Improvement of non-invasive tests of liver steatosis and fibrosis as indicators for non-alcoholic fatty liver disease in type 2 diabetes mellitus patients with elevated cardiovascular risk profile using the PPAR-α/γ agonist aleglitazar.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis. METHODS: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS). RESULTS: LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study. CONCLUSION: This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment.

Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas.

BACKGROUND: For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions. AIM: To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT [screen-detected CRCs (SD-CRCs)]. METHODS: FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs). RESULTS: Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039). CONCLUSION: Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT-interval CRCs.

Guaiac-based faecal occult blood tests versus faecal immunochemical tests for colorectal cancer screening in average-risk individuals.

BACKGROUND: Worldwide, many countries have adopted colorectal cancer (CRC) screening programmes, often based on faecal occult blood tests (FOBTs). CRC screening aims to detect advanced neoplasia (AN), which is defined as CRC or advanced adenomas. FOBTs fall into two categories based on detection technique and the detected blood component: qualitative guaiac-based FOBTs (gFOBTs) and faecal immunochemical tests (FITs), which can be qualitative and quantitative. Screening with gFOBTs reduces CRC-related mortality. OBJECTIVES: To compare the diagnostic test accuracy of gFOBT and FIT screening for detecting advanced colorectal neoplasia in average-risk individuals. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, BIOSIS Citation Index, Science Citation Index Expanded, and Google Scholar. We searched the reference lists and PubMed-related articles of included studies to identify additional studies. SELECTION CRITERIA: We included prospective and retrospective studies that provided the number of true positives, false positives, false negatives, and true negatives for gFOBTs, FITs, or both, with colonoscopy as reference standard. We excluded case-control studies. We included studies in which all participants underwent both index test and reference standard ("reference standard: all"), and studies in which only participants with a positive index test underwent the reference standard while participants with a negative test were followed for at least one year for development of interval carcinomas ("reference standard: positive"). The target population consisted of asymptomatic, average-risk individuals undergoing CRC screening. The target conditions were CRC and advanced neoplasia (advanced adenomas and CRC combined). DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies for inclusion. In case of disagreement, a third review author made the final decision. We used the Rutter and Gatsonis hierarchical summary receiver operating characteristic model to explore differences between tests and identify potential sources of heterogeneity, and the bivariate hierarchical model to estimate sensitivity and specificity at common thresholds: 10 µg haemoglobin (Hb)/g faeces and 20 µg Hb/g faeces. We performed indirect comparisons of the accuracy of the two tests and direct comparisons when both index tests were evaluated in the same population. MAIN RESULTS: We ran the initial search on 25 June 2019, which yielded 63 studies for inclusion. We ran a top-up search on 14 September 2021, which yielded one potentially eligible study, currently awaiting classification. We included a total of 33 "reference standard: all" published articles involving 104,640 participants. Six studies evaluated only gFOBTs, 23 studies evaluated only FITs, and four studies included both gFOBTs and FITs. The cut-off for positivity of FITs varied between 2.4 µg and 50 µg Hb/g faeces. For each Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability than gFOBTs for AN (P < 0.001) and CRC (P = 0.004). For the detection of AN, the summary sensitivity of gFOBTs was 15% (95% confidence interval (CI) 12% to 20%), which was significantly lower than FITs at both 10 µg and 20 µg Hb/g cut-offs with summary sensitivities of 33% (95% CI 27% to 40%; P < 0.001) and 26% (95% CI 21% to 31%, P = 0.002), respectively. Results were simulated in a hypothetical cohort of 10,000 screening participants with 1% CRC prevalence and 10% AN prevalence. Out of 1000 participants with AN, gFOBTs missed 850, while FITs missed 670 (10 µg Hb/g cut-off) and 740 (20 µg Hb/g cut-off). No significant differences in summary specificity for AN detection were found between gFOBTs (94%; 95% CI 92% to 96%), and FITs at 10 µg Hb/g cut-off (93%; 95% CI 90% to 95%) and at 20 µg Hb/g cut-off (97%; 95% CI 95% to 98%). So, among 9000 participants without AN, 540 were offered (unnecessary) colonoscopy with gFOBTs compared to 630 (10 µg Hb/g) and 270 (20 µg Hb/g) with FITs. Similarly, for the detection of CRC, the summary sensitivity of gFOBTs, 39% (95% CI 25% to 55%), was significantly lower than FITs at 10 µg and 20 µg Hb/g cut-offs: 76% (95% CI 57% to 88%: P = 0.001) and 65% (95% CI 46% to 80%; P = 0.035), respectively. So, out of 100 participants with CRC, gFOBTs missed 61, and FITs missed 24 (10 µg Hb/g) and 35 (20 µg Hb/g). No significant differences in summary specificity for CRC were found between gFOBTs (94%; 95% CI 91% to 96%), and FITs at the 10 µg Hb/g cut-off (94%; 95% CI 87% to 97%) and 20 µg Hb/g cut-off (96%; 95% CI 91% to 98%). So, out of 9900 participants without CRC, 594 were offered (unnecessary) colonoscopy with gFOBTs versus 594 (10 µg Hb/g) and 396 (20 µg Hb/g) with FITs. In five studies that compared FITs and gFOBTs in the same population, FITs showed a higher discriminative ability for AN than gFOBTs (P = 0.003). We included a total of 30 "reference standard: positive" studies involving 3,664,934 participants. Of these, eight were gFOBT-only studies, 18 were FIT-only studies, and four studies combined both gFOBTs and FITs. The cut-off for positivity of FITs varied between 5 µg to 250 µg Hb/g faeces. For each QUADAS-2 domain, we assessed risk of bias as high in less than 20% of studies. The summary curve showed that FITs had a higher discriminative ability for detecting CRC than gFOBTs (P < 0.001). The summary sensitivity for CRC of gFOBTs, 59% (95% CI 55% to 64%), was significantly lower than FITs at the 10 µg Hb/g cut-off, 89% (95% CI 80% to 95%; P < 0.001) and the 20 µg Hb/g cut-off, 89% (95% CI 85% to 92%; P < 0.001). So, in the hypothetical cohort with 100 participants with CRC, gFOBTs missed 41, while FITs missed 11 (10 µg Hb/g) and 11 (20 µg Hb/g). The summary specificity of gFOBTs was 98% (95% CI 98% to 99%), which was higher than FITs at both 10 µg and 20 µg Hb/g cut-offs: 94% (95% CI 92% to 95%; P < 0.001) and 95% (95% CI 94% to 96%; P < 0.001), respectively. So, out of 9900 participants without CRC, 198 were offered (unnecessary) colonoscopy with gFOBTs compared to 594 (10 µg Hb/g) and 495 (20 µg Hb/g) with FITs. At a specificity of 90% and 95%, FITs had a higher sensitivity than gFOBTs. AUTHORS' CONCLUSIONS: FITs are superior to gFOBTs in detecting AN and CRC in average-risk individuals. Specificity of both tests was similar in "reference standard: all" studies, whereas specificity was significantly higher for gFOBTs than FITs in "reference standard: positive" studies. However, at pre-specified specificities, the sensitivity of FITs was significantly higher than gFOBTs.

