NEWS

Arthritis Drug Approved for Polyp Prevention Blazes Trail For Other Prevention Trials

Kara Smigel

Compared to the media attention surrounding the approval of tamoxifen to reduce the risk of breast cancer in high-risk women, the approval of celecoxib for the reduction of polyps in familial adenomatous polyposis (FAP) patients was a sleeper.

But the approval of celecoxib is important for two reasons: its fast-track approval based on a noncancer endpoint and its potential to prevent more than one type of cancer.

The U.S. Food and Drug Administration approved the use of celecoxib (CelebrexTM, Searle Monsanto, Skokie, Ill.) as an adjunct to usual care for patients with FAP on Dec. 23, 1999, based on the results of a National Cancer Institute-sponsored phase II/III trial in 83 patients. That trial showed that patients taking 400 mg of celecoxib twice daily for 6 months had 28% fewer polyps on average than those on a placebo. The study has been submitted to a scientific journal for publication.

In a disease where the only treatment is surgery and more surgery, a nonsurgical intervention is a potential improvement. FAP patients develop hundreds to thousands of adenomas throughout their colon and rectum, beginning in adolescence. Left untreated, nearly all patients develop colorectal cancer by their 40s and 50s.

"First and foremost, the approval gives patients with FAP a pharmacologic approach to complement the surgical management of their disease," said Ernie Hawk, M.D., chief of the GI and Other Cancer Research Group in NCI’s Division of Cancer Prevention.

Gideon Steinbach, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston, who headed the phase II/III FAP trial conducted in Houston and at St. Mark’s Hospital in London agreed. He added, "But we will need a very long-term study to see if cancer is prevented." (Such studies are planned.)

The fact that celecoxib was approved for marketing without such long-term data and without definitive proof that decreasing the number of polyps means averting cancer was possible via FDA’s fast track approval — used for other life-threatening diseases, most notably AIDS and actual cancer, but not before for cancer prevention.

"Reducing adenomas in patients with FAP is a benefit in and of itself," Hawk said. "We expect that it will translate into a reduction in cancers as well."

Another celecoxib researcher put this shift in focus a different way. "If someone had high blood pressure, you wouldn’t wait until they had a stroke to treat it," said Craig Elmets, M.D., a University of Alabama at Birmingham researcher studying celecoxib for actinic keratoses. "Right now, even with a prior diagnosis of actinic keratoses, you wait until you have more lesions before you start treating them. . . . It would be nice to have something to prevent the development."

Seeking treatments for precancerous conditions — and seeking approval for those treatments — will hopefully kick start further investment and activity in the prevention field, said Hawk. And the celecoxib approval — which benefitted the FAP patients because it gave them another treatment option while also proving the principle that a COX-2 inhibitor could work in human neoplasia — becomes a win/win model.

Celecoxib inhibits the enzyme COX-2 and was developed to replace nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen, which block both COX-1 and COX-2 enzymes: the former is necessary for healthy mucosal tissues and the latter is typically induced in inflammation and precancerous tissues. Inhibition of COX-1 is the likely cause of the gastric problems that occur from long-term use of NSAIDs for diseases such as arthritis.

Traditional NSAIDs were the clue to the importance of COX-2 inhibition in cancer. Laboratory studies had shown that COX-2 was overexpressed in all stages of neoplasia and that the end products of COX activity — especially prostaglandins — were increased as well. Then, epidemiologic data showed that people who used NSAIDs regularly over long periods of time had a lower risk of colon polyps, colon cancer, and death from colon cancer.

"There was remarkable consistency that NSAIDs, as a class, reduced colon cancer incidence and mortality," noted Gary Kelloff, M.D., acting chief of the Chemopreventive Agent Development Reearch Group in NCI’s Division of Cancer Prevention. And the most likely mechanism was inhibition of COX enzymes.



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Dr. Gary Kelloff

 
So researchers had the three things they needed: a legitimate molecular target, solid preclinical efficacy data, and fairly convincing epidemiologic data showing NSAIDs had a role in colon cancer prevention. "We asked ourselves," said Hawk, "with all this evidence, why weren’t these agents being developed for cancer prevention more aggressively?" And the answer was their toxicity.

"The GI bleeding problem almost washed away the benefits from any NSAID for colon cancer prevention," said Kelloff, and were a consistent problem for treatment of arthritis as well.

COX-2 inhibitors were created by pharmaceutical companies because "a better, safer NSAID for arthritis was needed," he explained. (Celecoxib was approved for use in osteoarthritis and rheumatoid arthritis in December 1998.)

So when drug companies developed COX-2 inhibitors for arthritis, cancer was another logical area for investigation (See sidebar, opposite page.) NCI approached Searle about co-developing celecoxib for cancer, a piggy-backing method that "saves years and dollars" in getting a potential chemoprevention drug into investigation, notes Kelloff, and they agreed.

The FAP trial "supports the theory that COX-2 plays a role in human cancer and opens the door for further studies — in humans — of COX-2 inhibition for preventing sporadic colorectal tumors and other cancers," said Steinbach. And that role extends well beyond the colon.

The existing mechanistic data, epidemiology, and preclinical and clinical research results support the use of celecoxib for sporadic colon polyps, bladder cancer, Barrett’s esophagus, skin, and prostate cancers. Studies show that COX-2 is overexpressed in lung and breast tumors as well.

Five trials of celecoxib (see box) are already in progress — not counting the planned follow-up trials in FAP, in conditions where COX-2 is known to be over expressed. Key to each of these trials are biomarker and mechanistic studies to define the reason COX-2 inhibitors may work.


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