title: Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial.
abstract: OBJECTIVE
  Addition of carbogen and nicotinamide (hypoxia-modifying agents) to radiotherapy improves the survival of patients with high risk bladder cancer. The study investigated whether histopathological tumour features and putative hypoxia markers predicted benefit from hypoxia modification.
  
  
  METHODS
  Samples were available from 231 patients with high grade and invasive bladder carcinoma from the BCON phase III trial of radiotherapy (RT) alone or with carbogen and nicotinamide (RT+CON). Histopathological tumour features examined were: necrosis, growth pattern, growing margin, and tumour/stroma ratio. Hypoxia markers carbonic anhydrase-IX and glucose transporter-1 were examined using tissue microarrays.
  
  
  RESULTS
  Necrosis was the only independent prognostic indicator (P=0.04). Necrosis also predicted benefit from hypoxia modification. Five-year overall survival was 48% (RT) versus 39% (RT+CON) (P=0.32) in patients without necrosis and 34% (RT) versus 56% (RT+CON) (P=0.004) in patients with necrosis. There was a significant treatment by necrosis strata interaction (P=0.001 adjusted). Necrosis was an independent predictor of benefit from RT+CON versus RT (hazard ratio [HR]: 0.43, 95% CI 0.25-0.73, P=0.002). This trend was not observed when there was no necrosis (HR: 1.64, 95% CI 0.95-2.85, P=0.08).
  
  
  CONCLUSIONS
  Necrosis predicts benefit from hypoxia modification in patients with high risk bladder cancer and should be used to select patients; it is simple to identify and easy to incorporate into routine histopathological examination.
authors.affiliation: Translational Radiobiology Group, Institute of Cancer Sciences, The University of Manchester, Manchester Academic Health Centre, Christie Hospital, Manchester, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Eustace
authors.forename: Joely J
authors.initials: JJ
authors.lastname: Irlam
authors.forename: Janet
authors.initials: J
authors.lastname: Taylor
authors.forename: Helen
authors.initials: H
authors.lastname: Denley
authors.forename: Shailesh
authors.initials: S
authors.lastname: Agrawal
authors.forename: Ananya
authors.initials: A
authors.lastname: Choudhury
authors.forename: David
authors.initials: D
authors.lastname: Ryder
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Ord
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.forename: Ana M
authors.initials: AM
authors.lastname: Rojas
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hoskin
authors.forename: Catharine M L
authors.initials: CM
authors.lastname: West
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002245:Carbon Dioxide / Q000627:therapeutic use*; D030741:Carbonic Anhydrase IV / Q000032:analysis; D015687:Cell Hypoxia; D005260:Female; D051272:Glucose Transporter Type 1 / Q000032:analysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009536:Niacinamide / Q000627:therapeutic use*; D010100:Oxygen / Q000627:therapeutic use*; D012306:Risk; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D002245:Carbon Dioxide; D009536:Niacinamide; C011700:carbogen; D030741:Carbonic Anhydrase IV; D010100:Oxygen
keywords: Biomarker; Bladder cancer; Carbogen and nicotinamide; Hypoxic modification; Necrosis; Radiotherapy