title: Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial.
abstract: BACKGROUND
  The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up.
  
  
  METHODS
  RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b-T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3-6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397.
  
  
  RESULTS
  Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1-10·8). Overall survival at 10 years was 71% (95% CI 66-75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77-1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38-48) in the control group and 55% (50-61) in the escalated-dose group (HR 0·69, 95% CI 0·56-0·84; p=0·0003).
  
  
  CONCLUSIONS
  At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects.
  
  
  BACKGROUND
  UK Medical Research Council.
authors.affiliation: The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London and Sutton, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Dearnaley
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Gordana
authors.initials: G
authors.lastname: Jovic
authors.affiliation: Clatterbridge Centre for Oncology, Wirral, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Syndikus
authors.affiliation: The Royal Marsden NHS Foundation Trust, London and Sutton, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Khoo
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cowan
authors.affiliation: Musgrove Park Hospital, Taunton, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Graham
authors.affiliation: Mount Vernon Hospital, Northwood, UK.
authors.forename: Edwin G
authors.initials: EG
authors.lastname: Aird
authors.affiliation: St James University Hospital, Leeds, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bottomley
authors.affiliation: The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London and Sutton, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Huddart
authors.affiliation: Auckland Hospital, Auckland, New Zealand.
authors.forename: Chakiath C
authors.initials: CC
authors.lastname: Jose
authors.affiliation: Auckland Hospital, Auckland, New Zealand.
authors.forename: John H L
authors.initials: JH
authors.lastname: Matthews
authors.affiliation: Alfred Health, Melbourne, VIC, Australia.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Millar
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: J Martin
authors.initials: JM
authors.lastname: Russell
authors.affiliation: Ipswich Hospital, Ipswich, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Scrase
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Mahesh K B
authors.initials: MK
authors.lastname: Parmar
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK. Electronic address: mrcctu.trial-rt01@ucl.ac.uk.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D006801:Humans; D057194:Intention to Treat Analysis; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000401:mortality; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen