FIT v. Colonoscopy: Outcomes Comparison

Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population.

Methods

In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations.

Results

The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001).

Conclusions

Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.)

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Recommended strategies for colorectal-cancer screening fall into two broad categories: stool tests (occult blood and exfoliated DNA tests) and struc- tural examinations (flexible sigmoidoscopy, colo- noscopy, and computed tomographic colonogra- phy). Stool tests primarily detect cancer, and structural examinations detect both cancer and premalignant lesions.2Stool tests for occult blood (guaiac testing and fecal immunochemical test- ing [FIT]) are predominantly used in Europe and Australia, whereas colonoscopy is the predomi- nant screening method in the United States.

Colonoscopy is considered the most accurate test for early detection and prevention of colorectal cancer. Although data from randomized studies evaluating the effect of colonoscopy on the rate of death from colorectal cancer are lacking, the pro- cedure is recommended as a first-line screening test on the basis of indirect data and observational studies. Population-based case–control studies have suggested that colonoscopy markedly reduces the risk of colorectal cancer7,8and death.9Recent evidence suggests that patients with no abnor- malities on a previous colonoscopy have a mark- edly reduced risk of colorectal cancer.8,10,11In a cohort of average-risk subjects, the use of screen- ing colonoscopy was associated with a reduction in the incidence of colorectal cancer of 67% and a reduction in the rate of death of 65%.12Cohort studies involving patients with adenomas have sug- gested that polypectomy can prevent approximate- ly 80% of colorectal cancers.13,14

Comparative studies have shown that the semi- quantitative FIT is more accurate than the guaiac test for the detection of colorectal cancer and ad- vanced adenomas,15-19and this new test is now recommended as the first-choice fecal occult blood test in colorectal-cancer screening. Although FIT is less effective for neoplastic detection than colo- noscopy or sigmoidoscopy, evidence suggests that it may be better accepted,20,21and higher accep- tance may counteract its lower detection capacity. It has been suggested that FIT may be more effec- tive and less costly than other screening strate- gies. We conducted a randomized, controlled trial to compare semiquantitative FIT with colonos-

copy. We hypothesized that FIT screening every 2 years would be noninferior to one-time colonosco- py with respect to a reduction in mortality related to colorectal cancer among average-risk subjects. This interim report describes rates of participation, diagnostic findings, and the occurrence of major complications at the completion of the baseline screening.

Methods

StudyDesign

We conducted this randomized, controlled, nonin- feriority trial in eight Spanish regions (Aragón, Basque Country, Canarias, Catalonia, Galicia, Ma- drid, Murcia, and Valencia) with the participation of 15 tertiary care hospitals. The study was designed to assess the efficacy of one-time colonoscopy and biennial FIT for reducing the rate of death from colorectal cancer at 10 years (primary trial out- come). The study started in November 2008 with an informative nationwide campaign.22The recruit- ment period was initiated in June 2009, and the first round finished in June 2011. Ten-year follow-up will be completed in 2021.

The study protocol (available with the full text of this article at NEJM.org) was approved by the ethics committee at each hospital, and all subjects provided written informed consent.

Study Population

Asymptomatic men and women between the ages of 50 and 69 years were eligible for enrollment. Exclusion criteria, which were ascertained after randomization by means of a questionnaire at the local screening office, included a personal history of colorectal cancer, adenoma, or inflammatory bowel disease; a family history of hereditary or familial colorectal cancer (i.e., ≥2 first-degree rel- atives with colorectal cancer or 1 in whom the dis- ease was diagnosed before the age of 60 years)23,24; a severe coexisting illness; and previous colecto- my. Subjects were also temporarily excluded if they had undergone fecal occult blood testing in the previous 2 years or sigmoidoscopy or colo- noscopy within the previous 5 years or if they had symptoms requiring additional workup. The subjects with previous screening tests became eligible when sufficient time had elapsed since the tests,2and those with symptoms became eli- gible if the results of the clinical workup were negative.

leading cause of cancer-related deaths. Several studies have shown that colorectal-cancer screening is effective2-5and cost-effective6in the average-risk population.

Colonoscopy vs. Fecal Immunochemical Testing

Randomization

Subjects were identified through each Community Health Registry, sorted according to household, and stratified according to age (in 5-year age groups) and sex. Households were randomly assigned in a 1:1 ratio to undergo either one-time colonoscopy or biennial FIT. Randomization was performed be- fore invitation with the use of a computer-generated allocation algorithm on the basis of a randomized- blocks method. Subjects were sent a preinvitation letter containing information on colorectal-cancer screening and the rationale for the study. Two weeks later, an invitation letter was sent indicating the subject’s study-group assignment. Two addi- tional, reminder letters were mailed 3 and 6 months after the invitation to subjects who did not respond to the first mailed invitation. Subjects who agreed to participate in the study received an appointment at the local screening office, where they completed the questionnaire. The study design allowed for crossover between the two study groups.

Study Interventions

Among patients undergoing colonoscopy, bowel cleansing and sedation were performed as de- scribed previously.25All colonoscopies were per- formed by experienced endoscopists (those who had performed >200 colonoscopies per year).26Pol- yps were categorized as non-neoplastic or neoplas- tic. Adenomas measuring 10 mm or more in diam- eter, with villous architecture, high-grade dysplasia, or intramucosal carcinoma, were classified as ad- vanced adenomas. Invasive cancer was considered to be present when malignant cells were observed beyond the muscularis mucosae. Advanced neo- plasm was defined as advanced adenoma or inva- sive cancer. Tumor staging, performed according to the classification system of the American Joint Committee on Cancer,27was based on the most advanced lesion.

The FIT strategy consisted of analysis of a single stool sample with the use of the automated semi- quantitative OC-Sensor (Eiken Chemical) without specific restrictions on diet or medication use. Samples were processed as described previously28at each regional hospital. Subjects who were found to have a hemoglobin level of 75 ng per milliliter or more were invited to undergo colonoscopy.

Details regarding quality indicators for colonos- copy are provided in the study protocol and in Ta- ble 1 in the Supplementary Appendix, available at NEJM.org.

Study Oversight

Palex Medical and Biogen Diagnóstica donated sup- plies and automated fecal occult-blood analyzers used for FIT but provided no other support for the study. The companies were not involved in the de- sign of the study, in the analysis or interpretation of the data, or in the preparation of the manuscript.

Statistical Analysis

This study was based on the assumption that screening average-risk subjects by means of bien- nial FIT would not be inferior to one-time colonos- copy with respect to the rate of death from colorec- tal cancer at 10 years. The calculations were based on an overall compliance rate of 30% and a crude 10-year rate of death from colorectal cancer of 0.696%.29Therefore, assuming a crude 10-year rate of death from colorectal cancer of 0.174% among subjects undergoing colonoscopy (a 75% reduction) and of 0.341% among those screened by means of FIT (a 51% reduction) and accepting a noninferi- ority condition if the absolute difference was below 0.22 percentage points, we determined that a sam- ple of 55,498 subjects (27,749 in each study group) would provide a power of 80%. A P value of less than 0.025 was considered to indicate statistical significance with the use of a one-sided test of proportions.30

We assessed study outcomes in both intention- to-screen and as-screened analyses. In the latter analysis, the detection rate was calculated as the number of subjects with true positive results di- vided by the number of subjects who actually un- derwent testing. The diagnostic yield was the number of subjects with true positive results divided by the number of eligible subjects in the intention-to-screen analysis. Subjects were exclud- ed from the intention-to-screen analysis if they at- tended the screening office visit and met one or more exclusion criteria. Subjects who did not at- tend the screening office visit and thus did not provide information about exclusion criteria were classified as eligible and were included in the intention-to-screen analysis. Definitions of other outcomes are provided in the study protocol. Be- tween-group differences in rates of participation, diagnostic yield, detection, and complications were established by logistic-regression analysis, with adjustment for age, sex, and participating center, and are reported as odds ratios with 95% confi- dence intervals. All analyses were performed with the use of SPSS statistical software, version 15.0.

