American College of Surgeons 90th Annual Clinical Congress

NEW ORLEANS—A study presented at the 2004 annual Clinical Congress of the American College of Surgeons is the first to show that a commonly prescribed anti-inflammatory agent slowed the progression of recurrent prostate cancer. The rate of increase of prostate specific antigen (PSA), an enzyme that heralds recurrence of prostate cancer, stabilized, slowed, or declined in 22 of 24 men who took the anti-inflammatory drug celecoxib twice a day for a year. "This is the first report of a Cox-2 inhibitor having a therapeutic effect in prostate cancer at any stage of the disease," Raj Pruthi, MD, FACS, assistant professor of surgery, University of North Carolina, Chapel Hill, reported. Cox-2 inhibitors interfere with the action of cycloxygenase-2, an enzyme involved in prostaglandin synthesis, cell proliferation, and angiogenesis in a variety of disease processes.

Dr. Pruthi and his colleagues are beginning to test the Cox-2 inhibitor in other groups of men with prostate cancer. He is planning a study of the drug as adjuvant therapy in men with advanced disease as well as those at high risk for recurrence immediately after surgery. "The studies haven't been done yet, but it is interesting to think about giving a Cox-2 inhibitor to men with advanced disease who were not successfully treated with hormonal therapy. Those are the worst of the worst cases of prostate cancer patients. Even more exciting is to contemplate using the drug as a chemopreventive agent, before a man even gets prostate cancer," Dr. Pruthi said.

Men with recurrent prostate cancer, such as those in the study, typically have no immediate treatment option, he explained. After an operation or radiation therapy, first line treatment for prostate cancer, PSA levels drop to zero because the source of the enzyme, the prostate gland, has been removed. Any rise in PSA following initial treatment therefore reflects the presence of residual disease outside the prostate, which often cannot be targeted with second-line local therapies. Consequently, many men (an estimated 50,000 new men each year in the US) face PSA-recurrent disease with few treatment alternatives.

Although chemotherapy is an effective form of systemic treatment for some cancers, it has had limited value in men with recurrent prostate cancer and is often only reserved for the most advanced (so-called "hormone-resistant") disease. "Men with recurrent prostate cancer don't have symptoms, so you don't want to give them something toxic, like chemotherapy, that has an uncertain benefit," Dr. Pruthi explained.

Typically, the standard of treatment for men with rising PSA levels after surgery, therefore, is to do nothing until patients exhibit clear signs that prostate cancer has spread to distant parts of the body and can be treated with hormones. "By slowing the rate of rise of PSA with a Cox-2 inhibitor, we may be doing these patients a favor. If we can extend the time between PSA recurrence and clinical symptoms from seven or eight years to 10, 12, or 15 years, we may delay the onset of advanced disease and the need for palliative hormonal therapy," Dr. Pruthi explained.

Although the rate of increase of PSA was moderate or high in 17 of the men in the study before treatment, it was slow, stable, or decreased in 22 men who received 400 mg or 800 mg of celecoxib twice a day for three months. At the end of a year of therapy, only one man had a high rate of increase of PSA, and three had a moderate rise in PSA. The remaining 20 men had delayed, stable, or decreased PSA levels.

The use of Cox-2 inhibitors as antitumor medications is being studied by other investigators as treatment for a variety of cancers. According to Dr. Pruthi, 13 National Cancer Institute (NCI)-sponsored studies began exploring Cox-2 inhibitors for colon, prostate, and breast cancer in 2003 and 34 NCI-studies started looking at these drugs for cancers of the head and neck, lung, and bladder in 2004.

Interest in Cox-2 inhibitors as a potential cancer treatment is increasing because of its ability to interfere with the body's repair mechanism, which is out of control in the presence of cancer. "The Cox-2 enzyme is not normally expressed in the body. But if there is illness or injury, the body begins to produce Cox-2 to increase blood flow, create inflammation, and promote epithelial cell growth that will help it heal. The same processes occur in tumor development: excessive cell growth, angiogenesis [blood vessel generation], and excessive inflammation with cellular mediators and growth factors. Drugs that inhibit Cox-2 appear to work to prevent angiogenesis and to promote apoptosis [natural programmed cell death]," Dr. Pruthi observed.

The potential role of Cox-2 inhibitors in men with prostate cancer is supported by large-scale epidemiological investigations as well as animal studies. Population studies have shown that men who take anti-inflammatory drugs have less than half the risk of developing prostate cancer. In animal experiments, prostate tumors have shrunk in size by a factor of ten after being exposed to a Cox-2 inhibitor, explained Dr. Pruthi.

"The potential for anti-inflammatory medicines to have an antitumor effect has been observed for some time. We're just at the beginning of understanding the possibilities," he concluded. J. Eric Derksen, MD and Eric Wallen, MD, FACS, joined Dr. Pruthi in the study of celecoxib in men with recurrent prostate cancer.

News from the 2004 Clinical Congress