Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial | Colorectal Cancer | JAMA | JAMA Network
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Preliminary Communication
March 22/29, 2016

Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial

Author Affiliations
  • 1Huntsman Cancer Institute, University of Utah, Salt Lake City
  • 2Department of Medicine (Gastroenterology), University of Utah, Salt Lake City
  • 3Department of Oncological Sciences, University of Utah, Salt Lake City
  • 4Department of Medicine (Genetic Epidemiology), University of Utah, Salt Lake City
  • 5Department of Medicine (Epidemiology), University of Utah, Salt Lake City
  • 6Department of Pathology, University of Utah, Salt Lake City
  • 7Department of Medicine (Pulmonary), University of Utah, Salt Lake City
  • 8Department of Gastroenterology, University of Texas MD Anderson Cancer Center, Houston
  • 9Penrose Hospital, Colorado Springs, Colorado
  • 10University of Vermont Cancer Center, Burlington
  • 11Department of Medicine, University of Hawaii, Honolulu
JAMA. 2016;315(12):1266-1275. doi:10.1001/jama.2016.2522

Importance  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.

Objective  To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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.

Results  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; P < .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; P < .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 (P < .001). Only 2 participants experienced grade 3 adverse events: 1 in the treatment group experienced oral mucositis and 1 receiving placebo experienced abdominal pain.

Conclusions and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01187901