Long term outcomes of radical radiotherapy with hypoxia modification with biomarker discovery for stratification: Ten year update of the BCON (Bladder CarbOgen Nicotinamide) phase III randomised trial (ISRCTN45938399).

Abstract Background Many muscle invasive bladder cancers are hypoxic which limits efficacy of radiotherapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase III trial, XXXX. We present mature follow up with biomarker prediction of outcome. Patients and Methods XXXX is a prospective phase III multicentre randomised two arm non-blind clinical trial. Randomisation was to a control arm receiving radical radiotherapy alone or with the addition of carbogen (98% O2, 2% CO2) and nicotinamide (CON). Patients with muscle invasive or high grade non muscle invasive bladder cancer were included. Tumour tissue was collected at entry and has been analysed for tumour necrosis, hypoxia (24-gene signature) and basal and luminal tumour molecular subtypes. Overall and disease free survival and relationships with biomarker status outcome are analysed using multivariable Cox regression and log-rank analysis. Results 333 patients with a median follow up of 10.3 years were analysed. 10-year OS rates were 30% (95% CI 0.23-0.39) in RT+CON patients and 24% (95% CI 0.18-0.33) in the RT alone patients (HR = 0.80; 95% CI: 0.61-1.04; p=0.08). Greatest benefit from CON is seen in patients with tumour necrosis (n=79; 5 yr OS 53% v 33%; HR 0.59; 95% CI 0.36-0.99; p=0.04). The results for high hypoxia gene score (n=75) were 5 yr OS 51% v 34%; HR 0.64; 95% CI 0.38-1.08; p=0.09 and molecular subtype basal (n=70) were 5 yr OS 58% vs 38%; HR 0.58; 95% CI 0.32-1.06; p=0.08. Conclusions Although the improvement in long term overall survival in the whole population is not statistically significant, patients selected by necrosis and a high hypoxia gene score benefitted from hypoxia modification.