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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2691-2693 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.9709
Cyclooxygenase-2 Selective Inhibitors and Prostate Cancer: What Is the Clinical Benefit?Departments of Medicine, Cell-Developmental Biology, and Cancer Biology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN In this issue of the Journal of Clinical Oncology, Smith et al1 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.2 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.3 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.4 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.5 The PSA doubling time (PSADT) is thought to be a better predictor of eventual recurrence than the preoperative PSA, Gleason grade, or pathologic stage.6 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.7 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
The results of the clinical trial by Smith et al1 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 gastrointestinal side effects and the use of selective COX-2 inhibitors daily (> 12 months) is associated with increased cardiovascular side effects. Clearly, the risk versus the benefit of any intervention needs to be carefully considered before initiation of therapy. In those individuals in whom we can predict an almost certain recurrence of disease, the benefit of a chemopreventive agent might justify its use even if it is associated with other adverse effects. In men who have very little or no risk for disease recurrence, then the potential for adverse effects of COX-2 inhibitors is probably too high to recommend their use. As our ability to predict the course of this disease improves (ie, risk for recurrence) using modern technologies such as proteomic, genomic, or lipidomic profiling, the aggressiveness of our clinical intervention can be modified accordingly so that we reduce the harm we might do to the patient and maximize the beneficial effects of any intervention we recommend. However, all patients need to realize that most medications, when given chronically or in higher dosages, are associated with adverse effects. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Smith MR, Manola J, Kaufman D, et al: Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol 24:2723-2728, 2006 2. Solomon SD, McMurray JJ, Pfeffer MA, et al: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071-1080, 2005 3. Pruthi RS, Derksen JE, Moore D: A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib in recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. BJU Int 93:275-278, 2004[CrossRef][Medline] 4. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005 5. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1597, 1999 6. Patel A, Dorey F, Franklin J, et al: Recurrence patterns after radical retropubic prostatectomy: Clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 158:1441-1445, 1997[CrossRef][Medline] 7. Harris RE, Beebe-Donk J, Doss H, et al: Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: A critical review of non-selective COX-2 blockade (review). Oncol Rep 13:559-583, 2005[Medline] 8. Gupta RA, DuBois RN: Colorectal cancer and the cyclooxygenase pathway. Nat Rev Cancer 1:11-21, 2001[CrossRef][Medline] 9. Narayanan BA, Narayanan NK, Pttman B, et al: Adenocarcina of the mouse prostate growth inhibition by celecoxib: Downregulation of transcription factors involved in COX-2 inhibition. Prostate 66:257-265, 2006[CrossRef][Medline] 10. Gupta S, Adhami VM, Subbarayan M, et al: Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 64:3334-3343, 2004 11. Liu HL, Chang SH, Narko K, et al: Over-expression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563-18569, 2001 12. Muller-Decker K, Neufang G, Berger I, et al: Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis. Proc Natl Acad Sci U S A 99:12483-12488, 2002 13. Oshima H, Oshima M, Inaba K, et al: Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. Embo J 23:1669-1678, 2004[CrossRef][Medline] 14. Klein RD, Van Pelt CS, Sabichi AL, et al: Transitional cell hyperplasia and carcinomas in urinary bladders of transgenic mice with keratin 5 promoter-driven cyclooxygenase-2 overexpression. Cancer Res 65:1808-1813, 2005 15. Zha S, Gage WR, Sauvageot J, et al: Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma. Cancer Res 61:8617-8623, 2001 16. Palayoor ST, Arayankalayil MJ, Shoaibi A, et al: Radiation sensitivity of human carcinoma cells transfected with small interfering RNA targeted against cyclooxygenase-2. Clin Cancer Res 11:6980-6986, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
