Colorectal Cancer Screening by Colonoscopy, CT-Colonography, or Fecal Immunochemical Test

Colorectal cancer (CRC) screening is nowadays implemented in more than 50 countries worldwide (1). These screening programs differ according to the screening methods and the level of organization, from opportunistic to organized population screening. Imaging of the colon by colonoscopy, and ct-colonography (CTC) as first alternative, is the primary screening method in the United States as well as in several European countries such as Germany and Poland. Many other countries, in particular those with organized call-recall population screening, prefer a noninvasive stool test for primary screening. Testing for occult blood in feces was developed a century ago by Ismar Boas in Berlin, among others (2). He and his contemporaries did not aim to identify patients with colorectal cancer, a rare disease at that time. They instead used it for patients with peptic ulcer and gastric cancer, by far the most common malignancy then. In the present day, guaiac fecal occult blood testing is rapidly replaced by fecal immunochemical testing (FIT). This is related to easier handling, higher participation, higher sensitivity for advanced adenomas as well as cancer, automatic processing, and yield of quantitative results. The latter allows adjusting the cut-off to match available colonoscopy resources (3).

The international differences in CRC screening illustrate that there is no optimal test or optimal program design. However, it is recommended to monitor key parameters such as uptake or population coverage and diagnostic yield in terms of numbers of subjects identified with advanced neoplasia per 1000 screened and per 1000 invited. Follow-up provides further information on the distribution of screen-detected cancers, cancers in nonparticipants, and interval cancer over multiple screening rounds. These performance measures provide insight in the impact of a screening program (4,5).

With this in mind, randomized trials such as published in this issue of the Journal are very relevant. Previous randomized trials among others compared gFOBT, FIT and sigmoidoscopy (6,7), FIT and colonoscopy (8), as well as colonoscopy vs CTC (9,10). These studies led to the conclusion that FIT at low cut-off led to the highest cancer identification rate because of high sensitivity for cancer and high participation, whereas colonoscopy and ct-colonography tended to perform equally. The impact of FIT is further improved with multiple screening rounds.

In this issue of the Journal, Sali and colleagues from Italy report the results of a randomized comparison between FIT, colonoscopy, and CTC with either reduced (rCTC) or full preparation (fCTC) (11). The authors randomly assigned 16 087 inhabitants of the Florence region to any of these four screening modalities. Participation rates of FIT, colonoscopy, and reduced or full-prep CTC were respectively 50%, 15%, 28%, and 25%. Detection rates for advanced neoplasia were 1.7%, 7.2%, 5.5%, and 4.9%. The authors conclude that limitation of the bowel preparation increases the participation in CTC. This is an important new finding that is in line with previous observations that ease is an important determinant of screening uptake. A 3% difference in uptake may seem irrelevant but would even in a small country such as the Netherlands translate into 100 000 extra people willing to be screened. The study simultaneously confirms previous findings of a higher uptake of CTC than colonoscopy (9). This higher uptake was both in the current as well as in the previous study counterbalanced by a lower diagnostic yield among those undergoing CTC screening vs those screened by colonoscopy (9,11). As a result, both methods in the current Italian study yielded 10 individuals with advanced neoplasia per 1000 invitees with colonoscopy, 15 with rCTC, and 12.5 with fCTC. Sali et al. conclude that these detection rates are higher than those obtained by means of one FIT round (11). Indeed, while the participation to FIT screening was approximately two-fold higher, the detection rate of advanced neoplasia was approximately three-fold lower. This translated into identification of 8.5 subjects with advanced neoplasia per 1000 invitees.

However, a few additional remarks need to be made. These detection rates were according to routine practice determined with the use of complete colonoscopy as a gold standard for the diagnosis of advanced colorectal neoplasia. This implies that the referral rate to colonoscopy was an important determinant for the diagnostic yield in the FIT and CTC arms. In that respect, it is firstly important to note that complete colonoscopy was performed in 98% of screenees, with a positive CTC vs only 76% of screenees with a positive FIT. The authors do not explain the reason for this 1.3-fold difference. Secondly, while the authors accepted a 10% referral rate to colonoscopy after CTC, they decided to use a relatively high FIT cut-off of 20 mcg/g feces, associated with a 5.5% referral rate to colonoscopy. We know from previous FIT studies in Western populations that use of a lower cut-off of 10 mcg/g feces in first-round screening is associated with a close to 10% referral rate for colonoscopy and an approximate 1.3-fold higher detection rate of advanced neoplasia (12). When correcting for the lower referral rate and completion rate of colonoscopy after FIT than after CTC, the potential for detection of advanced neoplasia would increase by (1.3 x 1.3 =) 1.69-fold from 8.5 to 14.3 screenees with advanced neoplasia per 1000 invited. This is very similar to the rate obtained with CTC and is still lower than achieved in other FIT studies (6,7,13,14).

This firstly signifies that colonoscopy in this population screening setting was outperformed by CTC because of a higher uptake. Secondly, although the study suggests that colonoscopy and CTC are both more effective than FIT, a careful look at the data suggests that first-round FIT can perform equally with CTC, dependent on the cut-off used. The true impact of FIT screening is achieved by repeated rounds. This is often associated with a sustained or further increase in participation rate yet a gradual decrease in diagnostic yield per screening round (15–17). Over three to four rounds, the diagnostic yield can thus accumulate to more than 40 subjects identified with advanced neoplasia per 1000 invited (15,17,18). As a result, FIT screening has become the standard for primary assessment in organized population CRC screening (1). This is further supported by the important study of Sali and colleagues.