The use of radiosensitising agents in the treatment of muscle-invasive bladder cancer
Radical radiotherapy is the principal bladder-preserving treatment for muscle-invasive bladder cancer. 70% of muscle-invasive bladder cancers express epidermal growth factor receptor (EGFR), which is associated with poor prognosis. Recent evidence suggests that ionising radiation (IR) stimulates EGFR causing activation of cytoprotective signalling cascades, thereby mediating radioresistance. Tumour tissue from 110 patients who received radical radiotherapy for muscle-invasive bladder cancer was immunohistochemically stained for EGFR. Multivariate analysis assessed the prognostic utility of tumour EGFR status in predicting outcome following radical radiotherapy. The effect of IR on EGFR activation, and also on signalling pathways downstream of EGFR was assessed using Western blotting. Potential inhibition of radiation-induced activation of EGFR was assessed using the two small molecule tyrosine kinase inhibitors (TKI) Iressa and Tarceva. Finally we assessed the activity of TKI as a single agent treatment and in combination with IR, in vitro and in vivo. 72% of tumours stained positively for EGFR and 69% of these exhibited positive response to radiotherapy. Positive response to radiotherapy correlated significantly with negative EGFR status (X2 test; p=0.05). Response to radiotherapy at 3-months, local recurrence, metastatic spread and presence of ureteric obstruction were independent prognostic factors for diminished bladder cancer-specific survival. IR activated EGFR and Iressa partially inhibited this activation. Radiation-induced activation of EGFR activated MAPK and Akt but not STATl. Activation of the MAPK but not Akt was partially inhibited by Iressa. Bladder cancer cells treated with combined TKI and IR exhibited significantly greater growth inhibition in comparison to treatment with either IR or TKI alone both in vitro and in vivo (p=0.001-0.04). IR activates EGFR in bladder cancer cells and this activation is partially inhibited by TKI. Treatment of bladder cancer cells using combined TKI and IR results in significantly greater growth inhibition both in vitro and in vivo. Given the high frequency of EGFR expression by bladder tumours and its importance in local tumour control there is now justification to translate this work into a clinical trial.