The 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. Individuals 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 , , and is complete. Between 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. The 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. Stand Up to Cancer, Dutch Cancer Society, Dutch Digestive Foundation, and Health~Holland.

中文翻译：

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用于改善基于粪便的结直肠癌筛查计划的多目标粪便免疫化学测试：一项基于荷兰人群的配对设计干预研究

粪便免疫化学测试（FIT）广泛用于结直肠癌筛查。然而，其对晚期前驱病变的敏感性仍然不理想。多靶点 FIT (mtFIT) 可测量血红蛋白、钙卫蛋白和丝氨酸蛋白酶抑制剂家族 F 成员 2，已证明对晚期肿瘤（尤其是晚期腺瘤）的敏感性增强，且特异性与 FIT 相同。本研究旨在前瞻性验证和研究 mtFIT 与 FIT 在基于人群的结直肠癌筛查中的临床效用。年龄在 55-75 岁且有资格参加荷兰国家基于 FIT 的结直肠癌筛查计划的个人被邀请提交从同一排便中收集的 FIT 和 mtFIT 样本。阳性 FIT（47 μg/g 血红蛋白截止值）或 mtFIT（基于决策树算法）导致转诊结肠镜检查。主要结果是 mtFIT 与 FIT 对所有晚期肿瘤的相对检出率。次要结果是结直肠癌、晚期腺瘤和晚期锯齿状息肉的相对检出率，以及基于 mtFIT 与基于 FIT 的程序性筛查对结直肠癌发病率、死亡率和成本的长期影响，通过微观模拟模型确定。该研究已在 、 、 注册并已完成。 2022年3月25日至12月7日期间，共有35 786人受邀参与该研究，其中15 283人（42·7%）同意，15 283人中的13 187人（86·3%）同时提供了mtFIT和FIT样本具有有效的结果。在 13 187 名参与者中，6637 名（50·3%）为男性，6550 名（49·7%）为女性。 mtFIT 显示晚期肿瘤的阳性率为 9·11% (95% CI 8·62–9·61)，检出率为 2·27% (95% CI 2·02–2·54)，而阳性率为FIT 的检测率为 4·08% (3·75–4·43)，检出率为 1·21% (1·03–1·41)。对于结直肠癌，mtFIT 与 FIT 的检出率分别为 0·20% (95% CI 0·13–0·29) 和 0·17% (0·11–0·27)；晚期腺瘤为 1·64% (1·43–1·87) 与 0·86% (0·72–1·04)，0·43% (0·33–0·56) 与 0·17% (0·11–0·26) 适用于晚期锯齿状息肉。模型表明，与目前的荷兰结直肠癌筛查计划相比，基于 mtFIT 的筛查可以在成本可行的情况下将结直肠癌发病率降低 21%，并将相关死亡率降低 18%。此外，在相同的阳性率下，mtFIT 在诊断率方面优于 FIT。在同样低的阳性率下，与基于 FIT 的筛查相比，基于 mtFIT 的筛查预计将进一步降低结直肠癌发病率 5%，相关死亡率降低 4%。与 FIT 相比，mtFIT 对晚期腺瘤的检出率更高，有可能转化为额外的、具有临床意义的长期结直肠癌发病率以及程序性结直肠癌筛查中相关死亡率的降低。抵抗癌症、荷兰癌症协会、荷兰消化基金会和 Health~Holland。