Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Colorectal Neoplasms

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

This group will be screened with the risk-based model. The input of the model will be gathered with the FIT, a validated questionnaire, and from data of the Dutch general population registry. The threshold of the model will be set at a calculated risk of 0.10. To comply with ethical guidelines, all participants in this group with a FIT result of \>=15 mcg Hb/g faeces and a calculated risk of \<0.10 will also be offered a colonoscopy.

This group will be screened with the FIT. The threshold of the FIT will be set at \>= 15 mcg Hb/g faeces.

The intervention will be a risk-based logistic regression model that takes multiple variables into account to calculate the risk of advanced neoplasia as an outcome.

Risk-based logistic regression model

FIT is a stool-based test that detects human blood in faeces.

Evelien Dekker, PhD MD

Colorectal Carcinoma (CRC) is the third most frequent diagnosed cancer worldwide, with 1.4 million new cases every year. In an attempt to reduce this number many countries have implemented a nationwide screening programme targeted at detecting CRC in an early phase using fecal immunochemical tests (FITs). People with an elevated level of blood in their stool are offered a colonoscopy, an invasive medical procedure where CRCs and premalignant lesions (together also referred to as advanced neoplasia) can be detected accurately.

However, the current screening method using FIT is not optimal. In FIT-based CRC screening studies, 1 in 4 participants with CRC and 2 in 3 participants with advanced neoplasia receive a negative FIT result. In contrast, an estimated 1 in 2 FIT-positives have advanced neoplasia at colonoscopy.

Recent studies have demonstrated that a risk model that takes into account the FIT result and other risk factors for CRC could enhance the effectiveness of a FIT-based CRC screening programme.

The objective of this study is to assess the yield of advanced neoplasia in the colon and rectum of a FIT-based risk model at colonoscopy, compared to that of a FIT-only CRC screening strategy. Our hypothesis is that a risk-based model yields significantly more advanced neoplasia at colonoscopy than the FIT by itself, and that it does not affect participation rate.

To assess this hypothesis, the investigators have designed a clinical trial in which the investigators randomize 23,000 asymptomatic individuals between the age of 55 and 75 years old to either risk-based screening (intervention group) or FIT-only screening (control group). The intervention group will receive a questionnaire on risk factors of CRC (e.g. smoking, family history of CRC), and a FIT. The control group will only receive the FIT. The positivity threshold of the FIT in both groups will be set at 15 micrograms haemoglobin per gram faeces. The positivity threshold of the risk-based model in the intervention group will be set at 0.10 (out of a range of 0 to 1), a threshold that is calculated with a goal to match the positivity rate of the control group.

Participants with a result that is above the thresholds of the FIT and/or the risk-based model will be invited to undergo a colonoscopy according protocol of the Dutch national screening program. After the study has ended, the investigators will compare both groups to assess our hypotheses.

INTRODUCTION AND RATIONALE Colorectal Cancer (CRC) is the third most frequent diagnosed cancer worldwide, with 1.4 million new cases every year. Mortality of CRC is estimated at around 40%. To reduce the incidence of CRC and to abate the negative consequences associated with CRC, methods for early detection of (pre)malignant colorectal lesions have extensively been researched and implemented. Colonoscopy is the reference standard for the detection of advanced neoplasia, but it requires trained endoscopists, carries a high burden, harbours a risk for complications in patients, and increases societal costs.

Most screening programs use methods to select screening participants with a high risk of advanced neoplasia for colonoscopy. One such method is the detection of blood in stool with faecal immunochemical tests (FITs).

Multiple nation-wide screening programs have now been implemented using FIT, including one in the Netherlands. In the Dutch CRC screening program, using a FIT threshold of 47 µg Hb/g faeces, the sensitivity of FIT in detecting CRC is 85.5%. The sensitivity of FIT in detecting advanced neoplasia (AN) is however substantially lower: 38%.

FIT-based screening also generates a high number of false positives, leading to unnecessary colonoscopies and distress for those patients. Approximately 1 in 2 FIT-positives has advanced neoplasia; the first round of the Dutch CRC screening program, using a FIT threshold of 47 µg Hb/g faeces, reached a positive predictive value of 54%.

Previous studies have demonstrated the existence of clinical risk factors for CRC, such as male gender, age, family history of CRC, and smoking. In a ZonMW sponsored project (ZonMW 50-50115-96-521) our group has shown that higher age, male sex, a family history with close relatives in whom CRC was diagnosed, and active smoking were all associated with the presence of advanced neoplasia (Stegeman et al, Gut, 2014).

