title: Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial.
abstract: BACKGROUND
  Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.
  
  
  METHODS
  CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.
  
  
  RESULTS
  Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.
  
  
  CONCLUSIONS
  Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.
  
  
  BACKGROUND
  Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.
authors.affiliation: The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK. Electronic address: David.Dearnaley@icr.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Dearnaley
authors.affiliation: Clatterbridge Cancer Centre, Wirral, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Syndikus
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Mossop
authors.affiliation: The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Vincent
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authors.affiliation: Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK.
authors.forename: Alison
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authors.affiliation: Brighton and Sussex University Hospitals, Brighton, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bloomfield
authors.affiliation: Beacon Centre, Musgrove Park Hospital, Taunton, UK.
authors.forename: John
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authors.lastname: Graham
authors.affiliation: Sheffield Teaching Hospitals Foundation Trust, Sheffield, UK.
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authors.lastname: Kirkbride
authors.affiliation: Christie Hospital, Manchester, UK.
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authors.lastname: Logue
authors.affiliation: Clatterbridge Cancer Centre, Wirral, UK.
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authors.affiliation: Royal Surrey County Hospital, Guildford, UK.
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authors.affiliation: Queen's University Belfast, Belfast, UK.
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authors.affiliation: Lincoln County Hospital, Lincoln, UK.
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authors.lastname: Panades
authors.affiliation: The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Chris
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authors.affiliation: Addenbrooke's Hospital, Cambridge, UK.
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authors.affiliation: Ipswich Hospital, Ipswich, UK.
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authors.affiliation: Cardiff University/Velindre Cancer Centre, Cardiff, UK.
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authors.affiliation: University Hospital Coventry, Coventry, UK.
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authors.lastname: Stockdale
authors.affiliation: Brighton and Sussex University Hospitals, Brighton, UK.
authors.forename: Jean
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authors.lastname: Tremlett
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Margaret
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authors.lastname: Bidmead
authors.affiliation: Clatterbridge Cancer Centre, Wirral, UK.
authors.forename: Helen
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authors.lastname: Mayles
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Olivia
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authors.lastname: Naismith
authors.affiliation: Royal Surrey County Hospital, Guildford, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: South
authors.affiliation: The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Annie
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authors.lastname: Gao
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Cruickshank
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Shama
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authors.lastname: Hassan
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Pugh
authors.affiliation: The Institute of Cancer Research, London, UK.
authors.forename: Clare
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authors.affiliation: The Institute of Cancer Research, London, UK.
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mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005500:Follow-Up Studies; D006801:Humans; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D000069473:Radiation Dose Hypofractionation; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome