Multitarget Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population.

INTRODUCTION: We set out to evaluate the performance of a multitarget stool DNA (MT-sDNA) in an average-risk colonoscopy-controlled colorectal cancer (CRC) screening population. MT-sDNA stool test results were evaluated against fecal immunochemical test (FIT) results for the detection of different lesions, including molecularly defined high-risk adenomas and several other tumor characteristics. METHODS: Whole stool samples (n = 1,047) were prospectively collected and subjected to an MT-sDNA test, which tests for KRAS mutations, NDRG4 and BMP3 promoter methylation, and hemoglobin. Results for detecting CRC (n = 7), advanced precancerous lesions (advanced adenoma [AA] and advanced serrated polyps; n = 119), and non-AAs (n = 191) were compared with those of FIT alone (thresholds of 50, 75, and 100 hemoglobin/mL). AAs with high risk of progression were defined by the presence of specific DNA copy number events as measured by low-pass whole genome sequencing. RESULTS: The MT-sDNA test was more sensitive than FIT alone in detecting advanced precancerous lesions (46% (55/119) vs 27% (32/119), respectively, P < 0.001). Specificities among individuals with nonadvanced or negative findings (controls) were 89% (791/888) and 93% (828/888) for MT-sDNA and FIT testing, respectively. A positive MT-sDNA test was associated with multiple lesions (P = 0.005), larger lesions (P = 0.03), and lesions with tubulovillous architecture (P = 0.04). The sensitivity of the MT-sDNA test or FIT in detecting individuals with high-risk AAs (n = 19) from individuals with low-risk AAs (n = 52) was not significantly different. DISCUSSION: In an average-risk screening population, the MT-sDNA test has an increased sensitivity for detecting advanced precancerous lesions compared with FIT alone. AAs with a high risk of progression were not detected with significantly higher sensitivity by MT-sDNA or FIT.

Adding family history to faecal immunochemical testing increases the detection of advanced neoplasia in a colorectal cancer screening programme.

BACKGROUND: Faecal immunochemical testing (FIT) for colorectal cancer (CRC) screening has suboptimal sensitivity for detecting advanced neoplasia. To increase its performance, FIT could be combined with other risk factors. AIM: To evaluate the incremental yield of a screening programme using a positive FIT or a CRC family history, to offer a diagnostic colonoscopy. METHODS: For this post hoc analysis, data were collected in the colonoscopy arm of a colonoscopy or colonography for screening study. In this study, 6600 randomly selected, asymptomatic men and women (50-75 years) were invited for screening colonoscopy. 1112 Participants completed a FIT and a questionnaire prior to colonoscopy. We compared the yield of FIT-only and FIT combined with CRC family history, defined as having one or more first-degree relatives with CRC. RESULTS: At a 10 µg Hb/g faeces FIT-positivity threshold the combined strategy would increase the yield from 36 (3.2%; CI: 2.4-4.5%) to 53 (4.8%; CI: 3.7-6.2%) cases of advanced neoplasia, at the expense of 148 additional negative colonoscopies. Sensitivity in detecting advanced neoplasia would increase from 36% (CI: 26-46%) to 52% (CI: 42-63%), whereas specificity would decrease from 93% (CI: 92-95%) to 79% (CI: 76-81%). The strategy will be preferred if one accepts 8.8 false positives for every additional participant in whom advanced neoplasia can be detected. CONCLUSIONS: Offering colonoscopy to those with a positive FIT or CRC family history increases the yield of a FIT-based screening programme. Depending on the number of negative colonoscopies one accepts, this combined approach can be considered for improving CRC screening.

Smoking status informs about the risk of advanced serrated polyps in a screening population.

