This study is a national multicenter RCT of CRC screening in the population [TARGET-C study, Chinese Clinical Trial Platform (http://www.chitr.org.cn)]. Participants were recruited from communities and villages according to the uniform inclusion and exclusion criteria.

The inclusion criteria for patients were as follows: (1) Had permanent residency in the study area or had resided in the area for ≥ 3 years; (2) Aged 50 to 74 years; and (3) Provided informed consent.

The exclusion criteria were: (1) Had a history of CRC; (2) Had a previous history of colectomy; (3) Had been diagnosed with cancer or had been receiving any cancer-related treatment before enrollment; (4) Had undergone colonoscopy, fibersigmoidoscopy, computed tomography-simulated colonoscopy, or other examinations in the past 5 years; (5) Had received a FIT or FIT-DNA test within the past year; (6) Had symptomatic lower digestive tract diseases or symptoms suggesting the need for diagnostic colonoscopy; and (7) Had severe disease and were not eligible for CRC screening.

The TARGET-C study planned to conduct a single screening in the colonoscopy group, a total of four rounds of annual screening in the FIT and graded screening groups, and long-term follow-up for all enrolled subjects. In this study, eligible subjects were randomly assigned to three intervention groups at a ratio of 1:2:2: (1) Colonoscopy group: Subjects who received a single colonoscopy at baseline screening; (2) FIT group: Subjects who received FIT tests during baseline screening and those who were FIT-positive who received colonoscopies. At the annual follow-up once a year thereafter, FIT testing will continue to be performed on eligible subjects; and (3) Graded screening group: Subjects were assessed for CRC risk at baseline screening, those assessed as high risk received colonoscopy, and those assessed as low risk received FIT (FIT-positive received colonoscopy). At subsequent annual follow-up visits once a year, eligible subjects continue to be offered screening consistent with baseline screening protocols. During the implementation of this project, all screening and testing items were free. All subjects signed informed consent forms, and the First Affiliated Hospital of Zhengzhou University Ethics Committee approved this study (Approval number: 18-013-1619).

Statistical analysis R 3.5.1 software was used to create random assignment schemes using preset random number seeds, which were imported into the project information management platform. The researchers who created the randomized assignment schemes did not help find field subjects. After completing subject recruitment, the staff of each research center entered the subject information into the project information management platform and conducted a qualification review. When the audit is successful, the project information management platform will relay to the field staff and subjects the group information that the system assigned. The study adopted a single-blind design; that is, the subjects and the staff responsible for the recruitment and management of the subjects were aware of the study grouping information and arranged the corresponding screening interventions, while the doctors providing clinical examination for the subjects were unaware of the subjects' grouping information.

The field staff contacted all the subjects who required colonoscopy by phone and made an appointment for them. The project team's designated medical facilities carried out all colonoscopies in accordance with standardized operating procedures. Standardized forms were used to collect colonoscopy (including pathological diagnosis) examination results, which were checked by staff and entered into the project information management platform.

FIT was performed with a self-testing quantization kit (Hangzhou Nuohui Health Technology Co., Ltd.). The staff will take the initiative to contact the subject and issue the FIT kit and explain the FIT operation process in detail; then, the subject will complete the test according to the instructions. The test results (positive, negative, or invalid) were reported to the smartphone app developed by the project team or were actively tracked and followed up by the staff. If the FIT is invalid, it should be tested again. For those who receive an FIT, the program will provide free colonoscopy. The next round of screening will not include members of the FIT and graded screening groups (low-risk individuals) who are FIT-positive and have undergone colonoscopy, while other subjects (FIT-negative or FIT-positive but have not undergone colonoscopy) will undergo follow-up FIT screening in accordance with the study protocol.

