A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population

Study Overview
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Brief Summary
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to determine screening value of stool-based SDC2 DNA methylation test for advanced colorectal neoplasia in the asymptomatic Chinese community population.

Detailed Description
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In China, colorectal cancer (CRC) remains to be the leading cancer of the digestive system. According to nationwide cancer statistics using population-based cancer registry data in China, age-standardized incidence rate of CRC and age-standardized mortality rate increased significantly from 2000 to 2015. It induces a substantial financial burden in terms of healthcare utilization and quality-adjusted life years (QALY) lost. Fecal Occult Blood Tests (FOBT) and colonoscopy have been proposed as the main primary screening modalities for asymptomatic subjects by international guidelines and Asia Pacific Consensus Statements. Nevertheless, shortage and uneven distribution of colonoscopy resources combined with huge population base consisted of the current situation in China. Previous population-based CRC screening programs usually employed questionnaires and/or FOBT to assess high-risk groups and recommended colonoscopy. This algorithm faced difficulties such as complex traditional questionnaires, low colonoscopy adherence, and a high false-positive rate. When the Coronavirus disease 2019 pandemic further limited the implementation of colonoscopy, the contradictions developed more acute. A Hong Kong group had designed and validated a colorectal cancer risk scoring system based on age, gender, smoking history, and family history through the results of screening in 11 Asia-Pacific cities. The Asia-Pacific Colorectal Screening (APCS) score was more concise and divided the population into three categories: low risk, intermediate risk, and high risk. Compared with the low-risk population, the probability of advanced colorectal neoplasia in intermediate-risk and high-risk population increased by 2.6 times and 4.3 times respectively. Because of simplicity and efficiency, it was recommended by Asia-Pacific screening guidelines and several guidelines in China. Another APCS related multi-center study indicated that by selecting high-risk subjects and low/average-risk subjects with a positive fecal immunochemical test (FIT) for colonoscopy, the colonoscopy workload could be reduced by 50% compared with the strategy of primary colonoscopy in those same subjects. All these experiences deserved to be drawn on during the post-pandemic era. The recent decade has witnessed a rapid development of non-invasive biomarkers to detect CRC. Stool DNA(sDNA) Testing is a novel screening test for CRC, using molecular techniques to identify CRC-relevant biomarkers in stool. One of its toolkits, Multitarget Stool DNA Testing (FIT-DNA), was first approved by the FDA in 2014 for its application in clinical practice, which has been widely promoted in the United States. Subsequently, it was endorsed by multiple societies as one of the recommended screening tests. Recently, a stool test of methylated Syndecan-2(SDC2) has been developed as a fecal-DNA product targeted to improve the diagnostic accuracy of CRC screening. A meta-analysis of previous clinical studies reporting the accuracy of stool DNA methylation tests in detecting CRC included 46 studies totaling 16,149 patients. The most accurate single gene was found to be SDC2 with a pooled sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%). A recent study involving 1,110 subjects from 2017 to 2018 by three Chinese tertiary hospitals assessed the performance of the SDC2 sDNA test. The sensitivity of the SDC2 sDNA test was 301/359 (83.8%) for CRC, 16/38 (42.1%) for advanced adenomas, and 134/154 (87.0%) for early-stage CRC (stage I-II), while maintaining a specificity of 699/713 (98.0%). Nevertheless, there were limitations in the design of these original studies. For instance, most involved small, hospital-based CRC cases and controls that might not fill the knowledge gap between population screening. Additional clinical trials are required to further validate its diagnostic accuracy in other populations, especially community-setting. Potential participates would be recruited via community public communication. The subjects would be asked to fill in a concise questionnaire obtained through a public WeChat account after informed consent. Basic information would be acquired while APCS score and correspondent risk categories would be calculated automatically. After sampling education, stool collection devices of sDNA and quantitative fecal immunochemical test (qFIT) would be distributed to all subjects. Two samples of stool from single defecation would be requested to put into the two collection devices according to instructions respectively by the subjects themselves at home. Efforts would be made by the public WeChat account and the community staff to urge samples recover from subjects as quickly as possible (prefer within 24h after defecation). Community staff would deliver the samples qualified in the initial evaluation to the standardized laboratory for testing as quickly as possible. If APCS be evaluated high-risk or any of qFIT or sDNA tests positive, the risk of the subject would be considered increased. Colonoscopy would be strongly recommended, and priority and rapid arrangement would be made in the corresponding center. For subjects with low/intermediate-risk APCS and negative qFIT and sDNA, the project team also encourages the subjects to accept colonoscopy on the basis of a clear understanding of benefits and risks. We would help to arrange colonoscopy as early as possible. All colonoscopy examinations will be performed by experienced endoscopists while monitoring quality of colonoscopy (bowel preparation, cecal intubation rate and withdrawal time). Full-time recording personnel would be arranged to follow up and record the relevant information of colonoscopy. For the subjects diagnosed with colorectal cancer, the postoperative diagnosis and tumor-node-metastasis (TNM) staging of the subjects would be retrieved.

