Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial | Colorectal Cancer | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.204.227.34. Please contact the publisher to request reinstatement.
1.
Groden  J, Thliveris  A, Samowitz  W,  et al.  Identification and characterization of the familial adenomatous polyposis coli gene.  Cell. 1991;66(3):589-600.PubMedGoogle ScholarCrossref
2.
Jasperson  KW, Tuohy  TM, Neklason  DW, Burt  RW.  Hereditary and familial colon cancer.  Gastroenterology. 2010;138(6):2044-2058.PubMedGoogle ScholarCrossref
3.
Biasco  G, Pantaleo  MA, Di Febo  G, Calabrese  C, Brandi  G, Bülow  S.  Risk of duodenal cancer in patients with familial adenomatous polyposis.  Gut. 2004;53(10):1547.PubMedGoogle Scholar
4.
Conio  M, Gostout  CJ.  Management of duodenal adenomas in 98 patients with familial adenomatous polyposis.  Gastrointest Endosc. 2001;53(2):265-266.PubMedGoogle Scholar
5.
Giardiello  FM, Hamilton  SR, Krush  AJ,  et al.  Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.  N Engl J Med. 1993;328(18):1313-1316.PubMedGoogle ScholarCrossref
6.
Giardiello  FM, Yang  VW, Hylind  LM,  et al.  Primary chemoprevention of familial adenomatous polyposis with sulindac.  N Engl J Med. 2002;346(14):1054-1059.PubMedGoogle ScholarCrossref
7.
Debinski  HS, Trojan  J, Nugent  KP, Spigelman  AD, Phillips  RK.  Effect of sulindac on small polyps in familial adenomatous polyposis.  Lancet. 1995;345(8953):855-856.PubMedGoogle ScholarCrossref
8.
Nugent  KP, Farmer  KC, Spigelman  AD, Williams  CB, Phillips  RK.  Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis.  Br J Surg. 1993;80(12):1618-1619.PubMedGoogle ScholarCrossref
9.
Phillips  RK, Wallace  MH, Lynch  PM,  et al; FAP Study Group.  A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.  Gut. 2002;50(6):857-860.PubMedGoogle ScholarCrossref
10.
Arber  N, Eagle  CJ, Spicak  J,  et al; PreSAP Trial Investigators.  Celecoxib for the prevention of colorectal adenomatous polyps.  N Engl J Med. 2006;355(9):885-895.PubMedGoogle ScholarCrossref
11.
Steinbach  G, Lynch  PM, Phillips  RK,  et al.  The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.  N Engl J Med. 2000;342(26):1946-1952.PubMedGoogle ScholarCrossref
12.
Woodcock  J.  Withdrawal of approval of familial adenomatous polyposis indication for Celebrex. https://federalregister.gov/articles/2012/06/08/2012-13900/pfizer-inc-withdrawal-of-approval-of-familial-adenomatous-polyposis-indication-for-celebrex. Accessed February 29, 2016.
13.
Coffey  RJ, Hawkey  CJ, Damstrup  L,  et al.  Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells.  Proc Natl Acad Sci U S A. 1997;94(2):657-662.PubMedGoogle ScholarCrossref
14.
Eisinger  AL, Nadauld  LD, Shelton  DN,  et al.  The adenomatous polyposis coli tumor suppressor gene regulates expression of cyclooxygenase-2 by a mechanism that involves retinoic acid.  J Biol Chem. 2006;281(29):20474-20482.PubMedGoogle ScholarCrossref
15.
Roberts  RB, Min  L, Washington  MK,  et al.  Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis.  Proc Natl Acad Sci U S A. 2002;99(3):1521-1526.PubMedGoogle ScholarCrossref
16.
Torrance  CJ, Jackson  PE, Montgomery  E,  et al.  Combinatorial chemoprevention of intestinal neoplasia.  Nat Med. 2000;6(9):1024-1028.PubMedGoogle ScholarCrossref
17.
Marks  JL, Broderick  S, Zhou  Q,  et al.  Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma.  J Thorac Oncol. 2008;3(2):111-116.PubMedGoogle ScholarCrossref
18.
