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Chrysarobin

A diagnostic device measuring syndecan 2(SDC2) methylation status in stool DNA to detect colorectal cancer

Stool-based SDC2 DNA methylation test

A diagnostic device using immunoturbidimetric methods to measure fecal hemoglobin concentration

quantitative Fecal immunochemical test

Zhaoshen Li, MD

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

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.

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

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

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.

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.

Lesions will be confirmed as malignant by histopathologic examination.

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.

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.

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.

Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Gongli Hospital of Shanghai Pudong New Area

Shanghai Songjiang District Central Hospital

Shanghai Jing'an District Central Hospital

Shanghai Yangpu District Central Hospital

People's Hospital of Qingyuan

Guangdong Provincial Hospital of Traditional Chinese Medicine

900 Hospital of the Joint Logistics Team

First Affiliated Hospital of Suzhou Medical College

Affiliated Hospital of Jiangnan University

Traditional Chinese Medicine Hosipital of Kunshan

Ankang Central Hospital

Shandong Cancer Hospital and Institute

Ningjin County Hospital

Changhai Hospital

MD,Director, Head of Department of Gastroenterology and Digestive Endoscopy Center, Principal Investigator, Clinical Professor

Anti-Infective Agents

Central Nervous System Depressants

Anti-Inflammatory Agents, Non-Steroidal

Ethanol

Subjects randomized to the control arm will review the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled visit with their provider.

Subjects randomized to the experimental arm will complete the ACNI risk assessment tool after reviewing the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled office visit with their provider.

Patients randomized to the experimental arm will be asked a complete the ACNI risk assessment tool after reviewing a web-based colorectal cancer decision aid. The ACNI uses a point based system to stratify patients into low (mean rate of ACN \~3%) versus intermediate/high (\~ 8%) risk groups based on responses to 6 items: age (50-59, 60-69, 70+), sex (male/female), race/ethnicity (non-Hispanic black, other), smoking history (never, \<20 years, 20+ years), daily alcohol intake (\< 2 vs. \>/=2 drinks) and use of non-steroidal anti-inflammatory drugs (ever, never). The index represents a prototype version of the Advanced Colorectal Neoplasia Index (Am J Gastroenterol 2015;110:1062-71).

Risk Assessment

Paul C Schroy III, MD, MPH

Shared decision-making (SDM) has been advocated as a strategy for increasing colorectal cancer (CRC) screening rates. Our studies to date suggest that while the use of a novel computer-based decision aid facilitates several components of SDM from both the patient and provider perspective, there is a reluctance among providers to acquiesce to patient preferences for a particular screening strategy when its differs from their own. The overall objective of this study is to assess whether risk stratification for advanced colorectal neoplasia influences clinical decision-making related to screening test selection and adherence within a SDM framework. Eligible subjects will be randomized to either an experimental arm, in which they will be asked to complete a 6-item risk assessment questionnaire known as the "Advanced Colorectal Neoplasia Index \[ACNI\]" after reviewing a web-based decision aid, or a control arm, in which they will only review the decision aid. Both interventions will take place just before a prearranged office visit with their provider. The primary outcome will be screening test ordered; secondary outcomes will include test completion rates, concordance between test preference and test ordered,, patient satisfaction with decision-making process, screening intentions, 6-month test completion rates and provider satisfaction. Outcomes will be evaluated using computerized tracking systems or validated instruments.

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Screening by any of at least 6 different methods is a cost-effective yet underutilized strategy for reducing both CRC incidence and mortality. Because these methods differ with respect to risks and benefits and because existing evidence fails to identify a single best strategy, most authoritative groups advocate a shared decision-making (SDM) approach when selecting an appropriate screening strategy. SDM is a sequential, interactive process involving information exchange, values clarification, decision-making and mutual agreement. To facilitate this process, patient-oriented decision aids have been developed to enable patients to identify a preferred strategy based on personal values and empower them to participate in the decision-making process. Our recent studies to date find that although decision aids enable patients to make informed choices, providers are often unwilling to acquiesce to patient preferences when they differ from their own. Since accurate risk assessment is a critical component of effective clinical decision-making, the investigators postulate that risk stratification for the point prevalence of advanced colorectal neoplasia will enable providers to incorporate objective risk-based criteria in their decision-making when considering patient preferences for screening. To that end, the investigators have recently developed and validated the so-called "Advanced Colorectal Neoplasia Index \[ACNI\]" that stratifies patients into low versus intermediate/high risk categories based on available clinical data, including age, sex, race/ethnicity, smoking history, daily alcohol intake and use of non-steroidal anti-inflammatory drugs. The overall objective of this study is to determine whether risk stratification using the ACNI influences clinical decision-making related to screening test selection and adherence to screening within a SDM framework.