First steps towards combining faecal immunochemical testing with the gut microbiome in colorectal cancer screening.

OBJECTIVES: Many countries use faecal immunochemical testing (FIT) to screen for colorectal cancer. There is increasing evidence that faecal microbiota play a crucial role in colorectal cancer carcinogenesis. We assessed the possibility of measuring faecal microbial features in FIT as potential future biomarkers in colorectal cancer screening. METHODS: Bacterial stability over time and the possibility of bacterial contamination were evaluated using quantitative polymerase chain reaction analysis. Positive FIT samples (n = 200) of an average-risk screening cohort were subsequently analysed for universal 16S, and bacteria. Escherichia coli (E. coli), Fusobacterium nucleatum (F. nucleatum), Bacteroidetes and Faecalibacterium prausnitzii (F. prausnitzii) by qPCR. The results were compared with colonoscopy findings. RESULTS: Faecal microbiota in FIT were stably measured up to six days for E. coli (p = 0.53), F. nucleatum (p = 0.30), Bacteroidetes (p = 0.05) and F. prausnitzii (p = 0.62). Overall presence of bacterial contamination in FIT controls was low. Total bacterial load (i.e. 16S) was significantly higher in patients with colorectal cancer and high-grade dysplasia (p = 0.006). For the individual bacteria tested, no association was found with colonic lesions. CONCLUSIONS: These results show that the faecal microbial content can be measured in FIT samples and remains stable for six days. Total bacterial load was higher in colorectal cancer and high-grade dysplasia. These results pave the way for further research to determine the potential role of microbiota assessment in FIT screening.

Diagnostic Yield of One-Time Colonoscopy vs One-Time Flexible Sigmoidoscopy vs Multiple Rounds of Mailed Fecal Immunohistochemical Tests in Colorectal Cancer Screening.

BACKGROUND & AIMS: We compared the diagnostic yields of colonoscopy, flexible sigmoidoscopy, and fecal immunochemical tests (FITs) in colorectal cancer (CRC) screening. METHODS: A total of 30,007 asymptomatic persons, 50-74 years old, were invited for CRC screening in the Netherlands. Participants were assigned to groups that received 4 rounds of FIT (mailed to 15,046 participants), once-only flexible sigmoidoscopy (n = 8407), or once-only colonoscopy (n = 6600). Patients with positive results from the FIT (≥10 µg Hb/g feces) were referred for colonoscopy. Patients who underwent flexible sigmoidoscopy were referred for colonoscopy if they had a polyp of ≥10 mm; adenoma with ≥25% villous histology or high-grade dysplasia; sessile serrated adenoma; ≥3 adenomas; ≥20 hyperplastic polyps; or invasive CRC. The primary outcome was number of advanced neoplasia detected (diagnostic yield) by each test. Secondary outcomes were number of colonoscopies needed to detect advanced neoplasia and number of interval CRCs found during each primary screening test. Patients with interval CRCs were found through linkage with Netherlands Cancer Registry. