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Clinical Trial
. 2013 Jul;108(1):40-7.
doi: 10.1016/j.radonc.2013.05.017. Epub 2013 Jun 14.

Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial

Amanda Eustace  1 , Joely J Irlam, Janet Taylor, Helen Denley, Shailesh Agrawal, Ananya Choudhury, David Ryder, Jonathan J Ord, Adrian L Harris, Ana M Rojas, Peter J Hoskin, Catharine M L West
Affiliations
Clinical Trial

Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial

Amanda Eustace et al. Radiother Oncol. 2013 Jul.

Abstract

Background and purpose: 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.

Materials and 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.

Keywords: Biomarker; Bladder cancer; Carbogen and nicotinamide; Hypoxic modification; Necrosis; Radiotherapy.

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Figures

Fig. 1
Fig. 1
CONSORT diagram.
Fig. 2
Fig. 2
H&E-stained bladder cancer section with necrosis. Necrosis is identified by the presence of cell ghosts and is eosinophilic and granular. Original magnification 400×.
Fig. 3
Fig. 3
Kaplan–Meier plots for: (A, C, D) overall survival of BCON patients who received radiotherapy as primary treatment and (B) cancer-specific survival of patients who underwent radical cystectomy as primary treatment . Patients are stratified by the absence or presence of necrosis (A, B), CA-IX score (C) or Glut-1 score (D). Log rank P values and number of patients at risk in each yearly interval are also shown.
Fig. 4
Fig. 4
Kaplan–Meier plots for: overall survival after radiotherapy (RT) alone or with carbogen and nicotinamide (RT + CON) and stratified according to the (A) absence or (B) presence of necrosis, (C) CA-IX score = 0 or (D) >0, or (E) Glut-1 score <100 or (F) ⩾100. Log rank P values and number of patients at risk in each yearly interval are also shown.
See this image and copyright information in PMC

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