Hypothesis: Providers who incorporate risk estimates of ACN in their decision-making when recommending screening tests are more likely to consider patient preferences for options other than colonoscopy than providers lacking this information.

Risk Stratification to Promote Effective Shared Decision-Making for Colorectal Cancer Screening

Impact of Risk Stratification on Shared Decision-Making for Colorectal Cancer Screening

Test-specific concordance between patient preference for colonoscopy and test ordered for standard care versus risk assessment groups. It is defined as the number of patients who had their preferred test ordered.

Test-specific concordance between patient preference for a screening test other than colonoscopy (fecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema, CT colonography and stool DNA) and test ordered for standard care versus risk assessment arms. It is defined as the number of patients who had their preferred test ordered.

Test-specific concordance between patient preference for colonoscopy and test ordered for high versus low risk patients. It is defined as the number of patients who had their preferred test ordered.

Test-specific concordance between patient preference for a screening test other than colonoscopy (fecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema, CT colonography and stool DNA) and test ordered for high versus low risk patients. It is defined as the number of patients who had their preferred test ordered.

Concordance is a measure of the agreement between the patient's test preference and actual test ordered for standard care vs. risk assessment patients. It is defined as the number of patients who had their preferred test ordered.

Concordance between patient preference and test ordered for high versus low risk patients. It is defined as the number of patients who had their preferred test ordered.

SDMP was assessed on the posttest using the validated 12-item Satisfaction with the Decision-Making Process scale. Individual items are assigned a point value ranging from 1 for ''strongly disagree'' (or ''poor'') to 5 for ''strongly agree'' (or ''excellent''). A cumulative score is then calculated based on the summed response scores for each item (maximum score = 60). Data was missing for 11 patients in the concordant group and 6 patients in the discordant group

Screening intentions were assessed on the posttest. Patients were asked how sure they were that they would complete the screening test that got scheduled Scores ranged from 5 = ''completely'' to 1 = ''not at all sure.'' Data was missing for 11 patients in the concordant group and 6 patients in the discordant group.

Test completion rates were tracked using BMC's electronic medical record, which captures results for all endoscopic procedures, imaging studies, and stool blood tests.

Provider satisfaction was assessed based on responses to a 3-item pretest administered prior to commencement of the study and the same 3-item posttest. The 3 items assessed to the extent to which providers felt that personalized risk assessment would be useful for: (1) selecting an appropriate screening test for their average risk patients \[test selection\]; (2) reduce time to decide on an appropriate screening modality \[save time\]; and (3) make them more receptive to patient preferences and possibly order a screening test other than colonoscopy \[receptive to patient preferences\]. Responses were assigned a point value ranging from 5= "strongly agree" and 1 = "strongly disagree".

Boston Medical Center

BMC Attending Physician

Subjects randomized to the experimental arm will review the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled office visit with their provider.

Standard Care

Subjects randomized to the control arm reviewed the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled visit with their provider.

Subjects randomized to the experimental arm completed the ACNI risk assessment tool after reviewing the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled office visit with their provider.

Risk Assessment: Patients randomized to the experimental arm will be asked a complete the ACNI risk assessment tool after reviewing a web-based colorectal cancer decision aid The ACNI uses a point based system to stratify patients into low (mean rate of ACN \~3%)versus intermediate/high (\~ 8%) risk groups based on responses to 6 items: age 50-59,60-69, 70+), sex (male/female), race/ethnicity (non-Hispanic black, other), smoking history (never, \<20 years, \>20 years), daily alcohol intake (\< 2 vs. \>/=2 drinks) and use of non-steroidal anti-inflammatory drugs (ever, never).

