Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis
Authors: N. Jewel Samadder, Deborah W. Neklason, Kenneth M. Boucher, Kathryn R. Byrne, Priyanka Kanth, Wade Samowitz, David Jones, Sean V. Tavtigian, Michelle W. Done, Therese Berry, Kory Jasperson, Lisa Pappas, Laurel Smith, Danielle Sample, Rian Davis, Matthew K. Topham, Patrick Lynch, Elena Strait, Wendy McKinnon, Randall W. Burt, Scott K. Kuwada
Journal: JAMA (2016)

<h3>Importance</h3> Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. <h3>Objective</h3> To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. <h3>Design, Setting, and Participants</h3> Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. <h3>Interventions</h3> Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. <h3>Main Outcomes and Measures</h3> The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. <h3>Results</h3> Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped prematurely by recommendation of the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Over 6 months, the median duodenal polyp burden in the sulindac-erlotinib group decreased from 29.0 mm to 19.5 mm (median change, −8.5 mm), and in the placebo group increased from 23.0 mm to 31.0 mm (median change, 8.0 mm), for a net difference of −19.0 mm (95% CI, −32.0 to −10.9;<i>P</i> &lt; .001) between the groups. The median duodenal polyp count in the sulindac-erlotinib group decreased from 13.5 to 10.0 (median change, −2.8), and in the placebo group increased from 10.5 to 17.0 (median change, 4.3), for a net difference between treatment and placebo groups of −8.0 polyps (95% CI, −12.2 to −4.7;<i>P</i> &lt; .001). Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (<i>P</i> &lt; .001). Only 2 participants experienced grade 3 adverse events: 1 in the treatment group experienced oral mucositis and 1 receiving placebo experienced abdominal pain. <h3>Conclusions and Relevance</h3> Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01187901