Effect of sulindac and erlotinib vs placebo

On duodenal neoplasia in familial adenomatous polyposis: A randomized clinical trial

Niloy 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 & 1 others Scott K. Kuwada

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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 OUTCOMESAND 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 calculatedas 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 by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. 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. (Table presented) 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.

Original languageEnglish (US)
Pages (from-to)1266-1275
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume315
Issue number12
DOIs
StatePublished - Mar 22 2016
Externally publishedYes

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Sulindac
Adenomatous Polyposis Coli
Polyps
Randomized Controlled Trials
Placebos
Neoplasms
Clinical Trials Data Monitoring Committees
Duodenal Neoplasms
Erlotinib Hydrochloride
Acne Vulgaris
Chemoprevention
Exanthema
Duodenum
Adenoma
Genotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of sulindac and erlotinib vs placebo : On duodenal neoplasia in familial adenomatous polyposis: A randomized clinical trial. / Samadder, Niloy 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.

In: JAMA - Journal of the American Medical Association, Vol. 315, No. 12, 22.03.2016, p. 1266-1275.

Research output: Contribution to journalArticle

Samadder, NJ, Neklason, DW, Boucher, KM, Byrne, KR, Kanth, P, Samowitz, W, Jones, D, Tavtigian, SV, Done, MW, Berry, T, Jasperson, K, Pappas, L, Smith, L, Sample, D, Davis, R, Topham, MK, Lynch, P, Strait, E, McKinnon, W, Burt, RW & Kuwada, SK 2016, 'Effect of sulindac and erlotinib vs placebo: On duodenal neoplasia in familial adenomatous polyposis: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 315, no. 12, pp. 1266-1275. https://doi.org/10.1001/jama.2016.2522
Samadder, Niloy 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. / Effect of sulindac and erlotinib vs placebo : On duodenal neoplasia in familial adenomatous polyposis: A randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 315, No. 12. pp. 1266-1275.
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AU - Boucher, Kenneth M.

AU - Byrne, Kathryn R.

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AU - Samowitz, Wade

AU - Jones, David

AU - Tavtigian, Sean V.

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AU - Berry, Therese

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AU - Davis, Rian

AU - Topham, Matthew K.

AU - Lynch, Patrick

AU - Strait, Elena

AU - McKinnon, Wendy

AU - Burt, Randall W.

AU - Kuwada, Scott K.

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N2 - 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 OUTCOMESAND 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 calculatedas 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 by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. 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. (Table presented) 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.

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