Aafke H. van Roon

Random comparison of repeated faecal immunochemical testing at different intervals for population-based colorectal cancer screening

Objective Colorectal cancer screening by means of faecal immunochemical tests (FITs) requires successive screening rounds for an optimal preventive effect. However, data on the influence of the length of the screening interval on participation and diagnostic yield are lacking. Repeated FIT screening was therefore performed in a population-based trial comparing various repeat intervals. Design 7501 Dutch individuals aged 50–74 years were randomly selected and invited for two 1-sample FIT screening rounds (haemoglobin (Hb) concentration ≥50 ng/ml, corresponding to 10 μg Hb/g faeces) with intervals of 1 (group I), 2 (group II) or 3 years (group III). Results In group I, participation was 64.7% in the first screening round and 63.2% in the second. The corresponding percentages for groups II and III were 61.0% vs 62.5% and 62.0% vs 64.0%. Triennial screening resulted in a higher participation rate in the second screening round compared with annual screening (p=0.04). The overall positivity rate in the second screening round was significantly lower compared with the first round (6.0% vs 8.4%; OR 0.69, 95% CI 0.58 to 0.82) and did not depend on interval length (p=0.23). Similarly, the overall detection rate of advanced neoplasia was significantly lower in the second round compared with the first screening round (1.9% vs 3.3%; OR 0.57, 95% CI 0.43 to 0.76) and also did not depend on interval length (p=0.62). The positive predictive value of the FIT did not significantly change over time (41% vs 33%; p=0.07). Conclusion The total number of advanced neoplasia found at repeat FIT screening is not influenced by the interval length within a range of 1–3 years. Furthermore, there is a stable and acceptably high participation in the second screening round. This implies that screening intervals can be tailored to local resources.

Diagnostic Yield Improves With Collection of 2 Samples in Fecal Immunochemical Test Screening Without Affecting Attendance

BACKGROUND & AIMS The fecal immunochemical test (FIT) is superior to the guaiac-based fecal occult blood test in detecting neoplasia. There are not much data on the optimal number of FITs to perform. We conducted a population-based trial to determine attendance and diagnostic yield of 1- and 2-sample FIT screening. METHODS The study included 2 randomly selected groups of subjects aged 50-74 years (1-sample FIT, n=5007; 2-sample FIT, n=3197). The 2-sample group was instructed to collect fecal samples on 2 consecutive days. Subjects were referred for colonoscopy when at least 1 sample tested positive (≥50 ng hemoglobin/mL). RESULTS Attendance was 61.5% in the 1-sample group (2979 of 4845; 95% confidence interval, 60.1%-62.9%) and 61.3% in the 2-sample group (1875 of 3061; 95% confidence interval, 59.6%-63.0%; P=.84). In the 1-sample group 8.1% tested positive, and in the 2-sample group 12.8% had at least 1 positive test outcome and 5.0% had 2 positive test outcomes (P<.05). When the mean from both test results in the 2-sample group was used, 10.1% had a positive test outcome (P<.05). The detection rates for advanced neoplasia were 3.1% in the 1-sample group, 4.1% in the 2-sample group with at least 1 positive test outcome, 2.5% when both test results were positive, and 3.7% among subjects with the mean from both test results being positive. CONCLUSIONS There is no difference in attendance for subjects offered 1- or 2-sample FIT screening. The results allow for the development of efficient FIT screening strategies that can be adapted for local colonoscopy capacities, rather than varying the cut-off value in a 1-sample strategy.

Attendance and Yield Over Three Rounds of Population-Based Fecal Immunochemical Test Screening