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Study Population

Results

2.69; P<0.001). Nonadvanced adenomas were found in 1109 subjects (4.2%) in the colonoscopy group and in 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001).

When the diagnostic yield was analyzed ac- cording to the location of lesions, no significant between-group difference was found for either proximal or distal colorectal cancer (Table 2). However, colonoscopy performed significantly bet- ter than FIT in the diagnosis of advanced and nonadvanced adenomas that were either proximal or distal to the splenic flexure. The superior diag- nostic yield of colonoscopy for advanced adenomas was most evident for lesions in the proximal colon (Table 2).

Detection Rate

On the basis of the screening that was actually per- formed, 5059 subjects underwent colonoscopy and 10,611 underwent FIT (Fig. 1). Among subjects who were screened by means of FIT, 767 (7.2%) tested positive, and 663 of these subjects (86.4%) under- went colonoscopy. Among subjects who were screened by means of colonoscopy, 27 (0.5%) were found to have colorectal cancer, as compared with 36 subjects (0.3%) who were screened by means of FIT (odds ratio, 1.56; 95% CI, 0.93 to 2.56; P = 0.09) (Table 3).

Tumor staging was similar in the two groups. In the FIT group, 24 tumors were stage I, 6 were stage II, and 6 were stage III. In the colonoscopy group, 19 tumors were stage I, 6 were stage II, and 2 were stage III (P = 0.52). Colonoscopy was supe- rior to FIT in the rates of detection of advanced adenomas (odds ratio, 4.32; 95% CI, 3.69 to 5.07; P<0.001) and nonadvanced adenomas (odds ratio, 25.98; 95% CI, 21.27 to 31.74; P<0.001) (Table 3).

No significant difference was observed in the rate of detection of colorectal cancer when subjects were stratified according to tumor location (Table 2 in the Supplementary Appendix). However, colo- noscopy performed better than FIT with respect to detection rates for advanced and nonadvanced ad- enomas in both the proximal and distal colon.

Analysis of Resources

The numbers of subjects who needed to be screened to find one colorectal cancer were 191 in the colo- noscopy group and 281 in the FIT group, and the numbers who needed to be screened to find any advanced neoplasm were 10 and 36, respectively (Table 3 in the Supplementary Appendix). However,

Overall, 57,404 subjects were randomly assigned to undergo either colonoscopy or FIT. Of these sub- jects, 1970 could not be contacted and 2132 were excluded either permanently (1.7% in the colonos- copy group and 1.3% in the FIT group, P = 0.20) or temporarily (2.2% in the colonoscopy group and 2.2% in the FIT group, P = 0.11) (Fig. 1). The eligible population consisted of 26,703 subjects in the colo- noscopy group and 26,599 in the FIT group. The two groups were almost identical regarding both mean (±SD) age (59.2±5.5 years in the colonoscopy group and 59.3±5.6 years in the FIT group, P = 0.35) and the proportion of subjects who were women (53.5% in the colonoscopy group and 54.3% in the FIT group, P=0.25).

Participation

Among subjects who were assigned to undergo colonoscopy, 5649 subjects accepted the pro- posed strategy, whereas 1706 requested to be screened by means of FIT (Fig. 1). Of the 5649 subjects who agreed to undergo colonoscopy, 4953 actually did so, and 1628 underwent FIT, for a participation rate of 24.6%, according to the intention-to-screen analysis (average age, 59.1±5.5 years; proportion of subjects who were women, 53.4%). Among subjects who were assigned to undergo FIT, 9353 subjects accepted the pro- posed strategy, whereas 117 asked to be screened by colonoscopy. A total of 8983 subjects under- went FIT, and 106 underwent colonoscopy, for an overall participation rate of 34.2% (average age, 59.3±5.6 years; proportion of subjects who were women, 54.4%). Therefore, there were differenc- es between study groups regarding both the rate of participation (odds ratio in the colonoscopy group, 0.63; 95% confidence interval [CI], 0.60 to 0.65; P<0.001) and the crossover rate (odds ratio, 16.8; 95% CI, 13.9 to 20.2; P<0.001).

