Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis
Carol A Burke1, Evelien Dekker1, Patrick Lynch1
1From the Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland (C.A.B., J.C.); the Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam (E.D., F.G.K., V.H.R.); the Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston (P.L.); the Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix (N.J.S.), and Cancer Prevention Pharmaceuticals, Tucson (A. Cohen) - both in Arizona; the Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (F.B., A. Castells); the Department of Internal Medicine I, University of Bonn (R.H., C.P.S.), and the National Center for Hereditary Tumor Syndromes (R.H., C.P.S.), Bonn, Germany; Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne (J.B., A.H.), and Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester (F.L.) - both in the United Kingdom; Mount Sinai Hospital, Toronto (S. Gallinger, R.G.); the Division of Population Sciences, Dana-Farber Cancer Institute, the Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, and Harvard Medical School - all in Boston (R.L., S.S.); the Division of Gastroenterology, University of Michigan, Ann Arbor (E.M.S.); Veterans Affairs San Diego Healthcare System, San Diego, and the Division of Gastroenterology, University of California San Diego, La Jolla (S. Gupta); Huntsman Cancer Center, Salt Lake City (P.K.); the University of Pennsylvania, Philadelphia (G.G.G., A.K.R.); Mayo Clinic, Rochester, MN (F.A.S.); University Hospital Gasthuisberg, Leuven, Belgium (E.V.C.); Emory University School of Medicine, Atlanta (F.F.W.); Washington University School of Medicine, St. Louis (P.E.W.); University of Washington Medical Center, Seattle (W.M.G.); Vanderbilt University Medical Center, Nashville (M.F.); and the University of Wisconsin School of Medicine and Public Health, Madison (J.M.W.).
Background:
The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown.
Methods:
We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease.
Results:
A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups.
Conclusions:
In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).
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