Colorectal Cancer Clinical Trial
Official title:
Identifying the Risk of Hereditary and Familial Colorectal Cancer in Colorectal Cancer Patients by Using an Online Risk Tool: An Evaluation Based on a Stepped Wedge Design
In this trial the investigators will evaluate the effectiveness of the implementation of a digital familial risk questionnaire in the detection of CRC patients with hereditary or familial CRC. This will be done using a stepped wedge design with 5 participating hospitals for a duration of 1.5 years. A comparison is made between an intervention phase (offering the online risk assessment questionnaire) and a control phase (hospital-based standard practice for the detection of CRC patients with hereditary or familial CRC, informed by the referral criteria that are being used in the intervention group). All patients with a diagnosis of CRC who have a first appointment at the CRC outpatient clinic will be included. The primary outcome is the percentage of all included patients who receive a recommendation for regular surveillance colonoscopies for himself/herself and/or relatives, provided by a clinical geneticist. Data from clinical geneticists is being used to answer this question.
Design: This is a multicenter prospective comparative cohort study, using a stepped-wedge
design. All clusters (hospitals) start with the control strategy and switch, one by one, to
the intervention strategy. Every 9 weeks a hospital will start implementing the questionnaire
after a short training period of 1 week. As a referral to a clinical geneticist can take up
to several months, we allow at least 6 months for the collection of the results of the
genetic tests.
Control strategy: Each hospital starts with the control strategy. Just before the start of
this study, all hospitals will be sent a list with the clinical genetics referral criteria
that will be used for this study. Each hospital can decide on how to use these criteria.
Intervention strategy: Before the start of the study, all hospitals will be informed when the
use of the online questionnaire will be implemented. They will also receive a manual on how
to use the online CRF and questionnaire. The online CRF will be used to send out invitations
for the questionnaire, to report baseline characteristics (age, sex, nationality, educational
level, native language), reasons for non-participation, the number of changes that need to be
made when verifying completed questionnaires and to calculate referral advice. In the
training week, a researcher from the AMC will present the study to all involved persons and
he will facilitate the implementation of the online CRF and questionnaire. All nurses and
doctors participating in this study will be provided with their own login codes for the
online CRF. Patients included in the training week will not be included in the analysis. All
consecutive patients with CRC that have a first appointment at the outpatient clinic will be
invited to complete the online questionnaire and they receive a record number. In case
patients decline to complete the questionnaire, this will be reported by a nurse or
gastroenterologist in the online CRF. If the patient consents, an email will be sent to the
patient with a link to the questionnaire and the question to complete it before the next
visit to the outpatient clinic. The online CRF will automatically result in a check for
indications for referral to a clinical geneticist. The nurse or gastroenterologist can report
this advice in the patient file and can decide on referring the patient.
Checking referrals to a clinical geneticist: Every two months, all patients included in the
study will be tracked by searching for reports on clinical genetics consultation in their
medical files and a check with local genetic centers will be done.
Statistical analysis of the primary outcome measure: The difference between the control group
and intervention group in the proportion of patients who receive surveillance advice by a
clinical geneticist will be calculated. A nonlinear mixed model will be used for testing the
hypothesis of no difference. We will model the probability of receiving surveillance advice
as a linear function, after a logit transformation, with as explanatory variables the
hospital, the time interval, and the questionnaire effect: Logit(pijk)=μ+αi+βj+Χijθ, Where
Logit(pijk) is the natural logarithm of the odds of a referral to a clinical geneticist for
individuals (k) in cluster i at time j. μ is the overall mean, αi is a random effect for
hospital i, βj is a fixed effect corresponding to time interval j, and Χij is an indicator
variable for implementation of the questionnaire in hospital i at time j and θ is the
questionnaire effect. Time effects will be analyzed in a discrete way (season, month) in case
a primary effect is found. If no time effect is present, time function will be excluded from
the model. For the primary outcome measures, we will use the intention-to-treat principle,
including all eligible patients in the analysis.
Statistical analysis of the secondary outcome measures: for each secondary outcome measure,
differences between the control and intervention group will be calculated using relative
risks with corresponding 95% confidence intervals. Secondary outcome measures to be
calculated in the intervention group only, will be reported using descriptive statistics.
Sample size calculation: For the sample size calculation, a two-group chi-squared test of
equal proportions was used as a starting point for comparing proportions in referrals in the
control group versus the intervention group. Significance level was set at 5% (two sided)
with a power of 80%. Of all CRC cases, approximately 20% are related to familial or
hereditary factors. In the literature the reported proportion of CRC patients with an
increased familial risk of CRC that is appropriately referred to a clinical geneticist ranges
from 8% to 67%, with most studies reporting proportions between 10% and 30%. We estimate that
20% of patients at risk are referred, resulting in a referral rate of 4% of all CRC patients.
We anticipate that the implementation of the questionnaire can increase this proportion up to
15%.To detect this difference we would need a sample size of 111 patients per treatment
group. For the stepped wedge design the total sample size (111x2) needs to be multiplied by a
design effect, that can be calculated using the following formula, where k is the number of
steps, b is the number of baseline measurements, n is the number of patients per cluster, t
is the number of measurements after each step and ρ is the intracluster correlation (ICC),
which compares the within-group variance with the between-group variance:
DEsw= ((1+ρ(ktn+bn-1))/(1+ρ (0.5ktn+bn-1))) . ((3(1-ρ))/(2t(k-1/k)))
The ICC was estimated at 0.10 as no previously reported ICC for this topic was available.
As there are five participating hospitals, a total number of five steps (k) will be possible.
As the study duration will be one year, each step will take 2 months. After randomization,
each hospital starts with a training period of one week that will be added to these two
months. We expect two to eight eligible patients per week per hospital, which results in 16
to 64 patients per hospital per step. With this information, a DEsw can be calculated.
Assuming 16 patients per step, DEsw is 0.45. Assuming 64 patients per step, DEsw is 0.47.
This corresponds with a required total sample size of 100 and 104 patients, respectively.
When divided by the total number of patients per cluster, 6.2 and 1.6 clusters are needed for
the minimum and maximum number of included patients respectively. We therefore believe that
our number of five clusters would be sufficient.
Institutional review board: This study was approved by the institutional review board (IRB)
of the Academic Medical Center (AMC) in Amsterdam, the Netherlands. This IRB decided that the
study did not meet the requirements of the Medical Research Involving Human Subjects Act
(WMO). All local ethics committees confirmed the local practicability of this study.
Consent: According to the requirements of the AMC Research Code, digital approval will be
asked from the patients for making use of personal data for this study in the intervention
group. This means that questionnaires start with a question about the willingness to
participate in this study. They can answer this question by indicating 'yes' or 'no'. If 'no'
is answered, results will be removed from the database. Use of the digital questionnaire is
considered safe as all answers are collected anonymously and could only be linked to a
patient with a secured key document. This study will be carried out in accordance with the
Helsinki Declaration. No approval for data use will be asked from patients in the control
group, as this would increase awareness and would therefore bias results. Moreover, data from
these patients will only be collected anonymously.
Monitoring and quality assurance: The AMC researcher will monitor all centers every month.
Each site that is randomized will be visited for a training week.
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