OBJECTIVES:Fecal immunochemical test (FIT) screening for colorectal cancer (CRC) requires timely successive rounds for an optimal preventive effect. However, data on attendance and trend in yield over multiple rounds of FIT screening are limited. We therefore conducted a consecutive third round of FIT screening in a population-based CRC screening trial.METHODS:Average-risk subjects aged 50–74 years were approached for three rounds of 1-sample FIT (OC-sensor) screening. Subjects with a hemoglobin level ≥50 ng/ml (≥10 μg Hb/g) feces were referred for colonoscopy. Subjects with a positive FIT in previous rounds were not re-invited for FIT screening.RESULTS:In the first round, 7,501 subjects were invited. The participation rate was 62.6% in the first round, 63.2% in the second round, and 68.3% in the third round (P<0.001). In total, 73% (5,241/7,229) of all eligible subjects participated in at least one of three rounds. The positivity rate was significantly higher in the first (8.4%) round compared with the second (6.0%) and third (5.7%) screening rounds (P<0.001). The detection rate of advanced neoplasia (AN) declined from the first round to subsequent rounds (round 1: 3.3%; round 2: 1.9%; and round 3: 1.3%; P<0.001). The positive predictive value for AN was 40.7% in the first screening round, 33.2% in the second screening round, and 24.0% in the third screening round (P<0.001).CONCLUSIONS:Repeated biennial FIT screening is acceptable with increased participation in successive screening rounds, and >70% of all eligible subjects participating at least once over three rounds. The decline in screen-detected AN over three screening rounds is compatible with a decreased prevalence of AN as a result of repeated FIT screening. These findings provide strong evidence for the effectiveness of FIT screening and stress the importance of ongoing research over multiple screening rounds.

Cost-effectiveness of one versus two sample faecal immunochemical testing for colorectal cancer screening

Objective The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. Design The MISCAN–colon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. Results Within an exemplary screening strategy, biennial FIT from the age of 55–75 years, one-sample FIT provided 76.0–97.0 life-years gained (LYG) per 1000 individuals, at a cost of €259 000–264 000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3–12.4 additional LYG compared with one-sample FIT at an extra cost of €50 000–59 000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. Conclusion If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Are Fecal Immunochemical Test Characteristics Influenced by Sample Return Time? A Population-Based Colorectal Cancer Screening Trial

OBJECTIVES:Fecal immunochemical tests (FIT) are preferred over guaiac-based fecal occult blood testing as colorectal cancer (CRC) screening tool. However, hemoglobin (Hb) degradation over time may influence FIT outcome. We therefore evaluated the effect of sample return time on FIT performance characteristics in a population-based CRC screening trial.METHODS:A representative random sample of the Dutch population (n=17,677), aged 50–74 years, was invited for FIT screening (OC-Sensor Micro; cutoff ≥ 50 ng Hb/ml). Sample return time was defined as the interval in days between fecal sampling and FIT laboratory delivery. Moreover, a random sample of positive FITs were selected to be stored at room temperature and re-tested every 3–4 days.RESULTS:In total, 8,958 screenees fulfilled our inclusion criteria. The mean sample return time was 3 days (± 3). Overall, 792 screenees (8.8%) had a positive test. Between the sample return time groups, the positivity rate (PR) varied between 7.7 and 9.0%. No statistically significant associations were found between PR or detection rate (DR) and the different sample return time groups (P value=0.84 and 0.76, respectively). For the laboratory experiment, 71 positive FITs were stored at room temperature and re-tested with standard intervals. The mean daily fecal Hb decrease was 5.88% per day (95% confidence interval 4.78–6.96%). None of the positive FITs became negative before 10 days after fecal sampling.CONCLUSIONS:This population-based CRC screening trial demonstrates that both the PR and DR of FITs do not decrease with prolonged sample return times up to 10 days. This means that a delay in sending the FIT back to the laboratory, of up to at least 1 week, does not necessitate repeat sampling in case of a negative test result. These data support the use of FIT-based screening as a reliable tool for nationwide CRC screening programs.

Attendance and diagnostic yield of repeated two-sample faecal immunochemical test screening for colorectal cancer

