Adding Family History of Colorectal Cancer to the Dutch FIT-based Screening Program
Condition: Colorectal Neoplasms
MeSH terms: Colorectal Neoplasms
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Family history questionnaire
Intervention type(s): Other
Intervention description(s): 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.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Screening
Keywords: Advanced neoplasia; Colorectal cancer; Population screening; Family history