title: Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer.
abstract: BACKGROUND
  Intermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for nonmetastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described.
  
  
  METHODS
  Men with nonmetastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable off-treatment interval; AD was resumed when prostate specific antigen (PSA) reached a prespecified value (1 ng/mL, radical prostatectomy; 4 ng/mL, intact prostate). Cycles were repeated until castration resistance (marking the advent of castration-resistant prostate cancer [CRPC]), defined as 2 PSA rises with testosterone (T) ≤ 50 ng/dL. Kinetics and relationships of PSA and T levels were evaluated, with a focus on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality were estimated using Cox proportional hazards models controlling for age and Gleason score.
  
  
  RESULTS
  Each 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3%-36%; P = .02). Longer time (≥ 60 days) to PSA rise after rise to T > 50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation; P = .05). Time to first T > 50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for prostate cancer mortality.
  
  
  CONCLUSIONS
  During the first off-treatment interval of IAD, longer times to PSA rise overall and after T > 50 ng/dL were associated with reduced risk of developing CRPC.
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Kuo
authors.affiliation: Fred Hutchinson Cancer Research Center, Biostatistics and Biomathematics Program, Public Health Sciences Division, Seattle, WA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hunter-Merrill
authors.affiliation: Fred Hutchinson Cancer Research Center, Biostatistics and Biomathematics Program, Public Health Sciences Division, Seattle, WA.
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Oncology, Seattle, WA.
authors.forename: Suzanne P
authors.initials: SP
authors.lastname: Hall
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Oncology, Seattle, WA.
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Gambol
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Oncology, Seattle, WA.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: University of Washington/Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Oncology, Seattle, WA. Electronic address: evanyu@u.washington.edu.
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Yu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005485:Flutamide / Q000008:administration & dosage*; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D064129:Prostatic Neoplasms, Castration-Resistant / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D016019:Survival Analysis; D013739:Testosterone / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D013739:Testosterone; D005485:Flutamide; D017430:Prostate-Specific Antigen; D016729:Leuprolide
keywords: Biochemical Recurrence; Castration-resistant; Overall Survival; Prognosis; Prostate-specific Antigen Kinetics