Researchers followed 41 patients ages eight to 25 with known genetic mutations that result in a form of hereditary colon cancer, called familial adenomatous polyposis (FAP) or Gardner syndrome, who had not begun to develop polyps. FAP patients develop, on average, hundreds of polyps in their colon and rectum by age 15, and virtually always develop colon cancer, often by their early 30s or sooner.
Twenty-one patients took standard doses (75 to 150 mg) of sulindac twice daily and 20 patients were given a placebo. Nine of 21 (43 percent) patients taking sulindac and 11 of 20 patients (55 percent) taking a placebo developed polyps. Three of the sulindac recipients developed colon cancer. Diaries, pill counts, biopsies of the colon, and colonoscopies verified that patients took their pills and evaluated the number and size of new polyps.
"Despite prior evidence that sulindac is effective in older, symptomatic patients, investigators found no statistical difference between the two groups in thwarting the development of polyps or subsequent colon cancer," concludes Frank Giardiello, M.D., division director of gastroenterology/hepatology, professor of medicine and oncology, and director of the study.
"In medicine, learning what doesn't work is just as important as learning what does work," adds Giardiello. "Prior studies indicated that sulindac can reduce polyps in older, symptomatic FAP patients, but whether it could prevent polyps in FAP patients who hadn't developed any polyps yet was unknown." says Giardiello. "Unfortunately, our study says the answer is no."
Some mild side-effects were reported, including, flulike symptoms, headache and rashes although the occurrence of side-effects in the sulindac group was no different from those taking a placebo. The investigators also noted a potential for resistance to the drug with prolonged use.
Sulindac is a type of nonsteriodal anti-inflammatory drug (NSAID) that works by blocking two enzymes, cyclooxygenase (COX) 1 and 2. These enzymes produce inflammatory mediators called prostaglandins. Typically, sulindac is used for the treatment of arthritis, including rheumatoid and osteoarthritis. FAP patients taking sulindac in the current study had lower prostaglandin levels than those taking a placebo. With more research, Giardiello suggests that higher doses of sulindac, or giving it in combination with other targeted drug therapy, may have a better effect, and prostaglandin levels could serve as a biomarker for response. Current findings, however, do not provide evidence of prevention benefits of sulindac at usual doses for newly diagnosed, pre-symptomatic FAP patients, he says.
FAP is an inherited disease caused by mutations of the adenomatous polyposis coli (APC) gene. Hopkins researchers developed a genetic test for the APC gene mutation several years ago, allowing those with a family history of the disease to learn if they have inherited a genetic predisposition for FAP. Currently, regular screening for the initial development of polyps and surgery to remove the colon remains the treatment of choice for FAP patients.
This research was funded by the John G. Rangos Sr. Charitable Foundation, Merck, the Clayton Fund, and the National Institutes of Health.
Other participants in this research include Vincent Yang, M.D., Ph.D., Linda Hylind, B.S., R.N., Anne Krush, M.S., from Johns Hopkins; Gloria Petersen, Ph.D., from the Mayo Clinic; Jill Trimbath, M.S., Steven Piantadosi, M.D., Ph.D., Elizabeth Garrett, Ph.D., from Johns Hopkins; Deborah Geiman, M.S., Walter Hubbard, Ph.D., from Johns Hopkins, G. Johan Offerhaus, M.D., M.P.H., Ph.D., from the Academic Medical Center, Amsterdam, the Netherlands; and Stanley Hamilton, M.D., from the University of Texas M.D. Anderson Cancer Center.
Images are available at: http://www.hopkinsmedicine.org/press/2002/MARCH/sulindac.htm
Related Web sites:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: www.hopkinscancercenter.org
The Johns Hopkins Hereditary Colon Cancer Program: www.hopkins-coloncancer.org
"Primary Chemoprevention with Sulindac of Familial Adenomatous Polyposis," New England Journal of Medicine 2002, vol. 346
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