CRC risk was assessed using the Asia-Pacific CRC Risk Score system. The scoring system assigns different weights based on age, sex, family history of CRC in first-degree relatives, smoking history, and body mass index, which are then added together to obtain the final score. According to the results of previous studies, this study defined a total APCS score ≥ 4 as a high risk of CRC; otherwise, it was defined as a low risk of CRC. People at high risk should undergo colonoscopy; those at low risk should receive an FIT, and if the FIT is positive, further colonoscopy should be performed. The colonoscopy and FIT procedures were consistent with those described above. Risk assessment was performed at baseline and at the second follow-up screening, and appropriate screening was recommended based on the assessment results and colonoscopy status.

All subjects were recruited through an epidemiological questionnaire survey in which basic personal information, lifestyle information, intestinal disease examination history, family cancer history, and other information were collected. The staff checked and entered the data into the project information management platform after collecting all clinical examination information (colonoscopy, pathological examination, etc.) through standardized questionnaires.

The final diagnosis of the patient was based on a colonoscopy and pathology report. The main outcome indicators of this study were advanced tumors, including CRC and advanced adenoma. The secondary outcome measures were arbitrary colorectal tumors, including rectal carcinoma, progressive adenoma, and nonprogressive adenoma. Advanced adenomas were defined as adenomas with any of the following characteristics: (1) Diameter ≥ 1 cm; (2) Villous adenoma or tubular villous adenoma; (3) High-grade intraepithelial neoplasia; or (4) A serrated adenoma ≥ 1 cm in diameter or with dysplasia. Colorectal adenomas that do not have the characteristics of advanced-stage adenomas were defined as nonadvanced-stage adenomas. Colorectal tumors were categorized by where they were found in the colon. Tumors in the splenic flexure, descending colon, and sigmoid colon were called distal colon tumors. Tumors in the transverse colon, hepatic flexure of the colon, ascending colon, and ileocecal region are called proximal colon tumors.

To ensure the consistency of the pathological diagnosis results among the different research centers, all pathological sections of CRC, advanced adenoma, and nonadvanced adenoma patients included in this study were reviewed by the same pathologist. In cases where the diagnosis is inconsistent, the final diagnosis is discussed by the project expert group. All the data were logically checked and reviewed.

The main outcome measure (advanced tumor detection rate) was used to determine the sample size. It was thought that the advanced tumor detection rate in the graded screening group would be approximately the same as that in the colonoscopy group and greater than that in the FIT group. Based on this assumption and compared with previous study data, the expected tumor detection rates in the colonoscopy group, FIT group, and graded screening group were approximately 6.5%, 1.8%, and 5.0%, respectively; the population participation rates were 50%–70%, 60%–90%, and 60%–90%, respectively; and the overall loss to follow-up rate was 10%. When the test level α was 0.05, the degree of assurance (1-β) was 80%, and the detection rate of advanced tumors was 0.05%, the minimum sample sizes required for the colonoscopy group, the FIT group, and the graded screening group were 3417, 6834, and 6834, respectively, according to the 1:2:2 study design.

R 4.1.3 software was used to establish the database and carry out the statistical analyses. Age, sex, educational background, and other statistical data are expressed as frequencies, and a chi-square test was used for comparisons between groups. Intention analysis was used to compare the rates of advanced tumor detection and negative colonoscopy results among the three screening programs. A multivariate logistic regression model was used to compare the differences in tumor detection rates in the advanced stages of different screening schemes, and the results are expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The statistical tests used in this paper were bilateral tests, and differences with P < 0.05 were considered statistically significant.

The first subject was recruited and enrolled in May 2020; baseline screening (T0) was completed in May 2021; and the first follow-up screening (T1) was completed from June 2021 to May 2022. A second follow-up screening (T2) was completed between June 2022 and May 2023. A total of 19582 subjects who met the inclusion criteria were recruited. There were 3937, 7858, and 7787 patients in the colonoscopy group, FIT group, and graded screening group, respectively. After further qualification checks, 54, 65, and 90 participants were excluded, respectively. A total of 19373 subjects were ultimately included in this study, including 3883 in the mesenteroscopy group, 7793 in the FIT group, and 7697 in the graded screening group. The baseline data for the three groups are shown in Table 1.

