In this multicenter randomized controlled trial, screening uptake of FIT was not different than screening uptake of colonoscopy among FDR with a high-risk family history of non-syndromic CRC. In addition, the detection rate of advanced colorectal neoplasia was significantly higher among subjects undergoing screening colonoscopy than in those receiving FIT screening. Therefore, the results did not support the hypothesis that FIT screening might be better accepted and equally effective as colonoscopy screening for detecting advanced colorectal neoplasia in this population.
Our study has several strengths. First, randomization was performed before the initial appointment to avoid selection bias. Second, we included only asymptomatic FDR from index cases with non-syndromic CRC diagnosed no more than 2 years before the start of the study. This assured that they were within the frame of the recommendations of current guidelines. Third, family history was verified through the index case, and only FDR not previously screened were included. Therefore, using the index case as the provider of the family history assured that all eligible relatives could be contacted and helped to avoid the pitfalls of self-reported enrollment. Fourth, we included eligible relatives from 7 Spanish Autonomous regions, suggesting that the results might be extrapolated to familial CRC population in Spain. Fifth, colonoscopies and bowel cleansing preparation were offered free of charge in both study groups, which could facilitate participation in the study. Sixth, extended follow-up until December 2021 allowed us to identify participants that were screened outside the trial context, minimizing the negative effect that COVID-19 pandemic had on colon cancer screening during 2020.
On the other hand, the study also has some limitations. First, 536/870 (56.0%) eligible FDR (57.4% in the FIT group and 54.5% in the colonoscopy group) declined to participate and did not attend the initial appointment. We could not contact these individuals as Spanish law does not allow registering of data of individuals that have not given previous informed consent. Although a reminder letter was mailed to the index case to encourage the participation of their non-attending relatives, we cannot rule out delivery failure in some cases. Second, among the 383 FDR who signed the informed consent form, 78 (20.3%) refused to undergo screening. However, follow-up information from these individuals allowed us to estimate the rate of screening outside the trial protocol, which provided a more accurate global uptake in both study groups according to intention-to-screen analysis. Third, randomization was performed on the eligible subjects and not by family cluster to guarantee a homogeneous sample in each group of the study. Consequently, some individuals had a different screening strategy assigned in the same family, which could have led to refusal to participate in some cases. In fact, the assignment of different strategies to members of the same family was an independent factor for low participation in the logistic regression analysis. However, the rate of subjects who were assigned to different strategies in the same family was similar in the FIT group (51.3%) and in the colonoscopy group (48.7%). In addition, the screening uptake did not differ between the study groups that were assigned the same strategy or different strategies in the family, suggesting that this condition affected both groups equally.
Annual or biennial FIT is the most widely used screening strategy in countries and health organizations with organized CRC screening programs. Recently, it has been suggested that repeated FIT could be an alternative to colonoscopy screening in the familial-risk population, which could overcome the suboptimal uptake of colonoscopy in these individuals. This hypothesis has been formulated under the following premises. First, large prospective cohort studies have shown that only subjects with 2 or more FDR affected in the immediate family had a significantly higher risk of advanced colorectal neoplasia, compared to average risk individuals. In addition, a pooled analysis of 6 prospective cohort studies showed that family history of CRC is not associated with overall survival or CRC-specific survival after adjusting for confounders. Overall, these studies suggest that most FDR of patients with CRC would not benefit from intensive colonoscopy surveillance and could be screened in the same way as the average-risk population. Second, FIT screening may be equivalent to colonoscopy screening for detecting CRC and advanced adenomas in familial-risk population. This is supported by a meta-analysis that included 11 observational studies and a randomized controlled trial. Third, assuming that FIT is a reasonably well-accepted screening procedure in the average-risk population, it has been proposed that it could also be extended to the familial-risk population. However, this hypothesis has not been evaluated in a clinical trial.
