title: PSA nadir predicts biochemical and distant failures after external beam radiotherapy for prostate cancer: a multi-institutional analysis.
abstract: OBJECTIVE
  To determine the significance of prostate-specific antigen (PSA) nadir (nPSA) and the time to nPSA (T(nPSA)) in predicting biochemical or clinical disease-free survival (PSA-DFS) and distant metastasis-free survival (DMFS) in patients treated with definitive external beam radiotherapy (RT) for clinical Stage T1b-T2 prostate cancer.
  
  
  METHODS
  Nine participating institutions submitted data on 4839 patients treated between 1986 and 1995 for Stage T1b-T2cN0-NxM0 prostate cancer. All patients were treated definitively with RT alone to doses > or =60 Gy, without neoadjuvant or planned adjuvant androgen suppression. A total of 4833 patients with a median follow-up of 6.3 years met the criteria for analysis. Two endpoints were considered: (1) PSA-DFS, defined as freedom from PSA failure (American Society for Therapeutic Radiology and Oncology definition), initiation of androgen suppression after completion of RT, or documented local or distant failure; and (2) DMFS, defined as freedom from clinically apparent distant failure. In patients with failure, nPSA was defined as the lowest PSA measurement before any failure. In patients without failure, nPSA was the lowest PSA measurement during the entire follow-up period. T(nPSA) was calculated from the completion of RT to the nPSA date.
  
  
  RESULTS
  A greater nPSA level and shorter T(nPSA) were associated with decreased PSA-DFS and DMFS in all patients and in all risk categories (low [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level < or =10 ng/mL], intermediate [Stage T1b, T1c, or T2a, Gleason score < or =6, and PSA level >10 but < or =20 ng/mL, or Stage T2b or T2c, Gleason score < or =6, and PSA level < or =20 ng/mL, or Gleason score 7 and PSA level < or =20 ng/mL], and high [Gleason score 8-10 or PSA level >20 ng/mL]), regardless of RT dose. The 8-year PSA-DFS and DMFS rate for patients with nPSA <0.5 ng/mL was 75% and 97%; nPSA > or =0.5 but <1.0 ng/mL, 52% and 96%; nPSA > or =1.0 but <2.0 ng/mL, 40% and 91%; and nPSA > or =2.0 ng/mL, 17% and 73%, respectively. The 8-year PSA-DFS and DMFS rate for patients with T(nPSA) <6 months was 27% and 66%; T(nPSA) > or =6 but <12 months, 31% and 85%; T(nPSA) > or =12 but <24 months, 42% and 94%; and T(nPSA) > or =24 months, 75% and 99%, respectively. A shorter T(nPSA) was associated with decreased PSA-DFS and DMFS, regardless of the nPSA. Both nPSA and T(nPSA) were significant predictors of PSA-DFS and DMFS in multivariate models incorporating clinical stage, Gleason score, initial PSA level, and RT dose. The significance of nPSA and T(nPSA) was supported by landmark analysis, as well as by analysis of nPSA and T(nPSA) as time-dependent covariates. A dose > or =70 Gy was associated with a lower nPSA level and longer T(nPSA) in all risk categories, and a greater dose was significantly associated with greater PSA-DFS and DMFS in multivariate analysis. Regression analysis confirmed that higher clinical stage, Gleason score, and initial PSA were associated with a greater nPSA level.
  
  
  CONCLUSIONS
  The results of this large, multi-institutional analysis of 4833 patients have provided important evidence that nPSA and T(nPSA) after definitive external beam RT are not only predictive of a predominantly PSA endpoint (PSA-DFS), but are also predictive of distant metastasis in all clinical risk categories. Greater RT doses were associated with lower nPSA, longer T(nPSA), and improved PSA-DFS and DMFS.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109-0010, USA. mray@umich.edu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ray
authors.forename: Howard D
authors.initials: HD
authors.lastname: Thames
authors.forename: Larry B
authors.initials: LB
authors.lastname: Levy
authors.forename: Eric M
authors.initials: EM
authors.lastname: Horwitz
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Kupelian
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Martinez
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Michalski
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Pisansky
authors.forename: William U
authors.initials: WU
authors.lastname: Shipley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zelefsky
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Zietman
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Kuban
mesh_terms: D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000473:pathology / Q000532:radiotherapy*; D012016:Reference Values; D012044:Regression Analysis; D017211:Treatment Failure
chemical_list: D017430:Prostate-Specific Antigen