Diagnostic Yield

In the intention-to-screen analysis, colorectal can- cer was detected in 30 subjects (0.1%) in the colo- noscopy group and in 33 subjects (0.1%) in the FIT group (odds ratio in the colonoscopy group, 0.99; 95% CI, 0.61 to 1.64; P = 0.99) (Table 1). Advanced adenomas were found in 514 subjects (1.9%) in the colonoscopy group and in 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to

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* The diagnostic yield was calculated as the number of subjects with true positive results divided by the number of sub- jects who were eligible to undergo testing. Subjects were classified according to the most advanced lesion.

† Odds ratios were adjusted for age, sex, and participating center. CI denotes confidence interval.
‡ Advanced adenoma was defined as an adenoma measuring 10 mm or more in diameter, with villous architecture

(>25%), high-grade dysplasia, or intramucosal carcinoma.
§ Advanced neoplasia was defined as advanced adenoma or cancer.

the numbers of subjects who needed to undergo colonoscopy to find one colorectal cancer were 191 in the colonoscopy group and 18 in the FIT group; to find any advanced neoplasm, the num- bers were 10 and 2, respectively (Table 3 in the Supplementary Appendix).

Complications

Major complications occurred in 24 subjects (0.5%) in the colonoscopy group (12 subjects with bleed- ing, 10 subjects with hypotension or bradycardia, 1 subject with perforation, and 1 subject with de- saturation) and in 10 subjects (0.1%) in the FIT group (8 subjects with bleeding and 2 subjects with hypotension or bradycardia, all of whom required colonoscopy because of a positive result on FIT). Accordingly, the complication rate was higher in the colonoscopy group than in the FIT group (odds ratio, 4.81; 95% CI, 2.26 to 10.20; P<0.001).

Discussion

In this trial, participation rates were low in both groups of subjects who were invited to undergo colorectal-cancer screening, but subjects in the FIT group were more likely to agree to participate than those in the colonoscopy group. The number of pa- tients in whom colorectal cancer was detected was similar in the two study groups, but more patients with adenomas were identified in the colonoscopy group. Since the primary outcome of this trial is the reduction in the rate of death from colorectal can-

cer at 10 years, the relative benefits and risks of the two strategies will be assessed at the end of the trial.

Our study has a number of strengths. We used a randomized design to compare a sensitive, semi- quantitative FIT with colonoscopy. The study design accepts crossover between groups and in- cludes intention-to-screen and as-screened anal- yses.9Our analyses incorporated stratification of results according to the location of detected le- sions, thus allowing assessment of differences in procedure performance in both the proximal and distal colon, a critical issue that has become con- troversial in recent years.31

However, the study also has a number of limi- tations. First, the generalizability of the study findings is limited because participation in each screening strategy, a critical aspect with a direct effect on the diagnostic yield, depends on several factors and varies geographically. To overcome this limitation, we also evaluated the rate of detection of the screening procedure that was actually per- formed in order to establish the intrinsic efficacy of both strategies. Second, although recruitment was encouraged, the rate of participation was lower than expected according to European pop- ulation-based screening programs5and American colonoscopy-based strategies.31However, it is im- portant to note that our participation rate did not differ from the corresponding rates in other trials that were performed in a similar setting.19,21

The most relevant result of this interim analysis

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Colonoscopy vs. Fecal Immunochemical Testing

* The diagnostic yield was calculated as the number of subjects with true positive results divided by the number of sub- jects who were eligible to undergo testing. Subjects were classified according to the most advanced lesion that was proximal or distal to the splenic flexure. The total number of subjects with proximal and distal lesions may exceed the total number of subjects because subjects could have lesions in both locations.

