Abstract
Radical cystectomy for muscle-invasive bladder cancer (MIBC) patients frequently impairs their quality of life (QOL) due to urinary diversion. To improve their QOL, a bladder-sparing alternative strategy using chemoradiation has been developed. In bladder-sparing protocols, complete response (CR) to induction chemoradiation is a prerequisite for bladder preservation and favorable survival. Thus predicting chemoradiation resistance and overcoming it would increase individual MIBC patients' chances of bladder preservation. The aim of this study is to investigate putative molecular targets for treatment aimed at improving chemoradiation response. Expression levels of erbB2, NFκB, p53, and survivin were evaluated immunohistochemically in pretreatment biopsy samples from 35 MIBC patients in whom chemoradiation sensitivity had been pathologically evaluated in cystectomy specimens, and associations of these expression levels with chemoradiation sensitivity and cancer-specific survival (CSS) were investigated. Of the 35 patients, 11 (31%) achieved pathological CR, while tumors in the remaining 24 patients (69%) were chemoradiation-resistant. Multivariate analysis identified erbB2 and NFκB overexpression and hydronephrosis as significant and independent risk factors for chemoradiation resistance with respective relative risks of 11.8 (P = 0.014), 15.4 (P = 0.024) and 14.3 (P = 0.038). The chemoradiation resistance rate was 88.5% for tumors overexpressing erbB2 and/or NFκB, but only 11.1% for those negative for both (P <0.0001). The 5-year CSS rate was 74% overall. Through multivariate analysis, overexpression of erbB2 and/or NFκB was identified as an independent risk factor for bladder cancer death with marginal significance (hazard ratio 21.5, P = 0.056) along with chemoradiation resistance (P = 0.003) and hydronephrosis (P = 0.018). The 5-year CSS rate for the 11 patients achieving pathological CR was 100%, while that for the 24 with chemoradiation-resistant disease was 61% (P = 0.018). Thus, erbB2 and NFκB overexpression are relevant to chemoradiation resistance and are putative targets aimed at overcoming chemoradiation resistance in MIBC.
Highlights
Bladder cancer is the 5th most common cancer in the US, with 70,530 new patients and 14,680 deaths recorded in 2010 [1]
The current study showed that erbB2 and nuclear factor-kB (NFkB) overexpression play a potential role in CRT resistance and are independently associated with unfavorable cancer-specific survival (CSS) with marginal significance in Muscle-invasive bladder cancer (MIBC) patients treated with induction CRT plus cystectomy
This indicates that erbB2 and NFkB are putative therapeutic targets for treatments aimed at improving CRT sensitivity in MIBC
Summary
Bladder cancer is the 5th most common cancer in the US, with 70,530 new patients and 14,680 deaths recorded in 2010 [1]. Radical cystectomy is the reference standard of care for patients with MIBC, but urinary diversion, which must be performed concurrently with radical cystectomy, and postsurgical morbidity potentially compromise patients’ quality of life. To overcome these issues, bladder-sparing approaches with various modalities have been investigated. In most chemoradiotherapy (CRT)-based bladder-sparing protocols, patients who achieve complete response (CR) after induction CRT are selectively subjected to consolidative therapies for bladder preservation, whereas those who do not achieve CR are recommended to undergo radical cystectomy [5]. The ability to predict non-CR patients and the development of a novel strategy to improve their response to CRT would increase the chances of bladder preservation and potentially improve survival outcomes in MIBC patients
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