Objective Limited data exist on attendance and additional yield of 2-sample faecal immunochemical testing (FIT) screening during multiple rounds. We therefore conducted a population-based colorectal cancer screening trial comparing attendance and yield of repeated 1-sample and 2-sample FIT screenings. Design Two randomly selected groups of average-risk subjects aged 50–74 years were invited for two rounds of either 1-sample (n=5007) or 2-sample (n=3197) FIT (OC-sensor Micro) screening. The test was considered positive if at least one sample was positive (cut-off 50 ng/mL; 10 µg haemoglobin/g). Results The cumulative attendance rate was similar for repeated 1-sample and 2-sample FIT screenings (1-sample FIT: 68.1%; 2-sample FIT: 67.1%, p=0.368). The positivity rate in the second round was lower for 1-sample FIT (6.2%, 95% CI 5.4% to 7.2%) than for 2-sample FIT (8.4%, 95% CI 7.1% to 9.8%, p=0.007), whereas the detection rate of advanced neoplasia (AN, 1-sample FIT: 1.9%, 95% CI 1.2% to 2.2%; 2-sample FIT: 1.7%, 95% CI 1.2% to 2.5%, p=0.861) and the positive predictive value (1-sample FIT: 32%, 95% CI 24% to 40%; 2-sample FIT: 21%, 95% CI 15% to 29%, p=0.075) did not differ. After two rounds of screening, the cumulative diagnostic yield of AN for 1-sample FIT was 29.3 per 1000 invitees, compared with 34.0 for 2-sample FIT (p=0.241). Conclusions Using 2-sample FIT instead of 1-sample FIT does not result in a higher detection rate of AN in the second round of repeated FIT screening. Furthermore, both strategies lead to a similar yield of AN over two rounds. These findings imply that 1-sample FIT screening is preferred over 2-sample FIT screening.

Attendance and Diagnostic Yield of Repeated Fecal Immunochemical Test Screening With Intervals of 1, 2, or 3 Years: A Comparative Population-Based Colorectal Cancer Screening Trial

Introduction: Fecal immunochemical tests (FIT) have suboptimal sensitivity for advanced neoplasia and require successive screening rounds for an optimal preventive effect. However, data about the influence of screening interval length on attendance and diagnostic yield are lacking, nor is it known whether the increased sensitivity of FIT compared to the conventional guaiac-based FOBT allows for longer screening intervals. We therefore performed repeated FIT screening in a population-based trial comparing 1, 2, and 3 year intervals. Methods: Three representative samples of the Dutch population (total=7,500) aged 50-75 years were randomly selected prior to invitation. Individuals were invited for two 1-sample FIT screening rounds (cut-off ≥ 50 ng Hb/mL) with intervals of respectively 1 (group A), 2 (B), or 3 years (C). Subjects with a positive FIT in the 1st screening round, and those who had moved away/died were not invited for the 2nd round. Results: In group A, attendance was 64.6% (1,544/2,391) in the 1st and 62.7% (n=1,302/2,077) in the 2nd screening round. Of the 1st round participants, 89.8% also attended the 2nd screening round. Of the non-participants in the 1st screening round, 16.3% did participate in the 2nd round. We refer to Table 1 for group B and C. Corrected for 1st round attendance, a longer screening interval improved participation in the 2nd FIT-based screening round (group A (reference) 89.8% vs. group B 90.9%, and vs. group C 91.4%; p<0.05). Attendance of 1st round non-participants was also higher in group B and C compared to the reference group A (respectively 19.3%, and 18.9%, vs 16.3%; p<0.05). The proportion of participants attending at least one screening round did not significantly differ between the screening intervals (group A: 67.4%, group B: 66.1%, group C 67.0%; p=0.60). The overall positivity rate (PR) in the 2nd screening round was significantly lower compared to the 1st (6.0% vs. 8.4%, OR 0.69; CI 0.58-0.82). However, a longer interval was not associated with higher PR at repeated screening (p= 0.36). Similarly, the overall detection rate (DR) of advanced neoplasia was significantly lower in the 2nd round (1.8%, OR 0.55; CI 0.41-0.74) compared to the 1st screening round (3.3%). Colorectal cancers were found in 0.44% of 1st round participants vs. 0.17% in 2nd round participants (OR 0.39; CI 0.16-0.98). The length of screening interval did not affect the DR of advanced neoplasia in the 2nd round (p=0.33). Conclusion: Attendance of repeated FIT screening is moderately high with uptake percentages approximating 70%. A longer screening interval of 2 or 3 years results in significantly higher participation compared to annual screening. In the 2nd screening round, positivity and detection rates were significantly lower than in the 1st screening round. However, both were not affected by the length of the screening interval. Table 1

Mo1984 Third Round of Two-Sample Immunochemical Fecal Occult Blood Test Screening in the Netherlands