† Odds ratios were adjusted for age, sex, and participating center.
‡ Advanced adenoma was defined as an adenoma measuring 10 mm or more in diameter, with villous architecture

(>25%), high-grade dysplasia, or intramucosal carcinoma.
§ Advanced neoplasia was defined as either advanced adenoma or cancer.

is that one-time screening with FIT was very simi- lar to one-time colonoscopy with respect to the rate of detection of colorectal cancer, and there was no significant difference in the stage of tumors de- tected by the two strategies. Additional cases of colorectal cancer might be detected during ongo- ing biennial FIT screening, and this could lead to an increased rate of cancer detection and a de- creased rate of death in this group. On the other hand, more tumors might have been prevented in the colonoscopy group owing to the larger number of adenomas detected and removed, in comparison with the FIT group.

The higher detection rate and diagnostic yield of colonoscopy with respect to premalignant le- sions also warrant comment. First, since advanced adenomas are usually considered a surrogate marker for colorectal cancer,32,33the superiority of colonoscopy for detecting such lesions should be

considered a potential advantage of this strategy in terms of reducing not only the rate of death from colorectal cancer but also the incidence of dis- ease.34However, this effect was diminished in our study by the lower participation rate in the colo- noscopy group than in the FIT group. Moreover, the first round of FIT screening detected about half the number of advanced adenomas that were de- tected by colonoscopy. The lower participation rate in the colonoscopy group and the recurrent nature of FIT screening may reduce the apparent advan- tage of colonoscopy. On the other hand, the re- markably high detection rate with colonoscopy for patients with nonadvanced adenomas is more dif- ficult to interpret. Most of these lesions correspond to low-risk adenomas, with a natural history that is more unpredictable but unquestionably less prone to progression to colorectal cancer than the natural history of advanced adenoma.34,35Indeed,

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* The detection rate is the comparison between the number of positive results and the number of subjects who actually underwent testing. Subjects were classified according to the most advanced lesion.

† A total of 104 subjects with positive results on FIT did not undergo colonoscopy.
‡ Odds ratios were adjusted according to age, sex, and participating center.
§ Advanced adenoma was defined as an adenoma measuring 10 mm or more in diameter, with villous architecture

(>25%), high-grade dysplasia, or intramucosal carcinoma. ¶Advanced neoplasia was defined as advanced adenoma or cancer.

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recent European guidelines for quality assurance in colorectal-cancer screening consider patients with only one or two small adenomas (<10 mm in di- ameter) to be at low risk and thus to be appropriate candidates for the same screening strategy that is recommended for patients without adenomas.36Accordingly, the lower rate of detection of these lesions among patients who underwent screening by means of FIT might be seen as an additional advantage of this strategy, since it would reduce the number of patients who would need to un- dergo colonoscopy, with consequent reductions in costs and colonoscopy-related complications. This issue will be assessed at the end of the trial.

An interesting aspect of our study is the differ-

ential performance of screening strategies accord-

ing to the location of the neoplasm. This aspect of

colorectal-cancer screening is controversial since it

has been suggested that both colonoscopy and FIT

are less effective for detecting lesions located in the

37

distal colon were detected in the colonoscopy group than in the FIT group. This difference was significantly higher for advanced adenomas in the proximal colon than in the distal colon. Precise explanations for these differential findings or how they may influence long-term results are unclear.

In summary, in this interim analysis, subjects in the FIT group were more likely to participate in colorectal-cancer screening than subjects in the colonoscopy group. On the baseline screening ex- amination, the number of subjects in whom colorectal cancer was detected was similar in the two study groups, but more adenomas were de- tected in the colonoscopy group. The comparative effectiveness of FIT and colonoscopy for preventing death from colorectal cancer will be assessed at the completion of this 10-year trial.

Supported by grants from Asociación Española contra el Cáncer (Fundación Científica and Junta de Barcelona), Instituto de Salud Carlos III (PI08/90717), FEDER funds, and Agència de Gestió d’Ajuts Universitaris i de Recerca (2009SGR849). Centro de Inves- tigación Biomédica en Red de Enfermedades Hepáticas y Digesti- vas (CIBERehd) is funded by Instituto de Salud Carlos III. In the Basque Country, the study received additional grants from Obra Social de Kutxa, Diputación Foral de Gipuzkoa (DFG 07/5), Depar- tamento de Sanidad del Gobierno Vasco, EITB-Maratoia (BIO 07/ CA/19), and Acción Transversal contra el Cáncer del CIBERehd (2008). In Galicia, this work was supported by Dirección Xeral de Innovación e Xestión da Saúde Pública, Conselleria de Sanidade, and Xunta de Galicia. Eiken Chemical of Japan and its Spanish representatives, Palex Medical and Biogen Diagnóstica, donated supplies and automated analyzers used for FIT.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

