A phase III study of pharmacological prevention of progression in patients with familial adenomatous polyposis (FAP) did not show lower incidence of disease progression with the combination of eflornithine and sulindac than with either drug alone. Additional studies that focus on clinical endpoints in the lower gastrointestinal tract are warranted to better understand the potential of this combination for pharmacologic prevention in specific groups of patients with FAP, especially those who have not yet undergone prophylactic colectomy according to study investigators who published their results on 10 September 2020 in The New England Journal of Medicine.

FAP is a rare, autosomal dominant, hereditary colorectal cancer syndrome that is most commonly caused by pathogenic germline variants in the APC gene. Proctocolectomy is the standard of care for the management of colorectal polyposis and among patients who had undergone an initial colectomy and ileorectal anastomosis, proctectomy with ileal pouch–anal anastomosis resection is performed in up to 30% because of progressive polyposis or cancer.

Colectomy and proctocolectomy are associated with complications, including diarrhoea, foecal incontinence and adverse effects on sexual function, fertility, and health-related quality of life.

In the majority of patients with FAP, management of duodenal adenomas is necessary in addition to management of the initial colorectal polyposis; mesenteric desmoid tumours may also develop in these patients.

Surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms. Therefore, the most important and unmet clinical needs that could be addressed with pharmacological agents are to delay or avoid surgery or advanced endoscopic resection and to prevent the progression of polyposis.

The study team conducted a randomised, double-blind, phase III trial to evaluate the efficacy and safety of a combination treatment with eflornithine and sulindac, as compared with either drug alone and used a time-to-event analysis with a composite efficacy endpoint to determine the delay in disease progression or major endoscopic or surgical procedures in patients with FAP.

The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status. The patients were randomly assigned in a 1:1:1 ratio to receive eflornithine, sulindac, or both for up to 48 months. The primary endpoint, 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.

In total 171 patients underwent randomisation. Disease progression occurred in 18 of 56 patients (32%) in the group treated with eflornithine plus sulindac, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio (HR) of 0.71 (95% confidence interval [CI] 0.39 to 1.32) for eflornithine plus sulindac as compared with sulindac and 0.66 (95% CI 0.36 to 1.24) for eflornithine plus 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%) (HR 0.30 [95% CI 0.07 to 1.32] and HR 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%) (HR 2.03 [95% CI 0.43 to 9.62] and HR 0.84 [95% CI 0.24 to 2.90]). Among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%) and 13 of 33 (39%) (HR 0.73 [95% CI 0.34 to 1.52] and HR 0.76 [95% CI 0.35 to 1.64]).

In this study, side effects with the combination therapy with eflornithine and sulindac were similar to those with single agent treatment and the majority of side effects observed were mild to moderate in severity.

This study was larger than previous studies on pharmacologic prevention in patients with FAP, but it was relatively small. The study authors concluded that they did not observe that the percentage of FAP patients with disease progression was significantly lower with combination therapy than with either single agent. 

The study was funded by Cancer Prevention Pharmaceuticals.


Burke CA, Dekker E, Lynch P, et al. Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis. N Engl J Med 2020;383:1028-39. DOI: 10.1056/NEJMoa1916063.