title: Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series.
abstract: Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT).
  
  
  
  To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT.
  
  
  
  Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level ≤0.5ng/ml.
  
  
  
  We compared aRT versus observation followed by esRT.
  
  
  
  The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (≤6, 7, or ≥8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis).
  
  
  
  Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population.
  
  
  
  At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.
  
  
  
  At long-term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT.
authors.affiliation: Division of Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy. Electronic address: nicola.fossati@gmail.com.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fossati
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Boorjian
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Moschini
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morlacco
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Institute, Villejuif, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bossi
authors.affiliation: Department of Radiation Oncology, Gustave Roussy Institute, Villejuif, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seisen
authors.affiliation: Department of Radiotherapy; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Cozzarini
authors.affiliation: Department of Radiotherapy; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiorino
authors.affiliation: Department of Radiotherapy; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Noris Chiorda
authors.affiliation: Division of Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gandaglia
authors.affiliation: Division of Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Dell'Oglio
authors.affiliation: University Hospitals Leuven, Department of Urology, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Joniau
authors.affiliation: University Hospitals Leuven, Department of Urology, Leuven, Belgium.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Tosco
authors.affiliation: Department of Urology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.
authors.forename: Shahrokh
authors.initials: S
authors.lastname: Shariat
authors.affiliation: Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Goldner
authors.affiliation: Department of Radiation Oncology, Charité Universitätsmedizin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hinkelbein
authors.affiliation: Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Bartkowiak
authors.affiliation: University Hospitals Leuven, Department of Radiotherapy, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.affiliation: Department of Urology, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tombal
authors.affiliation: Division of Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.affiliation: University Hospitals Leuven, Department of Urology, Leuven, Belgium.
authors.forename: Hein
authors.initials: H
authors.lastname: Van Poppel
authors.affiliation: Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiegel
authors.affiliation: Division of Oncology/Unit of Urology; URI; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Briganti
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D000368:Aged; D018572:Disease-Free Survival; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D011471:Prostatic Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D012307:Risk Factors; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D062606:Tertiary Care Centers; D013997:Time Factors; D061665:Time-to-Treatment; D016896:Treatment Outcome; D057832:Watchful Waiting
chemical_list: C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Adjuvant; Prostatic neoplasms; Radiation therapy; Salvage therapy