Effect of COX and EGFR Inhibition on Duodenal Neoplasia in Familial Adenomatous Polyposis: a Randomized Placebo-Controlled Trial

Background: Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene and is characterized by the development of hundreds of colorectal adenomas and eventually colorectal cancer. FAP patients are also at increased risk for duodenal neoplasia, with duodenal adenomas forming in >50% and up to a 15% lifetime risk of duodenal carcinoma. Multiple studies have shown that sulindac inhibits colorectal adenomas in FAP patients, however, they have failed to show significant reduction in duodenal adenomas. Preclinical data has shown that the combination of COX and EGFR inhibition diminished small intestinal adenoma development by 87% in mice with germline Apc mutations. Aim: These results led us to test the hypothesis that a combination of COX and EGFR inhibition (sulindac and erlotinib) would inhibit duodenal adenoma formation in patients with FAP. Methods: We conducted a double blind, randomized, placebo-controlled trial in which FAP patients received combination therapy with 150mg sulindac twice per day and 75mg erlotinib daily or placebo tablets for 6 months. The total number and size of polyps in a segment of duodenum between 0 and 10cm from the bulb were mapped at baseline and 6 months. The primary outcome was change in total polyp burden, calculated as the sum of the diameters of polyps, following six months of treatment. A sample size of 100 patients was estimated to provide 95% power to detect a 30% reduction with treatment. Results: 92 patients had been recruited and randomized when the study was stopped early because statistical guidelines for an early halt were met. 72 randomized patients completed the study and were included in the analysis; 36 patients received sulindac/erlotinib and 36 placebo. Demographic characteristics between the treatment and placebo groups were comparable (Table 1). The major side effects were rash and diarrhea with none exceeding grade 2. The total duodenal polyp burden, defined as the sum of the diameters of polyps, was significantly different between the placebo and sulindac-erlotinib group at 6 months (P=1 × 10-9), with a 27% increase from baseline in the placebo group and a 40% decrease from baseline in the sulindac-erlotinib group (Table 1 and Figure 1). The total duodenal polyp count showed a similar statistically significant difference between the groups (P<0.0001), with the placebo group having a 10% increase and the therapy group a 20% decrease in total polyp count from baseline. Discussion: In this double-blind, placebo controlled, randomized trial we showed that combination COX and EGFR inhibition with sulindac and erlotinib effectively reduced duodenal polyp burden and polyp number in patients with FAP, as compared to placebo. This effect was evident after only 6 months of therapy. The effect was efficacious in both FAP and AFAP patients, including those with a wide range in polyp numbers. (table present).