At the baseline screening, a total of 1644 colonoscopy patients in the colonoscopy group completed colonoscopy according to the protocol, with a population participation rate of 42.3% (1644/3883). A total of 7327 participants in the FIT group completed the FIT examination according to the scheme, and the population participation rate was 94.0% (7327/7793). In the graded screening group, 25 patients did not complete the risk assessment, and 1453 of the remaining 7672 patients who were assessed as high risk were required to undergo colonoscopy; 712 of these patients completed the examination, and the colonoscopy screening population participation rate was 49.0% (712/1453). According to the protocol, 6219 people who were considered low risk had to undergo an FIT. Of those, 5845 completed the test, giving the graded screening group an overall participation rate of 85.2% (6557/6219) and a population participation rate of 94.0% (5845/6219). Overall, after three screenings, the overall population participation rates (total number of subjects or screening groups who completed at least one round of screening in accordance with the study protocol) in the colonoscopy, FIT, and graded screening groups were 42.3% (1644/3883), 99.3% (7740/7793), and 89.2% (6865/7697), respectively (P < 0.05), as shown in Figure 1.

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Figure 1 Population participation rate analysis of three groups of screening programs. FIT: Fecal occult blood test.

As shown in Table 2, at the baseline screening, the first follow-up screening, and the second follow-up screening, the percentages of positive FIT results among the subjects in the FIT group were 13.7%, 5.6%, and 5.5%, respectively. The compliance rates of colonoscopy in the FIT-positive population were 76.3%, 75.7%, and 71.7%, respectively. In the graded screening group, the FIT-positive rates of the low-risk group were 10.2%, 3.8%, and 2.7%, and the colonoscopy compliance rates of the FIT-positive group were 76.9%, 74.6%, and 60.1%, respectively. The high risk rates for the three screenings were 18.9% (1453/7697), 11.6% (737/6352), and 14.9% (915/6131), respectively. The compliance rates of colonoscopy in the high-risk groups were 49.0% (712/1453), 6.4% (47/737), and 10.5% (96/915), respectively.

The results of the intentional analysis showed that the detection rate for advanced tumors by single colonoscopy was 2.76%. In the FIT group, the cumulative detection rates at baseline, first follow-up screening, and second follow-up screening were 1.15%, 1.67%, and 2.17%, respectively. The cumulative detection rates of advanced tumors at baseline, first follow-up, and second follow-up were 1.65%, 1.91%, and 2.35%, respectively. After three screenings, the detection rate of advanced adenoma in the colonoscopy group was greater than that of the FIT group (OR = 1.30, 95%CI: 1.01-1.65, P = 0.037); there was no significant difference in the detection rate of advanced tumors between the colonoscopy group and the graded screening group (OR = 1.9, 95%CI: 0.93-1.51, P = 0.156), as well as between the graded screening group and the FIT group (OR = 1.09, 95%CI: 0.88-1.34, P = 0.440). Among the three screening programs, the detection rate of advanced tumors in the distal colon or rectum was greater than that in the proximal colon (P < 0.05), as shown in Table 3.

The intentional analysis showed that the colonoscopy load was 15.4 times and 4.1 times greater in the colonoscopy group for the detection of advanced tumors and arbitrary colorectal tumors, respectively. In the FIT group, the colonoscopy loads for detecting advanced tumors at baseline screening and ,first and second follow-up screening stages were 9.1, 8.3, and 7.8, respectively. The colonoscopy loads for detecting any colorectal tumor were 3.2, 3.1, and 3.0, respectively. The colonoscopy loads for advanced tumors detected at baseline screening, first follow-up screening, and second follow-up screening were 10.3 times, 10.5 times, and 10.2 times, respectively. The colonoscopy loads for detecting any colorectal tumor were 3.5, 3.4, and 3.5, respectively. The colonoscopy load for detecting lesions in the female population was greater than that in the male population in the three screening regimen groups (P < 0.05 for all), as shown in Tables 4 and 5.