BACKGROUND AND STUDY AIMS: Evidence has accumulated that approximately 15 % to 30 % of colorectal cancers (CRC) arise from serrated polyps (SP). Population screening, therefore, should be designated to detect advanced SP, in addition to advanced adenomas and CRC. We aimed to evaluate whether CRC risk factors also act as risk factors for advanced SP. PATIENTS AND METHODS: Data were collected in the colonoscopy arm of a multicenter randomized trial comparing colonoscopy with CT-colonography for primary population screening. Information on risk factors was obtained by screening participants before colonoscopy with a validated risk questionnaire. Advanced SP were defined as SP ≥ 10 mm and/or with dysplasia. Endoscopists were instructed to resect all detected lesions. Odds ratios (OR) for the detection of advanced SP as most advanced lesion were calculated using multiple logistic regression analysis. RESULTS: Of 6 600 invited participants, 1 426 underwent a colonoscopy and 1 236 also completed the questionnaire. In 40 participants an advanced SP was the most advanced lesion detected. Multivariate analysis demonstrated a strong association between current smoking and the presence of at least one advanced SP (OR 4.50; 95 % CI 2.23 - 8.89; P < 0.001). A significant association was also demonstrated for higher fiber intake (OR 1.36 per 20 gram intake; CI 1.07 - 1.73; P = 0.01). Other clinical CRC risk factors did not show a significant association with the presence of at least one advanced SP in the univariate analyses. Fecal haemoglobin levels were also not significantly associated with the presence of advanced SPs (OR 1.00 per 10 ng/mL CI 0.97 - 1.03, P = 0.99). CONCLUSIONS: Current smoking is a strong clinical risk factor for the presence of advanced SPs. As such, smoking status could contribute to risk stratification in targeted CRC population screening. Dutch Trial Register: NTR1829 (www.trialregister.nl).

Time requirements and health effects of participation in colorectal cancer screening with colonoscopy or computed tomography colonography in a randomized controlled trial.

BACKGROUND AND STUDY AIMS: Time limitations and unwanted health effects may act as barriers to participation in colorectal cancer (CRC) screening. The aim of the study was to measure the time requirements and health effects of colonoscopy and computed tomography colonography (CTC) screening. PATIENTS AND METHODS: This was a prospective diary study in a consecutive sample within a randomized controlled CRC screening trial, comparing primary colonoscopy and CTC screening for average-risk individuals aged 50 - 74 years. The diary ended when all screening-related complaints had passed. RESULTS: The diary was returned by 75 % (241/322) of colonoscopy and 75 % (127/170) of CTC screenees. The median interval between leaving home and returning from the examination was longer for colonoscopy (4 hours and 18 minutes [4:18], interquartile range [IQR] 3:30 - 5:00) than for CTC (2:30 hours, IQR 2:06 - 3:00; P < 0.001). Similarly, the time to return to routine activities was longer after colonoscopy (3:54 hours, IQR 1:48 - 15:00) than after CTC (1:36 hours, IQR 0:54 - 4:42). The duration of screening-related symptoms after the examination was shorter for colonoscopy (11:00 hours, IQR 2:54 - 20:00) than for CTC (22:00 hours; IQR 5:30 - 47:00; P < 0.001). Abdominal complaints were reported more frequently after CTC. Anxiety, pain, and quality of life worsened during the screening process, with no differences between the two examinations. CONCLUSIONS: Compared with colonoscopy, CTC screening required less time and allowed screenees to return to their daily activities more quickly. In contrast, CTC was associated with a twofold longer duration of screening-related symptoms. Feelings of anxiety, pain, and quality of life scores were similar during colonoscopy and CTC screening. These results should be incorporated into cost-effectiveness analyses of CRC screening techniques.

Face-to-face vs telephone pre-colonoscopy consultation in colorectal cancer screening; a randomised trial.

BACKGROUND: A pre-colonoscopy consultation in colorectal cancer (CRC) screening is necessary to assess a screenee's general health status and to explain benefits and risks of screening. The first option allows for personal attention, whereas a telephone consultation does not require travelling. We hypothesised that a telephone consultation would lead to higher response and participation in CRC screening compared with a face-to-face consultation. METHODS: A total of 6600 persons (50-75 years) were 1:1 randomised for primary colonoscopy screening with a pre-colonoscopy consultation either face-to-face or by telephone. In both arms, we counted the number of invitees who attended a pre-colonoscopy consultation (response) and the number of those who subsequently attended colonoscopy (participation), relative to the number invited for screening. A questionnaire regarding satisfaction with the consultation and expected burden of the colonoscopy (scored on five-point rating scales) was sent to invitees. Besides, a questionnaire to assess the perceived burden of colonoscopy was sent to participants, 14 days after the procedure. RESULTS: In all, 3302 invitees were allocated to the telephone group and 3298 to the face-to-face group, of which 794 (24%) attended a telephone consultation and 822 (25%) a face-to-face consultation (P=0.41). Subsequently, 674 (20%) participants in the telephone group and 752 (23%) in the face-to-face group attended colonoscopy (P=0.018). Invitees and responders in the telephone group expected the bowel preparation to be more painful than those in the face-to-face group while perceived burden scores for the full screening procedure were comparable. More subjects in the face-to-face group than in the telephone group were satisfied by the consultation in general: (99.8% vs 98.5%, P=0.014). CONCLUSION: Using a telephone rather than a face-to-face consultation in a population-based CRC colonoscopy screening programme leads to similar response rates but significantly lower colonoscopy participation.

