In a phase III trial reported in The New England Journal of Medicine, Burke et al found that the combination of eflornithine and sulindac did not reduce the risk of disease progression vs either agent alone in patients with familial adenomatous polyposis.
Study Details
In the international trial, 171 patients were randomly assigned 1:1:1 to receive the combination of eflornithine at 750 mg and sulindac at 150 mg (n = 56), sulindac alone (n = 58), or eflornithine alone (n = 57) once daily for up to 48 months. Patients were stratified according to anatomic site with the highest polyp burden and surgical status: the strata were precolectomy (shortest projected time to progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time).
The primary endpoint was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or ileal pouch, or progression of duodenal disease.
Disease Progression
KEY POINTS
- The combination of eflornithine and sulindac did not reduce risk of progression vs sulindac or eflornithine alone.
- Progression occurred in 32%, 38%, and 40% of patients, respectively.
Disease progression occurred in 18 (32%) of 56 patients in the eflornithine/sulindac group, 22 (38%) of 58 in the sulindac group, and 23 (40%) of 57 in the eflornithine group. Kaplan-Meier estimates of mean time to first progression event were 32.3 months in the eflornithine/sulindac group, 23.6 months in the sulindac group (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.39–1.32, for combination vs sulindac), and 21.8 months in the eflornithine group (HR = 0.66, 95% CI = 0.36–1.24 for combination vs eflornithine).
Among 37 precolectomy patients, the corresponding progression rates in the three treatment groups were 17% (2 of 12 patients), 46% (6 of 13), and 42% (5 of 12), with respective hazard ratios of 0.30 (95% CI = 0.07–1.32) and 0.20 (95% CI = 0.03–1.32). Among 34 patients with rectal or ileal pouch polyposis, the rates were 36% (4 of 11), 18% (2 of 11), and 42% (5 of 12), with respective hazard ratios of 2.03 (95% CI = 0.43–9.62) and 0.84 (95% CI = 0.24–2.90). Among 100 patients with duodenal polyposis, the rates were 36% (12 of 33), 41% (14 of 34) and 39% (13 of 33), with respective hazard ratios of 0.73 (95% CI = 0.34–1.52) and 0.76 (95% CI = 0.35–1.64).
Adverse Events
Treatment-related adverse events of any grade occurred in 68% of patients in the eflornithine/sulindac group, 74% of the sulindac group, and 55% of the eflornithine group. Grade ≥ 3 adverse events occurred in 21%, 21%, and 30%, respectively. Treatment-related serious adverse events occurred in 5%, 7%, and 2%. Discontinuation of a study drug due to adverse events occurred in 16%, 10%, and 9%.
The investigators concluded, “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.”
Disclosure: The study was funded by Cancer Prevention Pharmaceuticals. For full disclosures of the study authors, visit nejm.org.
