Discussion
CRC, non-syndromic CRC, neoplasia, colon cancer, colorectal neoplasia
REGRESSION, NEOPLASIA, COLON CANCER
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 (Annual or biennial FIT is the most widely used screening strategy in countries and health organizations with organized CRC screening programs [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 [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 [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 [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.