Preparation Scale (BBPS) and categorized as either excellent vs. not excellent (BBPS≥7 vs. BBPS<7) or adequate vs. inadequate (BBPS≥5 vs. BBPS<5). There was no change in attending endoscopy staff during the study period. A multivariate logistic regression analysis to identify factors independently associated with excellent bowel preparation was performed. Results Bowel preparation quality was excellent in 40% of patients and adequate in 90%. There was no seasonal variation for adequate bowel preparation. However, there was a significant increase in excellent bowel preparation in the spring and summer compared to autumn and winter (Table 1). A similar trend of increased rate of excellent bowel preparation was observed in the subgroup of patients using split dose bowel preparation (Table 2). Independent factors for excellent bowel preparation were spring and summer scheduling (OR, 1.8; 95% CI 1.52.2; p<0.0008), split bowel preparation (OR, 1.6; 95% CI, 1.2-2.1; p=0.002) and use of narcotics (OR, 0.7; 95%CI, 0.6-0.9; P= 0.003). Conclusions Spring and summer scheduled colonoscopies are associated with greater likelihood of achieving excellent bowel preparation. Seasonal variations in patients eating behavior, fluid consumption, exercise and circadian rhythm could alter colonic transit and hence, quality of bowel preparation for colonoscopy. Table 1

Su1212 Increase in Participation Rate With Successive Rounds of FIT Screening

Multivariable logistic regression was used to determine independent predictors of FOBT receipt. Results: The sample consisted of 115,414 individuals who underwent one or more CRC screening test, including 28,713 who had FOBT. African Americans (multivariate OR 0.84 95 % CI 0.810.88), Hispanics (OR 0.64 95 % CI 0.560.73) and Native American (OR: 0.61 95% CI 0.49 0.76) were less likely to undergo FOBT compared to Caucasians. There was no significant difference across gender in receiving FOBT. There were significantly lower odds of receiving FOBT for patients with Charlson comorbidity scores of higher index of 2 or higher compared to 0 (OR 0.83 95 % CI 0.800.85). An incremental association of small area measures of education, income, and GI density was observed across quartiles, with higher rates seen in areas with greater educational level, median income and GI density. Differences were not observed with HRRmeasures of primary care. There was also geographic variation, with significantly lower odds of FOBT receipt in Midwest (OR 0.58 95 % CI 0.550.60), south (OR 0.90 95 % CI 0.870.94), and west (OR 0.72 95 % CI 0.690.75) compared to northeast. Conclusion: Under Medicare coverage, consistent with other screening tests, there are disparities in the use of FOBT observed across race, educational level, comorbidity, income and geographic region. Further studies should better define the underlying reasons for these disparities.

S1137 Analytical Sensitivity of a Quantitative Immunochemical Fecal Occult Blood Test (FIT) in Screening for Colorectal Cancer

G A A b st ra ct s based on a nucleic acids multi-gene assay performed on peripheral blood mononuclear cells (PBMCs) that can detect early CRCs and adenomas. Methods: 116 patients (mean age: 55 years; range: 18 to 74 years; female/male ration 0.98) were included in this pilot, nonblinded, colonoscopy-controlled study. Colonoscopy revealed 21 patients with CRC, 30 patients with adenoma bigger than 1 cm, 24 patients with inflammatory bowel disease (IBD) and 41 patients had no neoplastic or inflammatory lesions. Blood samples were taken from each patient the day of the colonoscopy and PBMCs were purified. Total RNA was extracted following standard procedures. Multiplex RT-qPCR was applied on 92 different candidate biomarkers. Different univariate and multivariate statistical methods were applied on these candidates, and among them, 57 biomarkers with significant p values (<0.01, Wilcoxon test) were selected, including ADAMTS1, MMP9, CXCL10, CXCR4, VEGFA and CDH1. Two distinct biomarker signatures are used to separate patients without neoplastic lesion from those with cancer (named COLOX 1 test), respectively from those with adenoma (named COLOX 2 test). Result: COLOX 1 and 2 tests have successfully separated patients without neoplastic lesion from those with CRC (sensitivity 70%, specificity 90%, AUC 0.88), respectively from those with adenoma bigger than 1cm (sensitivity 61%, specificity 80%, AUC 0.80). 6/24 patients in the IBD group have a positive COLOX 1 test. Conclusion: These two COLOX tests demonstrated an acceptable sensitivity and a high specificity to detect the presence of CRCs and adenomas bigger than 1 cm. The false positives COLOX 1 test in IBD patients could possibly be due to the chronic inflammatory state. A prospective, multicenter, pivotal study is underway in order to confirm these promising results in a larger cohort.