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Researchers at KU Medical Center work to discover treatments for people with a rare condition that leads to colon cancer

Rare genetic condition results in thousands of polyps and either near-certain colon cancer or a lifetime of screenings and surgery

Microscopic view of cancer cells
Left untreated, 100% of people with this formidable disease get colon cancer.

For most people, middle age ushers in a variety of medical testing, including screening for colon cancer. During the most common form of screening, a colonoscopy, a gastroenterologist uses a scope to examine the large intestine and remove polyps, abnormal growths that may eventually become cancerous. Polyps are fairly common, but only between 5% and 10% turn into cancer, and it can take years for that cancer to develop.

But for people with familial adenomatous polyposis, a hereditary genetic condition that accounts for 1% of all people diagnosed with colon cancer, the risk of cancer skyrockets. Caused by a defect in a gene known as APC (adenomatous polyposis coli), familial adenomatous polyposis causes hundreds and often thousands of polyps to form throughout the gastrointestinal tract, which is why for these patients, preventing colon cancer is a constant endeavor. People with familial adenomatous polyposis may be diagnosed while they are still in grade school, either because of a known family history of the disease or because of symptoms such as abdominal pain and blood in the stool.

Left untreated, “it’s not a question of if people with this condition will get cancer, it’s a question of when,” said Ajay Bansal, M.D., associate professor of gastroenterology, hepatology and motility at the University of Kansas School of Medicine and medical director of the Gastrointestinal Cancers Prevention Clinic at The University of Kansas Cancer Center.

Before modern medicine, many people with the disease died by the age of 40. Because the condition is usually hereditary, the economic impact of the disease on families can be considerable, Bansal said, as previous generations often died before being able to accrue any assets — a house, a farm, some savings — to pass on to their children. “The rate of poverty is much higher in these patients,” said Bansal. “This is a disease that can cause multi-generational poverty.”

A need for new treatments

Today, the condition is managed by colonoscopies every six to 12 months to remove polyps until the patients reaches their late teens or 20s, when the polyps increase in number. At that point, patients face surgery to remove the colon and the rectum, which significantly impacts their quality of life. The surgery also does not prevent the polyps that the condition can also cause in the upper gastrointestinal tract, which can lead to cancers of the stomach and small intestine, pointing to the need for other therapies to manage this disease. There are no approved drugs that have been designed to treat familial adenomatous polyposis.

Colon polyps
Familial adenomatous polyposis causes
hundreds and often thousands of polyps
to form throughout the gastrointestinal
tract. There are no approved drugs
designed to treat it.

There are, however, some medications that are used to help slow the growth of the polyps, both in size and number, which can delay the need for surgery. This gives patients the chance to finish high school or college first, begin a career, or start a family. Delaying surgery can be especially important for women, because removal of the rectum causes infertility in up to 60% of female patients, Bansal said. Moreover, there are some patients who have milder forms of the disease for whom these drugs, combined with regular colonoscopies, could eliminate the need for surgery altogether.

The medications used to delay the development of cancer are prescription NSAIDS (non-steroidal anti-inflammatory drugs) such as sulindac, which is often prescribed to relieve arthritis symptoms, and aspirin. (Ibuprofen and naproxen, both over-the-counter NSAIDS, have not been studied for this disease, Bansal said.) NSAIDS inhibit an enzyme known as COX (cyclooxygenase) that is critical to polyps becoming cancerous.

But despite a number of trials, the effectiveness of NSAIDS has not been well defined, in terms of how much they reduce both the number and size of polyps, how the effectiveness of different NSAIDs compare to each other and how the drugs work across different types of patients.

An important step

Bansal and his colleagues have taken an important step toward answering some of these questions. They conducted a meta-analysis of a number of past studies to determine the impact of short-term use of NSAIDS on polyps in people with this genetic condition. They included in their analysis, published online in Gastro Hep Advances, only randomized controlled trials with a placebo as the control arm that looked at the efficacy of selective NSAIDS, which inhibit one form of the COX enzyme, and nonselective NSAIDS, which inhibits two forms of COX, or aspirin. The NSAIDs used in the eight studies that met the selection criteria were sulindac (nonselective) and celecoxib, tiracoxib and rofecoxib (selective). The average duration of treatment with these drugs was six months.

The researchers found that overall, treatment with NSAIDS, compared to a placebo, reduced the number of polyps by an average of 17% and reduced the polyp size by an average of 16%. Though positive, “the effect was more modest than we previously thought,” said Bansal.

The analysis also showed that the sulindac and aspirin outperformed the other NSAIDS in reducing the size and number of polyps, suggesting the superiority of nonselective NSAIDS for delaying cancer in these patients.

But the statistical tools used in the meta-analysis also revealed considerable serious limitations in the studies analyzed, including issues with sample size, a high risk of bias and a low certainty of evidence.

“We need to design a randomized controlled trial using modern design and modern technology to figure out the true effectiveness and which populations of patients benefit the most,” said Bansal, who noted that a trial addressing these questions was recently published in the New England Journal of Medicine, but much work remains. “This is one of the toughest inherited gastrointestinal cancer syndromes.”

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