Colorectal cancer (CRC) is one of the most common malignancies in China. Currently, its incidence rate is increasing at a rate of 4% per year, exceeding the global annual average growth rate. Screening and early diagnosis of colorectal cancer and precancerous lesions are key measures to reduce the disease burden of colorectal cancer in China. In previous clinical studies, colorectal cancer screening in high risk population received extensive attention. However, it cannot be ignored that the majority of sporadic colorectal cancers occur in the average risk population. Therefore, there is an urgent need to develop new approach for colorectal cancer screening in the average risk population in China.

Fecal Immunochemical Testing (FIT) initial screening followed by diagnostic colonoscopy is widely recommended by colorectal cancer screening guidelines worldwide. The current colorectal cancer screening approach faces challenges including limited sensitivity of initial screening technologies and insufficient population coverage in organized screening programs in China. As initial screening technologies, non-invasive blood tests which detects cfDNA methylation have been reported to have higher accuracy than FIT in detecting colorectal cancer. However, There is a lack of randomized controlled trials (RCTs) comparing the effectiveness of colonoscopy, FIT and FIT plus blood test for colorectal cancer screening.

In China Colorectal Cancer Screening Trial 1 (C-Cost1), we propose to perform a multicenter, cluster randomized, parallel group trial directly comparing colonoscopy with FIT and with FIT plus blood test in the average risk population in China. The main research hypotheses are: (1) The screening protocol of FIT group (Group B) is non-inferior to the colonoscopy group (Group A) in the colorectal cancer mortality rate at 10 years; (2) The screening protocol of FIT plus blood test group (Group C) is non-inferior to the colonoscopy group (Group A) in the colorectal cancer mortality rate at 10 years. Both of the two hypotheses should be met.

This study intends to recruit participants who meet the above inclusion and exclusion criteria in China, with the goal of recruiting at least 60300 eligible participants at baseline. The study adopts a cluster randomized controlled design. After signing the informed consent form, eligible participants will be randomly assigned to 3 colorectal cancer screening groups. All participants will undergo a 4-year screening phase, and then all participants will be followed up for a long term. Fecal, blood, and tissue samples will be collected from the participants during the study. The grouping and specific intervention measures are as follows:

1. Colonoscopy group (n = 20100): The internationally recommended screening protocol is adopted. The participants will only undergo a colonoscopy once at the first year. Suspicious lesions detected during the colonoscopy will be resected and further sent for pathological examination. All the participants will then receive annual follow-ups for the next 3 years, followed by long-term follow-ups.
2. FIT group (n = 20100): The internationally recommended screening protocol is adopted. In the first 4 years of the screening phase, all participants will receive annual FIT tests. Participants with positive FIT results are recommended to undergo diagnostic colonoscopy. Suspicious lesions detected during the colonoscopy will be resected and further sent for pathological examination. Participants who refuse FIT tests, have negative FIT tests, have positive FIT tests but do not receive diagnostic colonoscopy will be screened again in the first 4 years. All the participants will be followed by long-term follow-ups.
3. FIT plus blood test group (n = 20100): A new screening protocol is adopted. In the first 4 years of the screening phase, all participants will receive annual FIT tests and blood tests. Participants with positive FIT tests or positive blood tests are recommended to undergo diagnostic colonoscopy. Suspicious lesions detected during the colonoscopy will be resected and further sent for pathological examination. Participants who refuse FIT plus blood tests, have negative FIT plus blood tests, have positive FIT tests or positive blood tests but do not receive diagnostic colonoscopy will be screened again in the first 4 years. All the participants will be followed by long-term follow-ups.

Inclusion Criteria:

1. Age: 45-74 years old;
2. In good general condition, with normal mental state and voluntarily signing the informed consent form;

Exclusion Criteria:

1. Personal history of colorectal cancer or precancerous lesions;
2. History of previous colonrectal resection surgery;
3. Diagnosed with cancer before enrollment or currently receiving any cancer-related treatment;
4. Having received colonoscopy, flexible sigmoidoscopy, CT colonography and other examinations within the past 5 years;
5. Having received FIT or FIT-sDNA or cfDNA test within the past 1 year;
6. Symptomatic lower gastrointestinal diseases or symptoms suggesting the need for diagnostic colonoscopy for confirmation;
7. Accompanied by severe diseases that are not suitable for colorectal cancer screening;