Celebrex Before Prostate Surgery Ineffective, Study
Monday, October 05 2009 13:09
NSAID Made No Difference to Cancer Growth
To see whether Celebrex (celecoxib) can reduce prostate cancer size and spread, a team from several leading US cancer centers led by Dr. Alan Partin and Dr. Michael Carducci conducted a randomized, double-blind trial enrolling high-risk men before primary treatment with surgery or radiation. They measured the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy on these men.
The trial was conducted because Celebrex, a non-steroidal anti-inflammatory drug (NSAID) used primarily in treatment of conditions like arthritis, is designed to work by targeting and inhibiting Cyclooxygenase-2 (COX-2). COX-2 is of interest, the team explains, as "a potential pharmacologic target for the prevention of various malignancies, including prostate cancer."
As measurements of whether Celebrex controlled the prostate tumors, the investigators decided to focus on markers of prostate cancer progression in biopsy tissue removed from these higher-risk patients after half of the group took relatively high-dose Casodex for several weeks before undergoing surgery.
Patients with localized prostate cancer and Gleason sum of 7 or above, prostate-specific antigen (PSA) at 15 ng/mL or above, 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 measure of interest was difference in prostatic prostaglandin levels between the men who either took or did not receive Casodex. Prostaglandins are arachidonic acid metabolites of COX-2 and are used as biomarkers of tumor invasiveness.
Secondary end points to be measured were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. In addition, the trial aimed to assess drug safety and compliance (ability of the patients to stay on the drug).
RESULTS
Seventy-three patients consented to enroll in the trial. Of these, 64 men were randomly assigned either to take Celebrex or to take a dummy drug and all their results were counted in the final analaysis.
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.
But no treatment differences in any of the primary or secondary outcomes were seen. Statistical analysis 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. Ki-67 is a molecule that can be easily detected in growing cells in order to gain an understanding of the rate at which the cells within a tumor are growing and giving rise to more cancer cells.
The authors conclude: "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."
Psa-rising.com news story reported by Jacquie Strax.
Source and Links
The study was published in Journal of Clinical Oncology, online August 31, 2009.
Abstract
Phase II, Randomized, Placebo-Controlled Trial of Neoadjuvant Celecoxib in Men With Clinically Localized Prostate Cancer: Evaluation of Drug-Specific Biomarkers. Partin AW, Carducci MA, and colleagues.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Brady Urological Institute at Johns Hopkins, Baltimore; National Cancer Institute, Bethesda, MD; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; and Weill Cornell Medical College, New York, NY.
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 >/= 7, prostate-specific antigen (PSA) >/= 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.
Related
Requirement of cyclooxygenase-2 expression and prostaglandins for human prostate cancer cell invasion, William B. Campell et al. Clinical and Experimental Metastasis, 2004)
FATTY ACID EFFECTS ON COX-2 DEPENDENT PROSTATE CANCER, M Failla et al. COLLEGE OF HUMAN ECOLOGY, OHIO STATE UNIVERSITY
The resistance to the tumor suppressive effects of COX inhibitors and COX-2 gene disruption in TRAMP mice is associated with the loss of COX expression in prostate tissue. Xingya Wang, Jennifer K.L. Colby, Peiying Yang, Susan M. Fischer, Robert A. Newman and Russell D. Klein., Carcinogensis, October 2007.
