Cyclooxygenase-2 selective inhibitors and prostate cancer: what is the clinical benefit?

In this issue of the Journal of Clinical Oncology, Smith et al report that celecoxib use may reduce the mean prostate-specific antigen (PSA) velocity in men after a radical prostatectomy. However, the study was terminated prematurely due to concerns over the cardiovascular risks associated with cyclooxygenase-2 (COX-2) selective inhibitors. Despite this caveat, 78 patients were enrolled onto this study, which was a prospective, randomized, placebo-controlled clinical trial with optional cross-over at 6 months. Mean PSA velocity increased by 3.0% in the placebo group and decreased by 3.4% in the celecoxib group (P .02). These results could have been predicted from the results of an earlier pilot study of 12 patients, which evaluated similar end points following celecoxib treatment. The death toll from prostate cancer is high, making it an attractive target for prevention of recurrent disease. In 2005, more than 230,000 new cases of prostate cancer were diagnosed, resulting in more than 30,000 deaths. Eighty percent of cases involve localized disease, for which the treatment most often includes a radical prostatectomy or radiation therapy. A significant number of these patients (25% to 50%) will experience disease recurrence following treatment. PSA levels are usually measured serially following therapy, and a rising PSA is used as an indication of recurrent disease. Based on past experience, the median time to metastasis is about 8 years following the time at which a PSA elevation is observed. The PSA doubling time (PSADT) is thought to be a better predictor of eventual recurrence than the preoperative PSA, Gleason grade, or pathologic stage. Thus, men who present with a rising PSA after a radical prostatectomy, without measurable clinical disease, provide a great opportunity for testing agents that might be effective in delaying or preventing disease recurrence. Use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with a decreased risk of a number of malignancies. Daily intake of NSAIDs, primarily aspirin, results in risk reductions of 63% for colon cancer, 39% for breast cancer, 36% for lung cancer, and 39% for prostate cancer. Over the last decade, a key development for treatment of patients with arthritis and pain was the identification of selective COX-2 inhibitors. It has been postulated that the adverse effects of nonselective NSAIDs, such as peptic ulceration, gastrointestinal bleeding, and perforation, are mainly due to the inhibition of COX-1, while selective inhibition of COX-2 results in the anti-inflammatory activity with fewer gastrointestinal adverse effects. We now know that this claim is a gross oversimplification. Selective COX-2 inhibitors include rofecoxib (Vioxx; Merck & Co Inc, Whitehouse Station, NJ), celecoxib (Celebrex; Pfizer Inc, New York, NY), valdecoxib (Bextra; Pfizer Inc), and lumiracoxib (Prexige; Novartis Pharmaceuticals Corp, Basel, Switzerland). At the time of this publication, only celecoxib is available for clinical use in the United States. COX-2 inhibitors represent a novel class of compounds that have been shown to have potent anti-inflammatory and antihyperalgesic activity in animal models of arthritis and inflammatory pain. The COX-2 enzyme has also been shown to be involved in some aspects of cancer biology and is known to promote cancer development in certain mouse models. Cyclooxygenase enzymes (COX-1 or COX-2) catalyze the rate-limiting step in prostaglandin synthesis, which is the conversion of arachidonic acid to PGH2. PGH2 serves as a substrate for prostaglandin synthases, which produce individual bioactive lipid products such as PGE2, PGI2, PGF2 , PGD2, or TXA2 (see Fig 1). COX-2 expression is highly inducible and regulated by a number of inflammatory or mitogenic stimuli, such as bacterial lipopolysaccharides, proinflammatory cytokines (IL-1 , IL-2), tumor necrosis factor, growth factors, and androgens. Prostaglandins generated at sites of inflammation mediate a variety of responses to tissue injury and hypoxia, including inhibition of apoptosis, cell growth, increased cell migration, inhibition of the immune response, and stimulation of angiogenesis. Treatment of mice that develop prostate cancer (TRAMP model) with celecoxib results in a suppression of tumor growth and decreased metastatic spread of disease. Transgenic mice programmed to express COX-2 in the breast, stomach, skin, or bladder have an extremely high risk of developing tumors of each respective organ. Thus, the presence of COX-2 is proneoplastic in some contexts. The prostate lesion known as proliferative inflammatory atrophy (PIA), in which epithelial proliferation arises in atrophic foci, is associated with high levels of COX-2 expression. The presence of COX-2 in other prostatic lesions, including cancer, is somewhat controversial. The results of the clinical trial by Smith et al confirm that celecoxib does seem to inhibit rising PSA levels in men who have undergone treatment for prostate cancer. Questions still remain as to whether or not these effects will correlate with an actual decrease in clinical recurrence of prostate cancer. Many concerns exist over the safety of using NSAIDs or selective COX-2 inhibitors in an older population. NSAIDs are known to cause life-threatening JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 18 JUNE 2