ULTRA-high-risk Surveillance to Avoid Future Events: the ULTRA-SAFE Trial

Colorectal cancer (CRC) prevention is critically dependent on the timely detection and excision of precancerous lesions, particularly advanced adenomas. Advanced adenomas are defined as lesions exceeding one centimeter, or those possessing villous pathology or high-grade dysplasia, representing lesions with high malignant potential. Following the removal of polyps, patients who present with at least three low-risk adenomas or any advanced adenoma are classified as a high-risk population, facing a significantly increased risk of developing metachronous advanced colorectal neoplasms (meta-ACRN), which include metachronous advanced adenoma or CRC, in the future. Current international guidelines recommend that these high-risk individuals undergo follow-up colonoscopy by the third year after initial polyp resection. However, a prior analysis of a multicenter clinical trial in Taiwan revealed substantial diversity in the initial endoscopic presentations among patients with advanced adenomas. This variability in initial findings has been shown to significantly alter the future risk of developing meta-ACRN. For example, for those with multiple advanced adenoma, compared with individuals with 3-10 low-risk adenoma, although they both meet the definition of high-risk population, the risk of 3-year meta-ACRN was 20% and 9%. Therefore, the uniform recommendation for a three-year surveillance follow-up fails to provide personalized advice tailored to this diverse risk profile.

This ULTRA-SAFE clinical trial, which focuses on ULTRA-high-risk Surveillance to Avoid Future Events, is a prospective, randomized controlled study. It aims to determine if implementing early fecal immunochemical testing (FIT) screening can reduce the incidence of meta-ACRN in patients at ultra-high risk. This high-risk group includes individuals who had two or more advanced adenomas detected and removed during their initial colonoscopy. The trial compares a Standard Arm, which receives routine follow-up colonoscopy at year three (where the assumed meta-ACRN prevalence is 20%), against an Early Screening Group (FIT Arm). In the FIT Arm, participants undergo FIT at years one and two, triggering an earlier colonoscopy if positive. Based on assumptions regarding FIT sensitivity and false-positive rates, the intervention was predicted to reduce the 3-year prevalence of meta-ACRN to roughly 12.7%. To statistically detect this difference, a sample size of approximately 402 participants per arm was required. After inflating this number to account for an anticipated 10-15% loss to follow-up, the planned enrollment was set at 470 participants per arm, totaling approximately 940 participants. The primary endpoint is comparing the recurrence rate of meta-ACRN detected during the third-year surveillance colonoscopy between the two groups

Inclusion criteria

• Age: Adults aged 40 to 75 years.
• Initial Colonoscopy Findings: Detection and removal of at least two advanced adenomas during the baseline colonoscopy.
• Adherence: Willingness to comply with the assigned screening protocol, including fecal immunochemical testing (FIT) and follow-up colonoscopies

Exclusion criteria

• Age: Individuals younger than 40 or older than 75 years.
• High-Risk Predispositions: Patients with inflammatory bowel disease (IBD), Familial Adenomatous Polyposis (FAP), or a documented hereditary colorectal cancer syndrome (e.g., Lynch syndrome).
• Cancer History: A history of colorectal cancer (excluding carcinoma in situ).
• Contraindications: Patients for whom polypectomy is clinically inappropriate or unsafe.
• Adenoma Count/Type: Failure to meet the requirement of at least two advanced adenomas during the initial colonoscopy.

7.Extensive Low-Risk Lesions: Presence of more than ten low-risk adenomas.

8.Pregnancy: Currently pregnant individuals.