• Pieter H A Wisse, Willemijn de Klaver, Francine van Wifferen, Frejanne G van Maaren-Meijer, Huub E van Ingen, Lana Meiqari, Iris Huitink, Mariska Bierkens, Margriet Lemmens, Marjolein J E Greuter, Monique E van Leerdam, SpaanderManon C WMCWDepartment of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands., Evelien Dekker, CoupéVeerle M HVMHDepartment of Epidemiology and Data Science, Amsterdam University Medical Centers, Location Vrije Universiteit, Amsterdam, Netherlands., Beatriz Carvalho, Meike de Wit, and Gerrit A Meijer.
• Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands.
• Lancet Oncol. 2024 Mar 1; 25 (3): 326337326-337.

BackgroundThe faecal immunochemical test (FIT) is widely employed for colorectal cancer screening. However, its sensitivity for advanced precursor lesions remains suboptimal. The multitarget FIT (mtFIT), measuring haemoglobin, calprotectin, and serpin family F member 2, has demonstrated enhanced sensitivity for advanced neoplasia, especially advanced adenomas, at equal specificity to FIT. This study aimed to prospectively validate and investigate the clinical utlitity of mtFIT versus FIT in a setting of population-based colorectal cancer screening.MethodsIndividuals aged 55-75 years and who were eligible for the Dutch national FIT-based colorectal cancer screening programme were invited to submit both a FIT and mtFIT sample collected from the same bowel movement. Positive FIT (47 μg/g haemoglobin cutoff) or mtFIT (based on decision-tree algorithm) led to a colonoscopy referral. The primary outcome was the relative detection rate of mtFIT versus FIT for all advanced neoplasia. Secondary outcomes were the relative detection rates of colorectal cancer, advanced adenoma, and advanced serrated polyps individually and the long-term effect of mtFIT-based versus FIT-based programmatic screening on colorectal cancer incidence, mortality, and cost, determined with microsimulation modelling. The study has been registered in ClinicalTrials.gov, NCT05314309, and is complete.FindingsBetween March 25 and Dec 7, 2022, 35 786 individuals were invited to participate in the study, of whom 15 283 (42·7%) consented, and 13 187 (86·3%) of 15 283 provided both mtFIT and FIT samples with valid results. Of the 13 187 participants, 6637 (50·3%) were male and 6550 (49·7%) were female. mtFIT showed a 9·11% (95% CI 8·62-9·61) positivity rate and 2·27% (95% CI 2·02-2·54) detection rate for advanced neoplasia, compared with a positivity rate of 4·08% (3·75-4·43) and a detection rate of 1·21% (1·03-1·41) for FIT. Detection rates of mtFIT versus FIT were 0·20% (95% CI 0·13-0·29) versus 0·17% (0·11-0·27) for colorectal cancer; 1·64% (1·43-1·87) versus 0·86% (0·72-1·04) for advanced adenoma, and 0·43% (0·33-0·56) versus 0·17% (0·11-0·26) for advanced serrated polyps. Modelling demonstrated that mtFIT-based screening could reduce colorectal cancer incidence by 21% and associated mortality by 18% compared with the current Dutch colorectal cancer screening programme, at feasible costs. Furthermore, at equal positivity rates, mtFIT outperformed FIT in terms of diagnostic yield. At an equally low positivity rate, mtFIT-based screening was predicted to further decrease colorectal cancer incidence by 5% and associated mortality by 4% compared with FIT-based screening.InterpretationThe higher detection rate of mtFIT for advanced adenoma compared with FIT holds the potential to translate into additional and clinically meaningful long-term colorectal cancer incidence and associated mortality reductions in programmatic colorectal cancer screening.FundingStand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland.Copyright © 2024 Elsevier Ltd. All rights reserved.

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