title: Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial.
abstract: BACKGROUND
  Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer.
  
  
  METHODS
  We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3-T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m(2) and estramustine 10 mg/kg per day on days 1-5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov, number NCT00055731.
  
  
  RESULTS
  We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1-9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55-69) in the ADT plus docetaxel and estramustine group versus 50% (44-57) in the ADT only group (adjusted hazard ratio [HR] 0·71, 95% CI 0·54-0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 [13%] of 207 vs 22 [11%] of 206; p=0·57), and there were no treatment-related deaths.
  
  
  CONCLUSIONS
  Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival.
  
  
  BACKGROUND
  Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.
authors.affiliation: Institut Gustave Roussy, Villejuif, France. Electronic address: karim.fizazi@gustaveroussy.fr.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Centre François Baclesse, Caen, France.
authors.forename: François
authors.initials: F
authors.lastname: Lesaunier
authors.affiliation: Institut de Cancérologie de l'Ouest, Angers, France.
authors.forename: Remy
authors.initials: R
authors.lastname: Delva
authors.affiliation: Institut Paoli Calmettes, Marseille, France.
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rolland
authors.affiliation: Centre Hospitalier Départemental, La Roche-sur-Yon, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Priou
authors.affiliation: Centre Antoine Lacassagne, Nice, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Centre Hospitalier de Nimes, Nimes, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Houede
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Mourey
authors.affiliation: Hôpital Foch, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Theodore
authors.affiliation: Centre Alexis Vautrin, Nancy, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Krakowski
authors.affiliation: Clinique Sainte-Marguerite, Hyères, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Berdah
authors.affiliation: Centre Hospitalier La Timone, Marseille, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Baciuchka
authors.affiliation: Centre Eugène Marquis, Rennes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laguerre
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Fléchon
authors.affiliation: Hôpital Saint-André, Bordeaux, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cojean-Zelek
authors.affiliation: Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.affiliation: CHU Dupuytren, Limoges, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Labourey
authors.affiliation: Centre Henri Becquerel, Rouen, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Chinet-Charrot
authors.affiliation: Centre Médical Oncogard, Nimes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Legouffe
authors.affiliation: Hôpital Henri-Mondor, Créteil, France.
authors.forename: Jean-Léon
authors.initials: JL
authors.lastname: Lagrange
authors.affiliation: Hôpital Bretonneau, Tours, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Linassier
authors.affiliation: Hôpital Saint-Joseph, Paris, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Deplanque
authors.affiliation: Institut Curie, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beuzeboc
authors.affiliation: Clinique Sainte-Catherine, Avignon, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Davin
authors.affiliation: Unicancer, Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Martin
authors.affiliation: Unicancer, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Habibian
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Laplanche
authors.affiliation: Hôpital Saint-Louis, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Culine
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004961:Estramustine / Q000008:administration & dosage; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000473:pathology; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D017430:Prostate-Specific Antigen