Immunochemical fecal occult blood testing is equally sensitive for proximal and distal advanced neoplasia.

OBJECTIVE: Fecal immunochemical testing (FIT) is increasingly used for colorectal cancer (CRC) screening. We aimed to estimate its diagnostic accuracy in invitational population screening measured against colonoscopy. METHODS: Participants (50-75 years) in an invitational primary colonoscopy screening program were asked to complete one sample FIT before colonoscopy. We estimated FIT sensitivity, specificity, and predictive values in detecting CRC and advanced neoplasia (carcinomas and advanced adenomas) for cutoff levels of 50 (FIT50), 75 (FIT75), and 100 (FIT100) ng hemoglobin (Hb)/ml, corresponding with, respectively, 10, 15 and 20 µg Hb/g feces. RESULTS: A total of 1,256 participants underwent a FIT and screening colonoscopy. Advanced neoplasia was detected by colonoscopy in 119 (9%), 8 (0.6%) of them had CRC. At FIT50, 121 (10%) had a positive test result; 45 (37%) had advanced neoplasia and 7 (6%) had CRC. A total of 74 of 1,135 FIT50 negatives (7%) had advanced neoplasia including 1 (0.1%) CRC. FIT50 had a sensitivity of 38% (95% confidence interval (CI): 29-47) for advanced neoplasia and 88% (95% CI: 37-99) for CRC at a specificity of 93% (95% CI: 92-95) and 91% (95% CI: 89-92), respectively. The positive and negative predictive values for FIT50 were 6% (95% CI: 3-12) and almost 100% (95% CI: 99-100) for CRC, and 37% (95% CI: 29-46) and 93% (95% CI: 92-95) for advanced neoplasia. The sensitivity and specificity of FIT75 for advanced neoplasia were 33% (95% CI: 25-42) and 96% (95% CI: 94-97). At FIT100, 71 screenees (6%) had a positive test result. The sensitivity and specificity of FIT100 were for advanced neoplasia 31% (95% CI: 23-40) and 97% (95% CI: 96-98), and for CRC 75% (95% CI: 36-96) and 95% (95% CI: 93-96). The area under curve for detecting advanced neoplasia was 0.70 (95% CI: 0.64-0.76). FIT had a similar sensitivity for proximal and distal advanced neoplasia at cutoffs of 50 (38% vs. 37%; P=0.99), 75 (33% vs. 31%; P=0.85) and 100 (33% vs. 29%; P=0.68) ng Hb/ml. DISCUSSION: Nine out of ten screening participants with CRC and four out of ten with advanced neoplasia will be detected using one single FIT at low cutoff. Sensitivity in detecting proximal and distal advanced neoplasia is comparable.

Strategies in screening for colon carcinoma.

Colorectal cancer is the second most common cancer in Europe and meets the criteria for population screening. Population screening should lead to a reduction in CRC-related mortality and incidence. Several options are available for CRC screening, which can be itemised as stool-based tests and structural exams. Stool-based tests include guaiac and immunochemical faecal occult blood tests and DNA -marker tests. Structural exams comprise endoscopic techniques (flexible sigmoidoscopy, colonoscopy and capsule endoscopy) and radiological exams (double contrast barium enema, CT colonography and MR colonography). Each test has its own test performance characteristics and acceptability profile, which affect the participation and effectiveness of the associated screening programmes. Faecal occult blood tests (FOBT ) and flexible sigmoidoscopy (FS) are the only methods with a demonstrated mortality reduction during a ten-year period (FOBT 16% and FS 31%) while flexible sigmoidoscopy is the only screening test with a demonstrated reduction in CRC incidence (23%). It is likely that other screening techniques such as colonoscopy and CT colonography will also be effective in the reduction of CRC-related mortality. DNA -marker tests, capsule endoscopy and MR colonography are possible options for the future.