title: Intermittent hormonal therapy in the treatment of metastatic prostate cancer: a randomized trial.
abstract: Study Type - Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Intermittent androgen deprivation therapy (ADT) involves cycling ADT, allowing hormonal recovery during off-treatment periods. This could lead to a better quality of life during off-treatment periods and could delay progression to castration resistance. Safety and feasibility of intermittent ADT have been shown but tolerability and health-related quality of life improvement have been suggested but questioned by others. Results from randomized trials, including relapsing or mixed populations, have suggested intermittent ADT to be as effective as continuous ADT. In this study of only metastatic patients, no statistical difference in either overall survival or progression-free survival was shown between intermittent and continuous ADT and suggests that intermittent might be as safe as continuous castration. It could be an option in highly responding and well-informed metastatic patients even if no clear benefit in health-related quality of life was shown. This intermittent modality could be of interest in metastatic patients with significant treatment-induced side-effects.
  
  
  OBJECTIVE
  • To compare intermittent androgen deprivation therapy (ADT) and continuous ADT after 6 months of induction of ADT in patients with metastatic prostate cancer (PCa).
  
  
  METHODS
  • This is an open-label randomized multi-centre study conducted in 58 centres in Europe. • Patients with metastatic PCa and prostate-specific antigen (PSA) level >20 ng/mL at selection were randomized after 6 months of induction of ADT (leuprorelin and flutamide) if PSA level had decreased below 4 ng/mL. • Patients received either continuous or intermittent ADT. All patients were treated until signs of disease progression under treatment or until study end with a monthly central PSA determination and follow-up visits were performed every 3 months. • The primary endpoint was overall survival. Secondary endpoints included progression-free survival, health-related quality of life (QLQ C30 questionnaire) and safety criteria.
  
  
  RESULTS
  • Of 383 selected patients, 173 had a PSA level below 4 ng/mL after 6 months of induction of ADT and were randomized. Median overall survival (52 vs 42 months, P= 0.75) and median progression-free survival (15.1 vs 20.7 months, P= 0.74) were not significantly different between continuous and intermittent ADT. • Although some differences in quality of life were observed, most of the functional and symptom scales showed no significant difference between the two groups. • Significantly fewer treatment-emergent adverse events occurred in the intermittent group (P= 0.042), with the incidence of headache and hot flushes also lower.
  
  
  CONCLUSIONS
  • This first randomized trial comparing continuous with intermittent ADT in metastatic PCa suggests that intermittent ADT might be as safe as continuous ADT. • It could be an option in highly responding and well-informed patients even if no clear benefit in health-related quality of life was shown.
authors.affiliation: Département d'Urologie, Clinique Mutualiste de la Loire, Saint-Etienne, France. nmottet@mutualite-loire.com
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mottet
authors.forename: Jean
authors.initials: J
authors.lastname: Van Damme
authors.forename: Salim
authors.initials: S
authors.lastname: Loulidi
authors.forename: Christoph
authors.initials: C
authors.lastname: Russel
authors.forename: Armin
authors.initials: A
authors.lastname: Leitenberger
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Wolff
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000368:Aged; D000726:Androgen Antagonists / Q000008:administration & dosage*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005485:Flutamide / Q000008:administration & dosage*; D006801:Humans; D053208:Kaplan-Meier Estimate; D016729:Leuprolide / Q000008:administration & dosage*; D008297:Male; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D013607:Tablets; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D013607:Tablets; D005485:Flutamide; D016729:Leuprolide