title: Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial.
abstract: BACKGROUND
  How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy.
  
  
  METHODS
  This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475.
  
  
  RESULTS
  Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75-84] vs 62% [57-67]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred.
  
  
  CONCLUSIONS
  Adding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population.
  
  
  BACKGROUND
  French Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.
authors.affiliation: Department of Radiotherapy, Centre Léon Bérard, Lyon, France. Electronic address: christian.carrie@lyon.unicancer.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Carrie
authors.affiliation: Department of Radiotherapy, Clinique Armoricaine, Saint-Brieuc, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Hasbini
authors.affiliation: Department of Radiotherapy, Institut de Cancérologie de la Loire, Saint Priest en Jarez, France.
authors.forename: Guy
authors.initials: G
authors.lastname: de Laroche
authors.affiliation: Department of Radiotherapy, Institut Bergonié, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Richaud
authors.affiliation: Department of Radiotherapy, Centre Hospitalier Universitaire, Poitiers, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Guerif
authors.affiliation: Department of Radiotherapy, Groupe ONCORAD Garonne and Clinique Pasteur, Toulouse, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Latorzeff
authors.affiliation: Department of Radiotherapy, Institut de Cancérologie de l'Ouest René Gauducheau, Saint Herblain, University of Nantes, Nantes, France; INSERM UMR892, Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Supiot
authors.affiliation: Department of Radiotherapy, Centre Marie Curie, Valence, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bosset
authors.affiliation: Department of Radiotherapy, Hôpital Henri Mondor, Créteil, France.
authors.forename: Jean-Léon
authors.initials: JL
authors.lastname: Lagrange
authors.affiliation: Department of Radiotherapy, Institut de Cancérologie de Lorraine Alexis Vautrin, Nancy, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Beckendorf
authors.affiliation: Department of Radiotherapy, Centre François Baclesse, Caen, France.
authors.forename: François
authors.initials: F
authors.lastname: Lesaunier
authors.affiliation: Radiation Oncology and Medical Physics, QuantIF LITIS (EA4108), Centre Henri Becquerel, Rouen, France; Rouen University Hospital, University of Rouen, Rouen, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Dubray
authors.affiliation: Department of Radiotherapy, Centre de Radiothérapie, Strasbourg, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Wagner
authors.affiliation: Department of Radiotherapy, Institut Jean Godinot, Reims, France.
authors.forename: Tan Dat
authors.initials: TD
authors.lastname: N'Guyen
authors.affiliation: Department of Radiotherapy, Centre Hospitalier, Roanne, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Suchaud
authors.affiliation: Department of Radiotherapy, Centre George-François Leclerc, Dijon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Créhange
authors.affiliation: Department of Radiotherapy, Centre Catalan d'oncologie, Perpignan, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barbier
authors.affiliation: R&D, Unicancer, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Habibian
authors.affiliation: Direction of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Ferlay
authors.affiliation: Department of Radiotherapy, Centre Hospitalier Métropole Savoie, Chambéry, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Fourneret
authors.affiliation: Department of Urology, Hôpital Lyon Sud, Pierre Bénite, Lyon, France; Cancer Research Centre of Lyon, INSERM 1052 CNRS 5286, Lyon 1 University, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Ruffion
authors.affiliation: Direction of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dussart
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D003131:Combined Modality Therapy; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy / Q000532:radiotherapy* / Q000601:surgery; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000532:radiotherapy* / Q000601:surgery; D020266:Radiotherapy, Conformal; D016879:Salvage Therapy; D015996:Survival Rate
chemical_list: D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen