title: Gastrointestinal dose-histogram effects in the context of dose-volume-constrained prostate radiation therapy: analysis of data from the RADAR prostate radiation therapy trial.
abstract: OBJECTIVE
  To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint.
  
  
  METHODS
  Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose.
  
  
  RESULTS
  Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding.
  
  
  CONCLUSIONS
  Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning.
authors.affiliation: Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; School of Physics, University of Western Australia, Perth, Western Australia, Australia. Electronic address: Martin.Ebert@health.wa.gov.au.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Ebert
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Kerwyn
authors.initials: K
authors.lastname: Foo
authors.affiliation: Department of Physical Sciences, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: Haworth
authors.affiliation: Joint Department of Physics, Institute of Cancer Research and Royal Marsden National Health Service Foundation Trust, Sutton, Surrey, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gulliford
authors.affiliation: Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
authors.forename: Angel
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; School of Surgery, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Joseph
authors.affiliation: School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: James W
authors.initials: JW
authors.lastname: Denham
mesh_terms: D001003:Anal Canal / Q000528:radiation effects*; D003672:Defecation / Q000502:physiology / Q000528:radiation effects; D003967:Diarrhea / Q000209:etiology; D004307:Dose-Response Relationship, Radiation; D006471:Gastrointestinal Hemorrhage / Q000209:etiology; D006801:Humans; D008297:Male; D010146:Pain / Q000209:etiology; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000150:complications*; D011880:Radiotherapy Planning, Computer-Assisted; D012002:Rectal Diseases / Q000209:etiology; D012007:Rectum / Q000528:radiation effects*; D012044:Regression Analysis