Non-aspirin pain drugs may help men with recurrent prostate cancer

The new findings demonstrate that Cox-2 inhibitors may have anti-tumor effects on prostate cancer and may slow disease progression in men whose PSA blood tests indicate the cancer's recurrence, the researchers said. Findings were presented June 6 at the American Society of Clinical Oncology's annual meeting.

Currently, no effective treatment options exist for the estimated 50,000 men who annually develop the first signs of cancer recurrence - called biochemical relapse, a detectable and rising PSA level after surgery or radiation therapy for prostate cancer. For these otherwise healthy individuals, the first clinical signs of cancer relapse may be years ahead.

"If the PSA test points to a recurrence, the good news is it gives us a lead time of up to seven years. The bad news is we don't have anything appropriate and effective to offer at this early stage of recurrence," said Dr. Raj S. Pruthi, the study's principal investigator. "The use of chemotherapy in prostate cancer has been typically disappointing in these patients when viewed in terms of efficacy and toxicity."

Pruthi, assistant professor of surgery-urology at the School of Medicine, also co-directs the Multidisciplinary Program for Urologic Oncology at the UNC Lineberger Comprehensive Cancer Center.

The findings were based on 24 prostate cancer patients in biochemical relapse who were treated with a Cox-2 inhibitor and followed for more than one year. After three months, 22 of 24 patients (92 percent) showed a significant inhibitory effect on their PSA levels, including 11 patients whose PSA either declined or stabilized. For the remaining 13 patients, 11 had a dramatic slowing of their PSA doubling time, or rate of PSA increase, and two patients showed no initial change.

"Still, their rate of PSA increase slowed during their 12-month follow-up," Pruthi said.

Halting the disease through hormonal therapy aimed at shutting down male sex hormones has not been shown to influence disease progression or survival in this group of patients, Pruthi said. Moreover, it may unnecessarily expose symptom-free patients to the therapy's side effects, he added.

"The vast majority of patients are simply watched expectantly until they develop clinical symptoms of disease or metastatic disease (i.e. spread around the body), at which time we begin hormonal therapy," he said. "Therapeutic alternatives that are simple, non-toxic and efficacious clearly need to be identified."

Cox-2 inhibitors may represent the needed alternative, Pruthi said, considering that the cellular enzyme cyclooxygenase (Cox-2) has been implicated in the development and growth of some cancers, including colon, breast, bladder and prostate malignancies.

While the precise molecular mechanisms for Cox-2's effect on tumor growth remain unclear, increased gene expression of Cox-2 in tumor cells has been linked with decreased programmed cell death, increased tumor invasiveness, suppressed immune function and angiogenesis, or blood vessel growth.

In the laboratory, Cox-2 inhibitors have been shown to have anti-tumor activities in human colon, breast, lung and prostate cancer tissues. "Recent evidence has shown that Cox-2 is over-expressed in human prostate cancer tissue and that Cox-2 inhibition has potent anti-tumor activity both in vitro and in vivo," Pruthi said.

Late in the 1980s and 1990s, some evidence from epidemiologic studies had suggested that people who take non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief have a reduced risk of colon cancer, and more recent studies have suggested that this reduced risk may be true for prostate cancer, as well.

These drugs, which include aspirin, block Cox-2, which is produced in response to injury and enhances the inflammatory response, resulting in pain, inflammation and swelling. But NSAIDs also block expression of Cox-1, which is produced constantly and helps preserve the stomach's lining. Hence the increased risk of gastrointestinal side effects associated with taking NSAIDs.

The advent in 1998 of celecoxib, first of the two cyclooxygenase-2 specific (Cox-2) inhibitor drugs approved by the U.S. Food and Drug Administration, provided the same effectiveness against pain and swelling of inflammation as the older NSAIDs but without the increased gastrointestinal risk, including stomach ulcers. These drugs are sold in the United States under the brand names Celebrex and Vioxx.

In a clinical study, people at hereditarily high risk for developing pre-cancerous colon polyps were given celecoxib. They showed a decrease in the number of these polyps. Consequently, the FDA has approved the use of celecoxib for the prevention of pre-cancerous polyps in these patients.

"We think Cox-2 inhibitors may help delay or prevent disease progression in men with recurrent prostate cancer after definitive radiation therapy or surgery and thereby help extend the time until hormonal therapy is needed," Pruthi said.

"This clinical trial will better evaluate the clinical potential of Cox-2 as an anti-tumor medication in prostate cancer," he added. "We're interested in determining if this group of medications work for patients who otherwise are told 'Your cancer has come back but we have no appropriate treatment options for you at this stage.' "

Up to 100 patients will be studied in this UNC investigation. Support for the research comes from the Lineberger Center.