Pao  W, Miller  VA, Politi  KA,  et al.  Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.  PLoS Med. 2005;2(3):e73.PubMedGoogle ScholarCrossref
19.
Sos  ML, Zander  T, Thomas  RK, Staratschek-Jox  A, Claasen  J, Wolf  J.  Expression of signaling mediators downstream of EGF-receptor predict sensitivity to small molecule inhibitors directed against the EGF-receptor pathway.  J Thorac Oncol. 2008;3(2):170-173.PubMedGoogle ScholarCrossref
20.
Gibbons  DC, Sinha  A, Phillips  RK, Clark  SK.  Colorectal cancer: no longer the issue in familial adenomatous polyposis?  Fam Cancer. 2011;10(1):11-20.PubMedGoogle ScholarCrossref
21.
Bülow  S.  Results of national registration of familial adenomatous polyposis.  Gut. 2003;52(5):742-746.PubMedGoogle ScholarCrossref
22.
Morton  DG, Macdonald  F, Haydon  J,  et al.  Screening practice for familial adenomatous polyposis: the potential for regional registers.  Br J Surg. 1993;80(2):255-258.PubMedGoogle ScholarCrossref
23.
Bülow  S, Björk  J, Christensen  IJ,  et al; DAF Study Group.  Duodenal adenomatosis in familial adenomatous polyposis.  Gut. 2004;53(3):381-386.PubMedGoogle ScholarCrossref
24.
Heiskanen  I, Kellokumpu  I, Järvinen  H.  Management of duodenal adenomas in 98 patients with familial adenomatous polyposis.  Endoscopy. 1999;31(6):412-416.PubMedGoogle ScholarCrossref
25.
Lynch  TJ, Fenton  D, Hirsh  V,  et al.  A randomized phase 2 study of erlotinib alone and in combination with bortezomib in previously treated, advanced non–small cell lung cancer.  J Thorac Oncol. 2009;4(8):1002-1009. PubMedGoogle ScholarCrossref
26.
Wheatley-Price  P, Ding  K, Seymour  L, Clark  GM, Shepherd  FA.  Erlotinib for advanced non–small cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.  J Clin Oncol. 2008;26(14):2350-2357.PubMedGoogle ScholarCrossref
27.
Lynch  PM, Ayers  GD, Hawk  E,  et al.  The safety and efficacy of celecoxib in children with familial adenomatous polyposis.  Am J Gastroenterol. 2010;105(6):1437-1443.PubMedGoogle ScholarCrossref
28.
Tonelli  F, Valanzano  R, Messerini  L, Ficari  F.  Long-term treatment with sulindac in familial adenomatous polyposis: is there an actual efficacy in prevention of rectal cancer?  J Surg Oncol. 2000;74(1):15-20.PubMedGoogle ScholarCrossref
29.
Cruz-Correa  M, Hylind  LM, Romans  KE, Booker  SV, Giardiello  FM.  Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study.  Gastroenterology. 2002;122(3):641-645.PubMedGoogle ScholarCrossref
30.
Niv  Y, Fraser  GM.  Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy.  Gastroenterology. 1994;107(3):854-857.PubMedGoogle ScholarCrossref
31.
Thorson  AG, Lynch  HT, Smyrk  TC.  Rectal cancer in FAP patient after sulindac.  Lancet. 1994;343(8890):180.PubMedGoogle ScholarCrossref
32.
Sulindac [package insert]. Corona, CA: Watson Laboratories; 2008. http://pi.actavis.com/data_stream.asp?product_group=1310&p=pi&language=E. Accessed February 29, 2016.
33.
Qi  WX, Sun  YJ, Shen  Z, Yao  Y.  Risk of interstitial lung disease associated with EGFR-TKIs in advanced non–small cell lung cancer: a meta-analysis of 24 phase 3 clinical trials.  J Chemother. 2015;27(1):40-51.PubMedGoogle ScholarCrossref
34.
Shi  L, Tang  J, Tong  L, Liu  Z.  Risk of interstitial lung disease with gefitinib and erlotinib in advanced non–small cell lung cancer: a systematic review and meta-analysis of clinical trials.  Lung Cancer. 2014;83(2):231-239.PubMedGoogle ScholarCrossref
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
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 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

×