Multiple CRC risk models have been developed using these risk factors, but most show only weak discriminatory power. Others have proposed risk models that additionally included molecular markers, increasing performance and discriminatory power, but these markers can be cumbersome to collect and can be costly in respect to the relative cheap FIT test. the investigators propose to combine CRC risk factors with the quantitative FIT result. FIT is a quantitative test with a variable cut-off level, and individuals with higher values of faecal haemoglobin are at higher risk of having advanced neoplasia at the cost of a lower specificity. Therefore, the quantitative result can be used as a weight-factor in a risk model.

Based on information on these risk factors for CRC and the quantitative FIT-result, our FIT-based risk model for CRC screening calculates the personal risk of having advanced neoplasia at colonoscopy. Inviting screening participants with elevated risk for colonoscopy, rather than those whose FIT result exceeds a pre-specified threshold, has the potential to increase the effectiveness and efficiency of FIT-based CRC screening. However, this requires participants to complete the questions about risk.

Our hypothesis is that integration of FIT score with known risk factors (age, gender, smoking, and family history of CRC) improves the number of participants in whom advanced neoplasia is detected, relative to the number of invitees. The investigators will compare a risk-based approach to screening, as described above, to the conventional FIT-only screening in a randomized controlled screening trial.

OBJECTIVES The study hypothesis is that risk-based CRC screening significantly outperforms FIT-only CRC screening in terms of the relative number of invitees in whom advanced neoplasia is detected at colonoscopy.

Primary Research Question: does risk-based CRC screening result in a higher relative number of invitees in whom advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening?

Secondary Research Questions:

i) Does risk-based CRC screening result in a higher standardized screening yield in whom advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening? ii) Is the participation rate of risk-based CRC screening non-inferior compared to FIT-only screening? iii) Does risk-based CRC screening result in a higher relative number of invitees in whom advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening at higher FIT-positivity thresholds (from 15 µg Hb /g faeces)? iv) Does risk-based CRC screening result in a higher relative number of invitees in whom proximally located advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening?

METHODS The investigators will perform a randomized controlled trial in 23,000 randomly selected men and women (aged 55 to 75 years) eligible for participation in the national CRC screening programme. All eligible participants will be second time invitees, living within a 25 km radius from the colonoscopy centre Bergman Clinics Amsterdam, which is accredited for the national population screening program.

Eligible individuals are randomly allocated on a 1:1 basis to an invitation for either risk-based CRC screening (intervention group) or FIT-only screening (control group). Randomization per household will be done before invitation. Study invitations are sent out by Foundation of Population Screening Mid-West (BoMW) early November 2019 before sending the FIT sample kit of the national screening program to the study cohort from January 2020 to April 2020. The study invitation is combined with a leaflet containing information on study participation. It will also contain an informed consent form, and a one-page questionnaire (if allocated to the intervention arm) with a self-addressed envelope to the research facility. The informed consent form will bear a unique study identification code.

The model that the investigators will use in this study for risk-based screening is derived from a model developed in a primary colonoscopy screening trial (Stegeman et al, Gut, 2014). The investigators have re-evaluated our multivariable risk model for CRC, with the aim to simplify it for daily practice. A number of risk factors (such as elements from diet) added little to the performance of the model, whereas collecting the necessary information proved rather tedious. The quantitative FIT result, age, sex, family history and smoking behaviour were the most decisive factors in the model.

This simplified FIT-based risk model had a performance like that of the extended model in the development dataset. In this study the investigators will calculate the risk of harbouring advanced neoplasia with our simplified FIT-based risk model, based on the quantitative FIT result, age, sex, family history and smoking behaviour (see below). The threshold and expected positivity rate of the risk-based model will be matched to the expected positivity rate of the FIT-only group.

Regression equation of the updated model:

ln(odds AN) = -4.955073942+0.9196052173\*Smoking+0.3364761549\* √FIT+0.370575346\*family history of CRC-0.006934851\*FIT+0.0228752117\*age+0.070972656\*gender

Probability of advanced neoplasia:

P (AN)=e\^((odds AN))/(1+e\^((odds AN))) If invitees that are allocated to the intervention group (i.e. questionnaire and FIT) only return the questionnaire, they do not qualify for a colonoscopy. When consenting invitees in the intervention group prefer not to complete the questionnaire, FIT tests will be analysed at a cut-off of 15 µg Hb/g faeces.

