FORTE: A Randomized Clinical Trial Comparing Five or Ten Year Surveillance Colonoscopy
February 2, 2023
In February 2022, the first patient was enrolled in a multicenter, National Cancer Institute-funded clinical trial that could reduce the number of surveillance colonoscopy exams performed, freeing up resources to better serve public health. Robert E. Schoen, MD, MPH, and Jeffrey M. Dueker, MD, MPH, in the UPMC Division of Gastroenterology are national primary investigators of the FORTE (Five or Ten Year Colonoscopy for 1–2 Non-Advanced Adenomatous Polyps) trial, which will determine the best timing for a repeat colonoscopy in patients with nonadvanced adenomas found and removed at colonoscopy.
Screening with colonoscopy reduces colorectal cancer (CRC) incidence and mortality and is recommended for individuals over 45 years of age. Approximately 30% of individuals who undergo screening colonoscopy will be found to have adenomatous polyps, benign growths that can be a precursor to CRC. After adenomas are excised, patients are advised to return for surveillance colonoscopy exams to ensure that future malignant or premalignant lesions are detected in a timely fashion.
CRC Risk and Adenomatous Polyps
Adenomatous polyps are common. Most are small and nonadvanced and are unlikely to evolve into cancer. Since 2012, patients found to have one to two nonadvanced polyps removed during screening colonoscopy have been advised to return for surveillance colonoscopy in five to 10 years. Patients with no polyps detected during screening colonoscopy are advised to repeat colonoscopy in 10 years.1 However, in recent years, several large studies demonstrated a similar long-term cancer incidence for individuals with one to two small adenomatous polyps removed as compared with individuals with no polyps detected.2 In one study, Dr. Schoen and his colleagues examined the colonoscopy findings of over 16,000 patients enrolled in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which included patients treated at UPMC.
At the outset, approximately 50% had no adenoma, 31% had a nonadvanced adenoma, and 18% had an advanced adenoma. They were followed for a median of 12.9 years. There was no significant difference in colorectal cancer incidence between participants with nonadvanced adenoma as compared with participants with no adenoma (rate ratio [RR], 1.2 [95% CI, 0.8-1.7]; P = .30), and no significant difference in CRC mortality (RR, 1.2 [95% CI, 0.5-2.7], P = .68). In contrast, patients with advanced adenoma were significantly more likely to develop CRC (RR, 2.7 [95% CI, 1.9-3.7]; P < .001) and had an increased mortality risk (RR, 2.6 [95% CI, 1.2-5.7], P = .01) as compared with patients with no adenomas.3
As a result of these and similar findings, the U.S. Multi-Society Task Force on Colorectal Cancer modified its recommendations in 2020, extending the interval for repeat colonoscopy after the detection and removal of one to two small (< 10 mm) adenomatous polyps to seven to 10 years, from the previous recommendation of five to 10 years.2 However, there was concern in concluding that the patients with nonadvanced adenomas in the aforementioned studies had the same cancer risk as patients with no adenomas. The individuals with nonadvanced adenomas had much higher rates of surveillance colonoscopy, during which adenomatous polyps, and even advanced adenomatous polyps, were much more likely to have been removed during the follow-up period. Maybe the reason for the similar cancer incidence observed was not that the underlying risk was the same but rather that surveillance colonoscopy with polypectomy drove down the cancer incidence in patients with nonadvanced adenomas. So, rather than demonstrating that surveillance was not necessary, on the contrary, the findings may provide evidence that surveillance was effective and necessary. Only a randomized trial could answer the question of whether the recommended surveillance was beneficial — hence the rationale for FORTE.
FORTE – Five or Ten Year Colonoscopy for 1–2 Non-Advanced Adenomas
FORTE is a clinical trial sponsored by the National Cancer Institute Community Oncology Research Program (NCORP), a national network of investigators and cancer providers, which is led by NRG Oncology, a participating organization of the NCI National Clinical Trials Network (NCTN) program. NCORP conducts multi-site cancer clinical trials in prevention, screening, symptom management, and cancer care delivery. Dr. Schoen, Dr. Dueker, and their colleagues nationwide are recruiting 9,500 individuals to participate in the FORTE trial.
Candidates must be between the ages of 50 and 70 and have undergone a qualifying colonoscopy with a first-time diagnosis and complete removal of one or two adenomas. A history of adenomatous polyps, a genetic predisposition to CRC, or a high-risk family history of CRC exclude participation. Patients will be randomized to either surveillance colonoscopy at 5 and 10 years or at 10 years. Participants in either arm may undergo an unscheduled colonoscopy if medically indicated.
The primary endpoint of the FORTE trial is the incidence of CRC at 10 years; the two surveillance protocols — 10 years vs. 5 and 10 years — will be compared. Secondary endpoints are the incidence of advanced adenomas, the incidence of advanced CRC, and mortality due to CRC. A cost/benefit analysis is also planned. Additionally, blood and stool samples will be collected from this large study cohort and will provide a resource to study the relationships between genetics, stool microbial content, and outcomes.
If the FORTE trial finds that surveillance colonoscopy every 10 years is noninferior to 5- and 10-year surveillance, as observational studies have suggested, millions of individuals will avoid the inconvenience, costs, and medical risks incurred for a colonoscopy that does not add significant benefit.
Additionally, if millions fewer surveillance colonoscopies are performed, personnel and facility resources could be reallocated to better serve public health, for example, by increasing screening to underserved populations. The American College of Gastroenterology (ACG), the American Society for Gastrointestinal Endoscopy (ASGE), and the American Gastroenterological Association (AGA) have formally expressed their support for the conduct of the trial and encourage participation by endoscopists and eligible patients.
Because ~15 million colonoscopies are performed every year, and small, benign adenomas are found in a third of patients undergoing screening, there are numerous potential participants for the FORTE trial. Additionally, eligibility is not limited to patients with colonoscopy performed after a site launches the FORTE trial. Patients with a qualifying colonoscopy up to four years prior may be eligible. The FORTE team is applying innovative approaches to enhance patient recruitment for the trial. For example, they have contracted with Pieces, a healthcare artificial intelligence company with expertise in natural language processing (NLP). Using NLP, colonoscopy and pathology reports in the electronic medical record can be analyzed in bulk.4 A participating institution may be performing 30,000– 40,000 colonoscopies per year, and NLP will provide a more efficient and automated way to identify eligible participants.
The FORTE trial is off to a great start! Centers that have launched the study are enrolling well. For example, UPMC has enrolled ~50 patients in the first six months. New study locations are being added. FORTE is a landmark trial with the potential to definitively inform subsequent clinical practice.
References/Recommended Reading
1. Lieberman DA, Rex DK, Winawer SJ, Giardiello FM, Johnson DA, Levin TR. Guidelines for colonoscopy surveillance after screening and polypectomy: A consensus update by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012;143:844-857.
2. Gupta S, Lieberman D, Anderson JC, Burke CA, Dominitz JA, Kaltenbach T, et al. Recommendations for follow-up after colonoscopy and polypectomy: A consensus update by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2020;158:1131-1153 e1135.
3. Click B, Pinsky PF, Hickey T, Doroudi M, Schoen RE. Association of colonoscopy adenoma findings with long-term colorectal cancer incidence. JAMA. 2018;319:2021-2031.
4. Kreimeyer K, Foster M, Pandey A, Arya N, Halford G, Jones SF, et al. Natural language processing systems for capturing and standardizing unstructured clinical information: A systematic review. J Biomed Inform. 2017;73:14-29.
