This randomized, placebo-controlled trial investigated the effects of short-term, neoadjuvant celecoxib on intermediate biomarkers of prostate carcinogenesis. In our population of men with localized disease, 4 to 6 weeks of celecoxib did not significantly alter prostatic levels of various prostaglandins, COX-1/2 mRNA, oxidized DNA bases, Ki-67, p27kip1, p21waf1, or factor VIII, despite achieving measurable tissue concentrations. Moreover, effects on serum PSA were not significantly different between treatment arms.
Because of its unique methodology, this study provided additional important results and aided our understanding of the role of COX enzymes in prostate cancer progression. Multivariable regression analysis showed that COX-1 and -2 expressions were significantly lower in tumor samples than in benign prostate tissue, in contrast to many previous observations.14,15
Tumor tissue also contained lower levels of prostaglandin E2
, 6-keto–prostaglandin F1α
, and oxidized DNA bases and contained higher levels of Ki-67. In addition, a Gleason score ≥ 7 was associated with increased COX-1 and -2 expression. We do not believe this last factor affected interpretation of our results, because the treatment arms were balanced with respect to Gleason grade. Finally, white patients had higher levels of prostaglandins E2
, COX-1 expression, and oxidized DNA bases and had lower levels of p27kip1
Our observations mirror those of a similar randomized trial that evaluated the effect of 4 weeks of neoadjuvant celecoxib on several biologic end points.36
In that single-blinded study involving 45 men with localized prostate cancer (mean Gleason sum, 6.4; mean pretreatment PSA, 8.2 ng/mL), celecoxib therapy resulted in lower levels of prostatic Ki-67 (P
= .04) but did not modulate COX-2 expression or markers of angiogenesis, hypoxia, and apoptosis. Effects on serum PSA were not determined.
Other trials have shown potentially more promising results. In a randomized, placebo-controlled trial of celecoxib given for 6 months to 78 men with PSA-recurrent prostate cancer,37
mean PSA velocity increased by 3% with placebo and decreased by 3% with celecoxib (P
= .02). In a similar, nonrandomized, single-arm study of long-term celecoxib in men with PSA-recurrent disease,38
48% of 40 patients had a stable or declining PSA at 3 months. Celecoxib is also being studied currently in combination with radiation therapy as definitive treatment for localized prostate cancer39
; these results are pending. In addition, a large multi-arm, randomized trial (STAMPEDE)40
currently is recruiting men with advanced/metastatic prostate cancer to evaluate the role of hormone therapy plus celecoxib compared with other treatment arms, including hormone therapy used alone. Finally, celecoxib has been examined in two studies as an adjunct to chemotherapy in patients with castration-resistant prostate cancer (CRPC). In a phase II trial in which twice-monthly docetaxel was combined with daily celecoxib in 48 men with CRPC,41
PSA responses (ie, > 50% PSA decrease) were 46%, and mean time to PSA progression was 9.3 months. In a separate, phase II study of 48 men with CRPC,42
weekly docetaxel and estramustine given together with daily celecoxib produced PSA responses in 58% of men, and the median time to PSA progression was 8.7 months. Although none of these studies are definitive, these data raise the possibility that celecoxib may alter prostate cancer progression by COX-independent mechanisms, a notion that is supported by preclinical observations.33,43
This study had several limitations. Plasma celecoxib levels were not measured; hence, pharmacokinetic analyses could not be performed. We did not evaluate the long-term effects of celecoxib on serum PSA or examine other clinical end points after surgery. The duration of celecoxib treatment may have been too short to result in significant changes in our primary and secondary outcomes.
An additional concern is whether or not celecoxib reached adequate prostatic tissue levels to be able to influence the selected biomarkers. The mean tissue celecoxib concentration in patients receiving celecoxib was 0.16 μmol/L; this is approximately 50 times lower than maximal plasma concentrations, according to prior pharmacokinetic studies.44
This raises the issue of a potential blood-prostate barrier,45,46
capable of inhibiting adequate celecoxib concentrations from reaching the prostate. It also is possible that celecoxib entered the prostate but was unable to penetrate across the luminal side of the glandular epithelium,47
where many of the activated inflammatory cells that express COX-2 reside. In contrast, the tissue celecoxib levels achieved here appear adequate for at least partial COX-2 inhibition.48
Therefore, it seems unlikely that the lack of effect of celecoxib on our study end points was caused mainly by insufficient tissue celecoxib levels.
Recently, there has been concern about the cardiovascular sequelae of COX-2 inhibitors.49
In a trial of colorectal adenoma prevention, a composite cardiovascular end point (ie, cardiovascular death, myocardial infarction, stroke, or heart failure) was 2.9 times higher among 679 patients receiving celecoxib than among 1,356 patients receiving placebo.50
However, a recent, retrospective analysis of celecoxib in 67 men with metastatic CRPC reported four cardiovascular events (ie, myocardial infarction or stroke) in men receiving celecoxib compared with three events in men receiving placebo.51
The potential benefits of celecoxib in patients with prostate cancer should be weighed against the possible increase of cardiovascular toxicities linked to this agent. Notably, there were no cardiovascular events observed in our trial.
In summary, 4 to 6 weeks of neoadjuvant celecoxib (400 mg by mouth twice daily) in patients with localized prostate cancer did not significantly influence any of a number of COX-related biologic markers of prostate cancer progression, despite reaching prostatic tissues. We would caution, therefore, against additional studies to evaluate celecoxib at this dose for the chemoprevention of prostate cancer.