The type of FIT that will be used is the one used in the Dutch national screening programme: FOB-Gold (Sentinel, Italy). FIT-analyses and sending of FIT results will be performed according to the logistics as being used in the national screening. The FIT result and the result of the questionnaire will be entered in a database, to calculate the participant's risk. All FIT positives (≥15 µg Hb/g faeces) will be referred for consultation for colonoscopy at regional endoscopic centres. For the purpose of this study, FIT-negative but risk-positive participants (i.e. the combination of the results of the questionnaire and the quantitative FIT result) will also be invited for consultation for colonoscopy.

Colonoscopy will be performed by endoscopists accredited for our national screening programme and according to national and international quality guidelines. Quality indicators and endoscopic findings will be systematically recorded in a database, according to the standards of the national screening programme. Lesions will be immediately removed, if possible, and otherwise biopsies will be obtained. Histopathological assessment of these tissue samples will provide a definitive diagnosis. Data on location, size, macroscopic aspect, morphology and polypectomy will be recorded for all colonic lesions, which will be collected and evaluated by an accredited GI-pathologist according to the Vienna criteria. Advanced adenomas are defined as adenomas larger than 10 mm, adenomas with high-grade dysplasia or adenomas with a villous component of at least 25%. Advice regarding surveillance colonoscopy after removal of adenomatous polyps, large (≥10 mm) serrated lesions or cancer will be given to the clients according to the Dutch CBO consensus.

Screening invitees can leave the study at any time for any reason if they wish to do so without any consequences. The investigator can decide to withdraw a screening invitee from the study for urgent medical reasons.

STATISTICAL ANALYSIS

Primary outcome The difference in screening yield will be estimated and expressed as an absolute difference per 1,000 invitees, with 95% confidence intervals. The investigators will test the null hypothesis of no difference in yield between the intervention and control group using the chi-square test.

Secondary outcome The standardized screening yield will be calculated by ranking participants according to their calculated risk (in risk-based screening) and comparing the yield of risk-based screening for the number of positives that matches the number of FIT-positives with FIT-only screening with a chi-square test. Additionally, the investigators will use the McNemar test statistic to test the null hypothesis of no gain in screening yield in the intervention group only, where the investigators can compare referrals based on FIT only with referrals based on FIT and calculated risk.

The participation rate will be calculated through the number of participants relative to the number of invitees in each arm. Differences in participation rate will be assessed using the chi square test. The difference in screening yield of proximally located advanced neoplasia between both arms will be estimated and expressed as an absolute difference per 1,000 invitees (with 95% confidence intervals). The null hypothesis of no difference in yield will be tested using the chi square test.

Statistical significance level P-values of lower than 0.05 will be considered statistically significant. All analysis between both arms are based on the intention-to-screen principle, unless stated otherwise. Statistical analyses will be performed using R.

Additional outcomes Model performance in comparison to the FIT will be assessed with the net reclassification improvement (NRI). In addition, the yield of the FIT-based risk model and the FIT will be assessed at a broad range of FIT thresholds and will be estimated and expressed as the number of detected advanced neoplasia per 1,000 invitees (intention-to-screen) and per 1,000 colonoscopies (per protocol). Differences in the yield will be tested using a chi square test. Any missing data that was intended to be used as input for the risk-model, will be classified as '0'.

ETHICAL CONSIDERATIONS The study will be conducted according to the principles of the Declaration of Helsinki (Version October 2008) and the Population Screening Act (WBO). Permission to conduct this study has been granted by the Dutch Health Council and the Dutch Minister of Healthcare.

The researchers conduct a parallel group randomized controlled trial. Asymptomatic individuals will be randomized to either risk-based screening or FIT-only screening.

Combining Risk Factors and Faecal Immunochemical Testing in Colorectal Cancer Screening: a Randomized Controlled Trial

Conditional on the permission of the Dutch government, anonymized research data may be shared after publication of the results in a peer-reviewed paper.

The primary outcome is the yield of advanced neoplasia, defined as the relative number of invitees in whom advanced neoplasia is detected at colonoscopy.

standardized screening yield: ranking the number of participants according to their calculated risk and comparing the yield of risk-based screening for the number of positives that matches the number of FIT-positives with FIT-only screening.

participation rate, defined as the relative number of invitees participating in screening.

yield of advanced neoplasia, defined as the relative number of invitees with advanced neoplasia detected at colonoscopy, at FIT-positivity thresholds of 15 µg Hb/g faeces and higher.

yield of proximally located advanced neoplasia, defined as the relative number of referred participants in whom proximally located advanced neoplasia is detected at colonoscopy.

