A blinded, randomized controlled trial of neo-adjuvant celecoxib in patients with early prostate cancer

Abstract

4563 Background: Celecoxib inhibits tumorigenesis in many in vitro and in vivo models by anti-angiogenesis, induction of apoptosis, and inhibition of tumour cell proliferation and hypoxia. Methods: 45 cT1–2 prostate cancer patients were block randomized 2:1 to four weeks celecoxib 400mg b.d. or no drug prior to radical prostatectomy (RP). Tumour immunohistochemistry was performed for cell proliferation (Ki-67), angiogenesis (CD-31, VEGF, VEGF-R2), hypoxia (HIF-1), apoptosis (TUNEL), and COX-2. All scoring was performed blind by PS and a random 20% were validated blindly by an immunopathologist (SBF). In 19 patients (12 celecoxib-treated, 7 control), peri-operative peripheral zone biopsies were subjected to cDNA microarray analysis to identify differences in gene expression profiling (GEP) between the groups. Results: There was ‘substantial’ (kappa >0.6) or ‘almost perfect’ (kappa >0.8) inter-observer agreement in immunoscoring for all stains. Baseline scores were not significantly different between the celecoxib and control groups. In the celecoxib group, RP scores were significantly lower for Ki-67 (p = 0.036), and non-significantly lower for hypoxia (p = 0.15), KDR (p = 0.16), COX-2 (p = 0.19), microvessel density (p = 0.53), and VEGF (p = 0.83); tumour apoptosis was non-significantly higher (p = 0.26). MANOVA of the full model of stains showed that the difference between the two groups approached statistical significance (p = 0.058), and this was visualized with principal component analysis. GEP revealed that 76 genes were significantly differentially expressed between the celecoxib and control groups using uncorrected t-tests. In the celecoxib group, the tumour suppressor gene p73 and genes associated with protection against oxidative stress were significantly up-regulated; genes associated with cell adhesion were significantly down-regulated, consistent with a reduction in metastatic potential. Conclusions: Celecoxib appears to have marked anti-cancer effects on prostate tumours, most notably affecting cell cycle regulation, oxidative stress, and cell signalling. It may therefore be a promising agent in the management of prostate cancer and warrants further investigation. No significant financial relationships to disclose.