proximal colon than in the distal colon. A case– control study showed that colonoscopy was strong- ly associated with a reduction in mortality from left-sided colorectal cancer but not from right-sided tumors.9FIT seems to detect lesions that are mainly located distally to the splenic flexure.38In this interim analysis, we observed no significant between-group difference in side-specific colorec- tal-cancer detection, but more advanced and non- advanced adenomas in both the proximal and

Colonoscopy vs. Fecal Immunochemical Testing

Appendix

The authors’ affiliations are as follows: the Department of Gastroenterology, Hospital Universitario de Canarias, Tenerife (E.Q., I.A.-A.); the Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Ivestigacions Biomediques August Pi i Sunyer (A.C.), the Department of Gastroenterology, Parc de Salut Mar, Institut Municipal d’Investigació Mèdica (IMIM), Pompeu Fabra University (M. Andreu, X.B., O.F.-A.), the Department of Epidemiology and Evaluation, Parc de Salut Mar, IMIM (C.H.), and Unitat d’Avaluació, Suport i Preventiva, Hospital Clínic (J.G., A.S.) — all in Barcelona; the Department of Gastroenterology, Donostia Hospital, CIBERehd, University of Basque Country (L.B.), the Department of Gastroen- terology, Instituto Oncológico, Obra Social Kutxa (I.M.), and the Department of Gastroenterology, Policlinica Gipuzkoa, CIBERehd (J.A.) — all in San Sebastián; the Department of Gastroenterology, Complexo Hospitalario Universitario de Ourense, Ourense (J.C., E.C.); the Colorectal Cancer Screening Program, Dirección General de Salud Pública, Conselleria de Sanitat (D.S., T.S., M. Andres, G.T.), and the Department of Gastroenterology, Hospital Universitario La Fe (M.P.) — both in Valencia; the Department of Gastroen- terology, University of Zaragoza, IIS Aragón, CIBERehd, Zaragoza (A.L., M.-P.R., M.P.-T.); Unidad de Gestión Clínica de Digestivo, Hospital Universitario Virgen de la Arrixaca (F.C., A.O.), the Colorectal Cancer Prevention Program of the Región de Murcia, Servicio Murciano de Salud (J.C.), and the Colorectal Cancer Prevention Program of the Región de Murcia, Dirección General de Salud Pública, Consejería de Sanidad y Política Social (F.P.-R.) — all in Murcia; the Department of Gastroenterology, Hospital Clínico San Carlos (J.D.M., C.P.), the Department of Gastroenterology, Hospital Fundación Alcorcón (G.C.), the Department of Gastroenterology, Hospital 12 de Octubre (J.D.-T.), the Department of Gastroenterology, Hospital de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), and CIBERehd (C.S.), and the Regional Office for Oncology Coordination, Consejería de Sanidad (A.G.-N.) — all in Madrid; the Gas- troenterology Unit, Hospital General Universitario de Alicante, Alicante (R.J.); the Department of Gastroenterology, Lasarte-Oria Health Center, Osakidetza-Basque Health Service, Guipúzcoa (E.L.); the Department of Gastroenterology, Complexo Hospitalario Universitario de Vigo, Vigo (V.H., F.I.); Dirección Xeral de Innovación e Xestión da Saúde Pública, Conselleria de Sanidade, Xunta de Galicia (R.Z.); the Department of Gastroenterology, Consorcio Hospitalario de Castellón, Castellón (A.P.); the Colorectal Cancer Screening Program of the Comunidad de Canarias, Servicio Canario de la Salud (M.V.-P., J.M.R.-M.); and the Department of Gastroenterology, Hospital Puerta de Hierro, Majadahonda (A.H.-T.) — all in Spain.

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