Sulindac And Eflornithine Combination Delays The Need For Lower Gastrointestinal Surgery In Familial Adenomatous Polyposis: Cpp Fap-310 Trial

INTRODUCTION: An international phase III trial (CPP FAP-310) assessed the efficacy of low-dose sulindac, eflornithine, or their combination in reducing the time to disease progression in the lower (LGI) and upper gastrointestinal (UGI) tract in patients with familial adenomatous polyposis (FAP). This post-hoc analysis aimed to evaluate whether this combination of drugs delayed time to clinically significant LGI colorectal polyposis progression and need for FAP-related surgeries compared with monotherapy in FAP patients with an intact colon or with a retained rectum after colectomy with ileorectal anastomosis (IRA) or proctocolectomy with ileal pouch anal anastomosis (IPAA). METHODS: Adults with FAP were randomized 1:1:1 to receive sulindac (150 mg), eflornithine (750 mg), or both once daily for up to 48 months. The LGI study population for this post-hoc analysis was the intent-to-treat population of the trial excluding patients who had undergone prior proctocolectomy with end ileostomy. Efficacy was evaluated as time from randomization to disease progression, defined as need for surgery, and/or excision of >10mm polyps, and/or diagnosis of polyp with high-grade dysplasia. RESULTS: A total of 158 patients in the CPP FAP-310 trial fit the criteria for this LGI disease progression assessment. FAP disease progression was observed in 2/54 (3.7%), 9/53 (17.0%), and 10/51 (19.6%) patients in the combination, sulindac, and eflornithine arms, respectively, corresponding to risk reductions of 80% (hazard ratio [HR] = 0.20; 95% CI: 0.05–0.80; P = 0.02) and 83% (HR = 0.17; 95%CI: 0.04–0.70; P = 0.01) between combination and sulindac alone or eflornithine alone, respectively (Figure). The need for surgery as determined by the endoscopist occurred in 0, 7 (13.2%), and 8 (15.7%) patients in the combination, sulindac, and eflornithine arms, respectively, corresponding to risk reductions approaching 100% both between the combination and sulindac arms (HR = 0.00; 95%CI: 0.00–0.48; P = 0.005) and between the combination and eflornithine arms (HR = 0.00; 95%CI: 0.00–0.44; P = 0.003). Similar reductions were observed in pre-colectomy FAP patients as well as in those with an IRA or an IPAA.Figure 1.: Kaplan-Meier plot on time to disease progression in the LGI population.CONCLUSION: Combination therapy with eflornithine and sulindac was superior to either single agent alone in decreasing the risk of colorectal polyposis progression and delaying the need for surgery involving the LGI tract in FAP patients with an intact colon, IRA, or IPAA.