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

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 sulin...

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Published in:JAMA : the journal of the American Medical Association 2016-03, Vol.315 (12), p.1266-1275
Main Authors: Samadder, N. Jewel, Neklason, Deborah W, Boucher, Kenneth M, Byrne, Kathryn R, Kanth, Priyanka, Samowitz, Wade, Jones, David, Tavtigian, Sean V, Done, Michelle W, Berry, Therese, Jasperson, Kory, Pappas, Lisa, Smith, Laurel, Sample, Danielle, Davis, Rian, Topham, Matthew K, Lynch, Patrick, Strait, Elena, McKinnon, Wendy, Burt, Randall W, Kuwada, Scott K
Format: Article
Language:English
Subjects:
Adenomatous Polyposis Coli - drug therapy
Adenomatous Polyposis Coli - genetics
Adenomatous Polyposis Coli - pathology
Adult
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Cancer
Clinical trials
Drugs
Duodenal Neoplasms - drug therapy
Duodenal Neoplasms - genetics
Duodenal Neoplasms - pathology
Erlotinib Hydrochloride - administration & dosage
Erlotinib Hydrochloride - adverse effects
Female
Genes, APC
Humans
Male
Middle Aged
Placebo effect
Risk factors
Sulindac - administration & dosage
Sulindac - adverse effects
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Summary: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 
ISSN:0098-7484
1538-3598
DOI:10.1001/jama.2016.2522