Drug Combo Curbs Duodenal Polyps in FAP

Patients with familial adenomatous polyposis (FAP) aren't just susceptible to colorectal tumors; they are also vulnerable to duodenal polyps, which form in the first section of the small intestine. A new study suggests that sulindac (Clinoril; Merck) and erlotinib (Tarceva; Genentech) can shrink these growths.

FAP results from germline mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Because the risk of developing colorectal cancer in patients with FAP is close to 100%, physicians recommend removing the colon, which comprises most of the large intestine. Yet even people who have had a prophylactic colectomy face another risk: More than half of patients with FAP develop duodenal polyps, and up to 12% of them develop duodenal tumors, which typically require risky surgery.

Researchers have found that EGFR activity and APC-inactivating mutations spur polyp formation by increasing expression of COX2. NSAIDs such as sulindac, a COX inhibitor, reduce colon polyp formation in patients with FAP, but they don't work as well against duodenal polyps. Deborah Neklason, PhD, of the University of Utah in Salt Lake City, and colleagues tested whether pairing sulindac with the EGFR-blocker erlotinib would be more effective.

The scientists randomized 92 patients with duodenal polyps to receive sulindac and erlotinib or a placebo for 6 months. Endoscopies at the start and end of the trial allowed the researchers to track each patient's polyp burden, the total diameter of all polyps in their duodenum. They found that the median polyp burden increased by 8 mm in the control group but decreased by 8.5 mm among the treated patients (JAMA 2016;315:1266–75). Because the trial was brief, they don't yet know whether the drug combination actually prevents duodenal tumors.

Sulindac and erlotinib triggered side effects in 93% of the treated patients, whereas 72% of the control patients reported them. The most common side effect was a rash, which occurred in 87% of the treated patients and 20% of the control patients. Other adverse effects from the drug combo included mouth sores, diarrhea, and nausea.

“It's the first study to show effectiveness of chemoprevention in the management of duodenal polyposis,” says Carol Burke, MD, of the Cleveland Clinic, OH, who wasn't connected to the research. The results are “provocative and compelling,” she adds. Ernest Hawk, MD, of The University of Texas MD Anderson Cancer Center in Houston, agrees. “It's a first step, but it's a promising first step because of the level of efficacy they have demonstrated.”

However, Hawk and Burke say they are concerned by the drugs' side effects. Along with the side effects that occurred in the trial, studies have linked the drugs to cardiac toxicity and interstitial lung disease. Both researchers say future studies need to determine how to reduce these risks, perhaps by further decreasing doses or by treating patients intermittently. —Mitch Leslie

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