The current study shows that in Spain, a country with universal public health care and more than a decade of experience with a FIT-based nationwide screening program, FIT screening did not improve the screening acceptance compared to colonoscopy screening in the familial-risk population. The low uptake of colonoscopy screening in our study was to be expected if we compare it with those from European studies performed in the average-risk or in the familial-risk population. However, we did not expect such low acceptance of FIT screening. Adherence was already low (35.9%) in the first screening round but dropped to 17% for individuals that completed the 3 tests, which is unacceptable for any FIT screening program. Although we could not obtain information of the subjects who did not attend the invitation to participate in the study, we had data of 78/383 (20.4%) individuals that refused to participate after signing the informed consent. The comparison of demographic data between participants and this representative sample of non-participants was similar regarding age, sex, smoker status, kinship, and educational level. Therefore, these conditions do not seem to clarify the reasons why these subjects refused screening.
A relevant aspect that could at least partially explain the low uptake rate observed in our study is that the invitation was formulated in an opportunistic setting. However, this is not different from what occurs in real clinical practice. Traditionally, FDR of patients with CRC have been excluded from nationwide screening programs because they are considered candidates for straightforward colonoscopy. Paradoxically, this approach is associated with a suboptimal acceptance rate, leaving a substantial number of these individuals unscreened. Nevertheless, the reasons why more than half of subjects with a high-risk family history of CRC refused to be screened are unknown and cannot be ascertained by our study for the reasons mentioned above.
Among the major barriers for screening adherence or for non-follow-up with colonoscopy after a positive FIT in these individuals could be the lack of symptoms, low knowledge of one’s risk for developing CRC, decision-making difficulties, and low provider awareness about recommendations established by clinical guidelines [31]. One step forward to improve the screening uptake of these individuals could be to involve them in organized screening programs. In fact, a study performed in the setting of a Dutch screening program revealed that providing familial risk assessment to individuals with a positive FIT may facilitate the identification of high-risk FDR and prevent the development of a substantial number of CRC cases. However, this approach would not improve the participation of those who decline to be screened or have a negative FIT. In line with this finding, a recent meta-analysis of 4 controlled trials showed that tailored communication based on written and verbal information increased the participation rate in colonoscopy screening by about 2-fold. In addition, a recent trial performed within the framework of the Polish Colonoscopy Screening Program have shown that offering screening strategies that combine FIT and colonoscopy can result in participation rates 8% to 10% points higher compared to offering colonoscopy screening alone. Despite the design of our study did not allow for changing the randomly assigned group, 34% of subjects that were noncompliant with colonoscopy screening and 20.7% of those noncompliant with FIT screening crossed over to the other group during the follow-up period. This suggests that the screening uptake of this population could have improved if both options had been offered together.
As expected, the similar screening uptake of straightforward colonoscopy and annual FIT screening observed in our study was associated with a significantly higher detection rate of advanced neoplasia in individuals assigned to one-time colonoscopy compared to those screened by FIT. This finding differs from previous studies suggesting that FIT screening might be equivalent to colonoscopy screening for detecting advanced neoplasia in this population [15]. This discrepancy can be explained by the fact that in previous studies, recruitment was carried out among family members who were willing to be screened, while in the current study, all eligible family members were included in a more pragmatic intention-to-screen analysis. In addition, the current study was performed in FDR with a high-risk family history of CRC, whereas previous studies included most relatives at low or moderate risk, which could justify different detection rates of advanced colorectal neoplasia. Nevertheless, these data should be analyzed with caution as only a very low number (29 individuals) fulfilled 3 round of testing and only 19 colonoscopies were performed in the FIT group. So, detection rates of advanced colorectal neoplasia might be based on chance in these individuals.
In conclusion, this randomized controlled trial indicates that in the setting of an opportunistic screening, annual FIT does not increase the screening uptake compared to colonoscopy screening in FDR at high risk of developing CRC, resulting in a significantly lower detection rate of advanced colorectal neoplasia. New initiatives are needed to assess whether screening uptake can be improved for these individuals through their inclusion in population-based screening programs or by offering a choice between fit and colonoscopy screening.