title: The predictive and prognostic value of tumour necrosis in muscle invasive bladder cancer patients receiving radiotherapy with or without chemotherapy in the BC2001 trial (CRUK/01/004).
abstract: BACKGROUND
  Severe chronic hypoxia is associated with tumour necrosis. In patients with muscle invasive bladder cancer (MIBC), necrosis is prognostic for survival following surgery or radiotherapy and predicts benefit from hypoxia modification of radiotherapy. Adding mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy to radiotherapy improved locoregional control (LRC) compared to radiotherapy alone in the BC2001 trial. We hypothesised that tumour necrosis would not predict benefit for the addition of MMC and 5-FU to radiotherapy, but would be prognostic.
  
  
  METHODS
  Diagnostic tumour samples were available from 230 BC2001 patients. Tumour necrosis was scored on whole-tissue sections as absent or present, and its predictive and prognostic significance explored using Cox proportional hazards models. Survival estimates were obtained by Kaplan-Meier methods.
  
  
  RESULTS
  Tumour necrosis was present in 88/230 (38%) samples. Two-year LRC estimates were 71% (95% CI 61-79%) for the MMC/5-FU chemoradiotherapy group and 49% (95% CI 38-59%) for the radiotherapy alone group. When analysed by tumour necrosis status, the adjusted hazard ratios (HR) for MMC/5-FU vs. no chemotherapy were 0.46 (95% CI: 0.12-0.99; P=0.05, necrosis present) and 0.55 (95% CI: 0.31-0.98; P=0.04, necrosis absent). Multivariable analysis of prognosis for LRC by the presence vs. absence of necrosis yielded a HR=0.89 (95% CI 0.55-1.44, P=0.65). There was no significant association for necrosis as a predictive or prognostic factor with respect to overall survival.
  
  
  CONCLUSIONS
  Tumour necrosis was neither predictive nor prognostic, and therefore MMC/5-FU is an appropriate radiotherapy-sensitising treatment in MIBC independent of necrosis status.
authors.affiliation: Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre; Manchester M20 4BX, UK.
authors.forename: Ananya
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre; Manchester M20 4BX, UK.
authors.forename: Catharine M
authors.initials: CM
authors.lastname: West
authors.affiliation: Clinical Trials and Statistics Unit, Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Nuria
authors.initials: N
authors.lastname: Porta
authors.affiliation: Clinical Trials and Statistics Unit, Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hall
authors.affiliation: Department of Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Manchester, M13 9WL, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Denley
authors.affiliation: Cancer Research Unit, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Carey
authors.initials: C
authors.lastname: Hendron
authors.affiliation: Clinical Trials and Statistics Unit, Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lewis
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Clatterbridge Cancer Centre, Liverpool, L69 3GA, UK.
authors.forename: Syed A
authors.initials: SA
authors.lastname: Hussain
authors.affiliation: Academic Radiotherapy Unit, Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Huddart
authors.affiliation: Cancer Research Unit, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: James
mesh_terms: D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage* / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
chemical_list: C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D016685:Mitomycin; D005472:Fluorouracil