.
abstract: BACKGROUND
  The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial.
  
  
  METHODS
  Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%-90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided.
  
  
  RESULTS
  Three-month PSA level declines of 20%-40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P < .001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy.
  
  
  CONCLUSIONS
  Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.
authors.affiliation: Columbia University, New York, NY 10032, USA. dpp5@columbia.edu
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
authors.forename: Donna Pauler
authors.initials: DP
authors.lastname: Ankerst
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Jiang
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Tangen
authors.forename: Maha H A
authors.initials: MH
authors.lastname: Hussain
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Taplin
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Burch
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Benson
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.forename: Derek
authors.initials: D
authors.lastname: Raghavan
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D003907:Dexamethasone / Q000008:administration & dosage; D000077143:Docetaxel; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D015337:Multicenter Studies as Topic; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000208:ethnology / Q000276:immunology* / Q000401:mortality*; D011237:Predictive Value of Tests; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000208:ethnology / Q000276:immunology* / Q000401:mortality*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D043823:Taxoids; D000077143:Docetaxel; D003907:Dexamethasone; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; D011241:Prednisone