Total

Age, Continuous

Sex: Female, Male

Ethnicity : Hispanic

Ethnicity : Non-Hispanic

Ethnicity : Refused

Race : White

Race : Black

Race : Other

Race/Ethnicity, Customized

Education

Marital status

Insurance

Desired role in decision-making

Single institution setting; lack of provider education about the utility of risk stratification into their decision-making.

Paul C. Schroy III, MD, MPH

Subjects randomized to the standard care arm reviewed the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled office visit with their provider.

Subjects randomized to the experimental arm completed the ACNI risk assessment tool after reviewing the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled office visit with their provider.

Concordance Between Patient Preference and Test Ordered

Patients with cumulative ACNI scores of 5 to 12 were classified as intermediate/high risk (hereafter referred to as high risk), with a mean ACN rate of 8.3% (95% CI, 7.1% - 29.6%)

High Risk

Patients with cumulative scores of less than 5 were classified as low risk, with a mean ACN rate of 3.1% (95% confidence interval \[CI\], 2.4% - 24.1%).

Low Risk

Patients with cumulative ACNI scores of 5 to 12 were classified as intermediate/high risk (hereafter referred to as high risk), with a mean ACN rate of 8.3% (95% CI, 7.1% - 29.6%). Patients with cumulative scores of less than 5 were classified as low risk, with a mean ACN rate of 3.1% (95% confidence interval \[CI\], 2.4% - 24.1%).

Concordance Between Patient Preference and Test Ordered for High vs. Low Risk Patients

The subgroup of patients who had their preferred test ordered, regardless of study arm or risk-category.

Concordance

The subgroup of patients who had a non-preferred test ordered, regardless of study arm or risk-category.

Discordance

The subgroup of patients who had their preferred test ordered, regardless of study arm or risk-category. The subgroup of patients who had a non-preferred test ordered, regardless of study arm or risk-category.

Satisfaction With Decision-making Process (SDMP)

Screening Intentions

Screening Test Completion

Test selection

Save time

Receptive to patient preferences

Provider responses to a 3-item pretest administered prior the commencement of the study.

Pretest

Provider responses to the same 3-item posttest administered after completion of study enrollment. Provider responses to a 3-item pretest administered prior the commencement of the study.

Posttest

The difference in the number of providers reflect provider attrition during the 2-year study period.

Provider Satisfaction

Subjects randomized to the experimental arm reviewed the web-based decision aid (http://www.colorectalcancerscreening4u.com) just prior to a scheduled office visit with their provider.

Concordance Between Patient Preference for Colonoscopy and Test Ordered

Concordance Between Patient Preferences for Screening Tests Other Than Colonoscopy and Test Ordered

Concordance Between Patient Preference for Colonoscopy and Test Ordered for High Versus Low Risk Patients

Concordance Between Patient Preferences for a Screening Tests Other Than Colonoscopy and Test Ordered for High Versus Low Risk Patients

Subjects randomized to the experimental arm reviewed the web-based decision aid (http://www.colorectalcancerscreening4u.com) and the ACNI risk assessment tool just prior to a scheduled office visit with their provider.

Risk Assessment: Patients randomized to the experimental arm will be asked a complete the ACNI risk assessment tool after reviewing a web-based colorectal cancer decision aid The ACNI uses a point based system to stratify patients into low (mean rate of ACN \~3%)versus intermediate/high (\~ 8%) risk groups based on responses to 6 items: age 50-59,60-69, 70+), sex (male/female), race/ethnicity (non-Hispanic black, other), smoking history (never, \<20 years, \>20 years), daily alcohol intake (\< 2 vs. \>/=2 drinks) and use of non-steroidal anti-inflammatory drugs (ever, never).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population	NCT04786704	Colorectal Canc... Colorectal Neop... Advanced Adenom... Adenoma Serrated Lesion	Stool-based SDC... quantitative Fe...	45 Years - 75 Years	Changhai Hospital
Risk Stratification to Promote Effective Shared Decision-Making for Colorectal Cancer Screening	NCT01596582	Colorectal Canc...	Risk Assessment	50 Years - 75 Years	Boston Medical Center
A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population	NCT04786704	Colorectal Canc... Colorectal Neop... Advanced Adenom... Adenoma Serrated Lesion	Stool-based SDC... quantitative Fe...	45 Years - 75 Years	Changhai Hospital

Spots Global Cancer Trial Database for advanced colorectal neoplasia