title: A systematic review of hypofractionation for primary management of prostate cancer.
abstract: BACKGROUND
  Technological advances in radiation therapy delivery have permitted the use of high-dose-per-fraction radiation therapy (RT) for early-stage prostate cancer (PCa). Level 1 evidence supporting the safety and efficacy of hypofractionated RT is evolving as this modality becomes more widely utilized and refined.
  
  
  OBJECTIVE
  To perform a systematic review of the current evidence on the safety and efficacy of hypofractionated RT for early-stage PCa and to provide in-context recommendations for current application of this technology.
  
  
  METHODS
  Embase, PubMed, and Scopus electronic databases were queried for English-language articles from January 1990 through June 2014. Prospective studies with a minimum of 50 patients were included. Separate consideration was made for studies involving moderate hypofractionation (doses of 2.5-4Gy per fraction) and extreme hypofractionation (5-10Gy in 4-7 fractions).
  
  
  RESULTS
  Six relatively small superiority designed randomized trials of standard fractionation versus moderate hypofractionation in predominantly low- and intermediate-risk PCa have been published with follow-up ranging from 4 to 8 yr, noting similar biochemical control (5-yr freedom from biochemical failure in modern studies is >80% for low-risk and intermediate-risk patients) and late grade ≥2 genitourinary and gastrointestinal toxicities (between 2% and 20%). Noninferiority studies are pending. In prospective phase 2 studies, extreme hypofractionation has promising 2- to 5-yr biochemical control rates of >90% for low-risk patients. Results from a randomized trial are expected in 2015.
  
  
  CONCLUSIONS
  Moderate hypofractionation has 5-yr data to date establishing safety compared with standard fractionation, but 10-yr outcomes and longer follow-up are needed to establish noninferiority for clinical effectiveness. Extreme hypofractionation is promising but as yet requires reporting of randomized data prior to application outside of a clinical protocol.
  
  
  RESULTS
  Hypofractionation for prostate cancer delivers relatively high doses of radiation per treatment. Prospective studies support the safety of moderate hypofractionation, while extreme fractionation may have greater toxicity. Both show promising cancer control but long-term results of noninferiority studies of both methods are required before use in routine treatment outside of clinical protocols.
authors.affiliation: Department of Radiation Oncology, Duke Cancer Institute, Durham, NC, USA. Electronic address: bridget.koontz@duke.edu.
authors.forename: Bridget F
authors.initials: BF
authors.lastname: Koontz
authors.affiliation: Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bossi
authors.affiliation: Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Cozzarini
authors.affiliation: Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiegel
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: D'Amico
mesh_terms: D001918:Brachytherapy / Q000009:adverse effects; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D000069473:Radiation Dose Hypofractionation; D011832:Radiation Injuries / Q000209:etiology; D012307:Risk Factors; D016896:Treatment Outcome
keywords: Gastrointestinal toxicity; Genitourinary toxicity; Hypofractionation; Prostate cancer; Prostate-specific antigen; Randomized trials; Stereotactic radiation therapy