Official Title
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Detection of Advanced Colorectal Neoplasia for Stool DNA in Asymptomatic Chinese Population : A Multi-central Community-based Screening Study

Conditions
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Adenoma, Colorectal Cancer, Colorectal Neoplasm, Advanced Adenoma, Serrated Lesion

Intervention / Treatment
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* Diagnostic Test: Stool-based SDC2 DNA methylation test
* Diagnostic Test: quantitative Fecal immunochemical test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asymptomatic screening individual (no alarm features predicting colorectal cancer including hematochezia, melena, anemia of unknown cause, weight loss, abdominal mass, a positive result of digital rectal examination) Age between 45 to 75 years old, the gender is not limited Willing to participate and sign informed consent Exclusion Criteria: Patients with contraindications for bowel preparation or colonoscopy Patients with known colorectal adenoma or serrated lesions History of colonoscopy within 5 years or polypectomy Patients with inflammatory bowel disease History of CRC and patients clinically highly suspected with colorectal cancer History of hereditary CRC syndrome (including polyposis) Patients taking anticoagulants such as aspirin and warfarin within 7 days, or who have coagulopathy Pregnancy, or severe organ insufficiency (heart, lung, or kidney et al)

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: Stool-based SDC2 DNA methylation test|A diagnostic device measuring syndecan 2(SDC2) methylation status in stool DNA to detect colorectal cancer|
|Diagnostic Test: quantitative Fecal immunochemical test|A diagnostic device using immunoturbidimetric methods to measure fecal hemoglobin concentration|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Detection of advanced colorectal neoplasia | Advanced colorectal neoplasia is defined as a colorectal adenoma or sessile serrated lesion ≥10 mm, adenoma or sessile serrated lesion with tubulovillous or villous histology, adenoma with high-grade dysplasia, traditional serrated adenoma, or presence of colorectal cancer. | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compliance rate of colonoscopy | The compliance rate of colonoscopy was calculated as the number of recieving colonoscopy divdied the number of accomplishing primary evaluation of APCS, stool DNA or FIT. | Through study completion, an average of 1 year | 
| Detection of colorectal cancer | Lesions will be confirmed as malignant by histopathologic examination. | Through study completion, an average of 1 year | 
| Detection of colorectal neoplasia | Advanced colorectal neoplasia is defined as a colorectal adenoma or sessile serrated lesion, traditional serrated adenoma, hyperplastic polyp ≥10 mm, or colorectal cancer. Lesions will be confirmed as malignant or precancerous by histopathologic examination. | Through study completion, an average of 1 year | 
| Efficacy of sDNA in the detection of advanced colorectal neoplasia in high-risk asymptomatic subgroup. | High-risk subgroup: APCS calculated high-risk or qFIT positive. A diagnostic colonoscopy procedure is the reference method. Lesions will be confirmed as malignant or precancerous by histopathologic examination. | Through study completion, an average of 1 year | 
| Efficacy of sDNA in the detection of advanced colorectal neoplasia in low-risk asymptomatic subgroup. | Low-risk subgroup: APCS calculated low or medium risk, and qFIT negative. A diagnostic colonoscopy procedure is the reference method. Lesions will be confirmed as malignant or precancerous by histopathologic examination. | Through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Methylated Syndecan-2(SDC2), Stool DNA, Fecal immunochemical test, Advanced colorectal neoplasia, Asia-Pacific Colorectal Screening score