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Professor

Six thousand persons eligible for the national CRC screening program will be selected. They will be selected from four areas that are considered representative of the Netherlands. All invitees receive an invitation to complete a FIT (FOB-Gold) and a validated, online family history questionnaire. Answers from the questionnaire are compared with the Dutch criteria for referral for genetic testing and/or surveillance colonoscopies for persons at a potential familial risk for CRC. Invitees are invited to perform both tests, but if they only perform one this will be assessed. Participants with a positive FIT and/or a positive family history and a diagnosis of familial CRC by a clinical geneticist will be referred for colonoscopy.

All invitees receive an invitation to complete a FIT (FOB-Gold) and a validated, online family history questionnaire. Answers from the questionnaire are compared with the Dutch criteria for referral for genetic testing and/or surveillance colonoscopies for persons at a potential familial risk for CRC. Invitees are invited to perform both tests, but if they only perform one this will be assessed. Participants with a positive FIT (cut-off value 275 ng/ml) and/or a positive family history and a diagnosis of familial CRC by a clinical geneticist will be referred for colonoscopy.

Family history questionnaire

Evelien Dekker, MD PhD

The aim of this study is to identify more persons with advanced neoplasia in the current national CRC screening, by adding data on family history of CRC (using a validated online questionnaire) to FIT. In addition, the aim is to identify those persons and their family members who should not be participating in a FIT based screening but receive surveillance colonoscopies instead, because of a familial CRC syndrome. It is aimed to increase detection without affecting participation, thereby increasing the yield of screening.

This is a prospective CRC population-based screening trial, using FIT and a family history questionnaire, inviting those with a positive FIT, a familial CRC syndrome, or both for colonoscopy.

All invitees receive an invitation to complete a FIT (FOB-Gold) and a validated, online family history questionnaire. Answers from the questionnaire are compared with the Dutch criteria for referral for genetic testing and/or surveillance colonoscopies for persons at a potential familial risk for CRC. Invitees are invited to perform both tests, but if they only perform one this will be assessed. Participants with a positive FIT (cut-off value 275 ng/ml) and/or a positive family history and a diagnosis of familial CRC by a clinical geneticist will be referred for colonoscopy.

The investigators will compare the diagnostic yield, participation rate, and positive predictive value for two strategies: referral for colonoscopy based on FIT and family history versus referral for colonoscopy based on FIT-only.

