title: Intermittent versus continuous androgen deprivation in prostate cancer.
abstract: BACKGROUND
  Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence.
  
  
  METHODS
  Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization.
  
  
  RESULTS
  A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events.
  
  
  CONCLUSIONS
  Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).
authors.affiliation: University of Michigan, Division of Hematology/Oncology, 1500 E Medical Center Dr., 7314 CC, Ann Arbor, MI 48109-0946, USA. mahahuss@umich.edu
authors.forename: Maha
authors.initials: M
authors.lastname: Hussain
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Tangen
authors.forename: Donna L
authors.initials: DL
authors.lastname: Berry
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Stephen
authors.initials: S
authors.lastname: Prescott
authors.forename: Subramanian
authors.initials: S
authors.lastname: Kanaga Sundaram
authors.forename: Eric Jay
authors.initials: EJ
authors.lastname: Small
authors.forename: Nancy Ann
authors.initials: NA
authors.lastname: Dawson
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Donnelly
authors.forename: Peter M
authors.initials: PM
authors.lastname: Venner
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.forename: Paul F
authors.initials: PF
authors.lastname: Schellhammer
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Derek
authors.initials: D
authors.lastname: Raghavan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ely
authors.forename: Carol M
authors.initials: CM
authors.lastname: Moinpour
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Ian M
authors.initials: IM
authors.lastname: Thompson
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000008:administration & dosage*; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects; D016001:Confidence Intervals; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017273:Goserelin / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D010410:Penile Erection / Q000187:drug effects; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011788:Quality of Life; D016019:Survival Analysis; D014105:Tosyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014105:Tosyl Compounds; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone; C053541:bicalutamide; D017430:Prostate-Specific Antigen
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