Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers

Abstract

Purpose: Cyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy.

Patients and methods: Patients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance.

Results: Seventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities.

Conclusion: Treatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

Fig 1.

CONSORT diagram.

Fig 2.

Tissue levels of celecoxib achieved in the prostate: differences between patients treated with celecoxib and placebo. Tissue celecoxib concentrations are in the log scale. Results are shown as box-and-whisker plots: the height of the box is the interquartile range (IQR), the horizontal line inside the box is the median, and the whiskers extend beyond the upper and lower quartiles by 1.5× IQR. Values lying outside of this range are considered outliers. Open circles denote that outlier values (solid circles) extend beyond the upper and lower quartiles by more than 1.5× IQR.

Fig 3.

The effect of celecoxib compared with placebo on drug-specific biomarkers collected from (A-H) fresh and (I-L) fixed tissues. Biomarker levels are in the log scale. Only prostaglandin (PG) analyses performed with arachidonic acid are shown. Celecoxib did not significantly alter (A-E) tissue PG levels; (F-G) cyclooxygenase (COX) enzyme expression; (H) levels of oxidized DNA bases; or (I) markers of proliferation, (J-K) apoptosis, or (L) angiogenesis. A trend toward statistical significance was seen with the apoptotic marker p21^waf1. TXB₂, thromboxane B₂; 6kPGF_1α, 6-keto PG F_1α; 8-OHdG, 8-hydroxy-2-deoxyguanosine; 2-dG, 2-deoxyguanosine.