The sample size is justified by the anticipated gain in diagnostic yield from combining FIT-only with family history screening. With a sample size of 6.000 persons the investigators expect to detect 130 persons with advanced neoplasia after a positive FIT (21.7 per 1.000 invitees). By adding the family history questionnaire, the investigators anticipate detecting an additional number of 11 persons with advanced neoplasia, resulting in a yield of combined FIT-based and family history screening of 141 persons with advanced neoplasia (23.5 per 1.000 invitees), which is an increase of 1.8 per 1.000 invitees. Using the McNemar test with the significance level set at 5%, there is a power of 91% to show that the gain in diagnostic yield is statistically significant. Previous CRC test screening studies using FIT showed that participation rates are approximately 60% in a first screening round. The participation rate in the Dutch national CRC screening in 2014 (the first year of introduction) was even higher, 68%. The investigators expect that 80% of these persons will fill out the familial risk questionnaire, resulting in 3.264 persons who perform both tests. As the investigators recommend invitees to perform the questionnaire in addition to FIT, the investigators assume that the percentage of persons only filling out the questionnaire and not performing FIT are negligible. Based on previous screening studies using a FIT positivity cut-off value of 50 ng Hb/mL for the OC-Sensor, it is assumed that 8% of these participants have a positive FIT result. In the current Dutch screening program, a different FIT is used (FOB-Gold) with a cut-off value of 275 ng Hb/ml. The FIT positivity rate with this test and with this cut-off value is unknown. However, a governmental announcement recently reported that the positivity rate is expected to remain 8% with this cut-off value. Therefore, the investigators expect 326 FIT positives in this study (8% of 4.080). Based on previous studies, approximately 40% of all persons with a positive FIT result will have advanced neoplasia. In our sample this concerns 130 persons. The percentage of persons with a familial CRC risk requiring surveillance colonoscopies in a screening population varies between 2.3% and 4%. Differences in the definition of an increased familial CRC risk could explain the variability in reported numbers. As the investigators are using a relatively large range in criteria for fulfilling the definition of a familial CRC risk, the highest reported percentage (4%) is assumed, which concerns 131 persons. The previously developed family history questionnaire has a sensitivity of 90% and 100% in identifying those persons qualifying for referral, in two subsequent validation phases respectively. For the purpose of this study, this validated questionnaire is adjusted to the recently renewed referral criteria. The investigators make the assumption that the questionnaire can identify all persons with a familial CRC syndrome based on referral criteria. Persons with a familial CRC syndrome who do not fulfill these criteria will be missed. This concerns an unknown number and will not be taken into account. A previous screening study showed that 6% of those with a positive FIT have an increased familial CRC risk. One can calculate that 3.8% of persons with a negative FIT have a familial CRC risk: 4% minus 6% of 8% (FIT positives), divided by 92% (FIT negatives). If one assumes that there is no difference in familial CRC risk between those who do and those who do not fill out the questionnaire, this involves 114 of 3.264 persons. Based on unpublished data by this research group it is estimated that 10% of those with a negative FIT have a familial CRC risk: 11 persons (10% of 114). A similar percentage was found in another screening study. Additionally, all participants with a familial CRC syndrome will be offered surveillance recommendations. In this sample, 131 persons are estimated to have a familial CRC syndrome. Of these, 16 persons (12%) will undergo a colonoscopy due to a positive FIT (6% of 8% FIT positives) and their familial CRC risk could be addressed at their visit to a colonoscopy center. The other 115 persons (88%) are expected to have a negative FIT and these persons (and their family members) would otherwise be unlikely to be identified as having a familial CRC syndrome.

Adding Family History of Colorectal Cancer to the Dutch FIT-based Screening Program

Adding Family History of Colorectal Cancer to the FIT-based Screening Program in a Dutch Colorectal Cancer Population Sample

This will be analyzed in a telephone interview

number of participants in whom advanced neoplasia is detected relative to the number of invitees

Number of invitees completing the screening tests relative to the number of invitees

Number of participants in whom advanced neoplasia is detected, relative to the number of participants testing positive

Dutch Digestive Diseases Foundation

Prof. Evelien Dekker, MD, PhD

Professor MD

Consecutive patients admitted with CRC diagnosis (index case, IC) were prospectively evaluated. Following the systematic identification of ICs with inherited predispositions to CRC, ICs who agreed to contact their FDRs ≥40 years old were included. Available FDRs were invited to undergo non-cathartic CTC, with OC the following day.

CT colonography

Background: Although subjects with first-degree relatives (FDR) with a history of colorectal cancer (CRC) are at increased risk for CRC, compliance to screening colonoscopy is suboptimal. Computed tomographic colonography (CTC) has been recognized as an alternative for CRC screening in average risk subjects, but less information is available on its performance in FDRs.

Aims: To prospectively assess the accuracy of CTC as a screening tool in FDRs using colonoscopy (OC) with segmental unblinding as reference standard.

Methods: Consecutive patients admitted with CRC diagnosis (index case, IC) were prospectively evaluated. Following the systematic identification of ICs with inherited predispositions to CRC, ICs who agreed to contact their FDRs ≥40 years old were included. Available FDRs were invited to undergo non-cathartic CTC, with OC the following day. Sensitivity/specificity/PPV/NPV of CTC was assessed for detecting subjects with any lesion ≥6 mm, ≥10 mm, and for advanced neoplasia ≥6 mm.

Non-cathartic Computed Tomographic Colonography to Screen Subjects With a Family History of Colorectal Cancer

Non-cathartic Computed Tomographic Colonography to Screen for Colorectal Neoplasia in Subjects With a Family History of Colorectal Cancer

Istituto Clinico Humanitas

Individuals who consent to participate in the study, will be asked to take two stool samples from the same bowel movement. In a central laboratory these two samples then will be analyzed. One with the standard of care faecal immunochemical test (FIT) and the other with the multi-target faecal immunochemical test (mtFIT). If either one of these two tests is positive, individuals will be referred to undergo a colonoscopy procedure. The performance of mtFIT, in comparison to FIT, will be evaluated against the colonoscopy findings.

Invitees for the Dutch National CRC screening program will be randomly selected by the Screening Organization and invited to participate in this study, where next to the current FIT, participants will also perform the mtFIT in one bowel movement. Both tests will be analysed and if one of the two test results is positive, the individual will be referred for colonoscopy.

Comparison of two tests (FIT and mtFIT) in the same bowel movement

Gerrit A Meijer, MD, PhD

Evelien Dekker, MD, PhD

Manon CW Spaander, MD, PhD

The primary goal of the population-based colorectal (CRC) screening is early detection and interception of CRC and its precursors to decrease CRC-related morbidity and mortality. To improve current CRC screening programs, the investigators have developed and retrospectively validated a test that combines the detection of multiple proteins in stool (the multitarget faecal immunochemical test, mtFIT). mtFIT was found to have a higher accuracy to detect advanced neoplasia (AN), which includes CRC, advanced adenomas and advanced serrated polyps, in comparison to FIT. Thus, this multitarget test has the potential to improve the screening program's efficiency in reducing CRC-related incidence, morbidity and mortality. This new test, in comparison to FIT, shows specifically higher sensitivity in the detection of advanced adenomas, without affecting specificity.

Background:

The primary goal of population-based CRC screening is early detection and interception of CRC and its precursors to decrease CRC-related morbidity and mortality. New tests, with higher sensitivity for advanced precursor lesions than the current FIT, are desired. The investigators have developed a protein-based multitarget faecal immunochemical test (mtFIT) that shows higher sensitivity for advanced adenomas without losing in specificity.

Objective:

To prospectively validate the better performance of the mtFIT in comparison to FIT in the setting of a population-based CRC screening program.

Material and Methods:

In this prospective study, participants of the Dutch National CRC screening program (55-75 years of age) will be invited to participate. Individuals who consent to participate in the study, will be asked to take two stool samples from the same bowel movement. In a central laboratory these two samples then will be analyzed. One with the standard of care faecal immunochemical test (FIT) and the other with the multi-target faecal immunochemical test (mtFIT). If either one of these two tests is positive, individuals will be referred to undergo a colonoscopy procedure. The performance of mtFIT, in comparison to FIT, will be evaluated against the colonoscopy findings.

Expected results:

mtFIT has higher sensitivity for AN, and in particular advanced adenomas, than FIT, at equal positivity rate.

Prospective Clinical Validation of a Novel Multitarget FIT in CRC Screening

Clinical Validation of a Multi-target Faecal Immunochemical Test (mtFIT) Versus a Faecal Immunochemical Test (FIT) for Detecting Advanced Neoplasia in Population Screening for CRC: a Prospective Cohort Study With Paired Design

mtFIT reduces CRC incidence and CRC-related mortality compared to FIT and is cost-effective to be used in a CRC screening program.

Relative sensitivity of mtFIT compared to FIT in the detection of advanced neoplasia (AN; CRC, advanced adenomas and advanced serrated polyps) at an equal positivity rate.

mtFIT detects more CRC, more early-stage CRC and more advanced polyps (advanced adenomas and advanced serrated polyps) compared to FIT.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combining Risk Factors and Faecal Immunochemical Testing in Colorectal Cancer Screening: a Randomized Controlled Trial	NCT04490551	Colorectal Canc... Colorectal Carc... Colorectal Neop... Colorectal Aden... Colorectal Aden...	Risk-based logi... FIT	55 Years - 75 Years	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Adding Family History of Colorectal Cancer to the Dutch FIT-based Screening Program	NCT02698462	Colorectal Neop...	Family history ...	59 Years - 75 Years	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Non-cathartic Computed Tomographic Colonography to Screen Subjects With a Family History of Colorectal Cancer	NCT01766479	Colorectal Neop...	CT colonography	40 Years -	Istituto Clinico Humanitas
Adding Family History of Colorectal Cancer to the Dutch FIT-based Screening Program	NCT02698462	Colorectal Neop...	Family history ...	59 Years - 75 Years	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Non-cathartic Computed Tomographic Colonography to Screen Subjects With a Family History of Colorectal Cancer	NCT01766479	Colorectal Neop...	CT colonography	40 Years -	Istituto Clinico Humanitas
Prospective Clinical Validation of a Novel Multitarget FIT in CRC Screening	NCT05314309	CRC Advanced Neopla...	Comparison of t...	55 Years - 75 Years	The Netherlands Cancer Institute

Spots Global Cancer Trial Database for advanced neoplasia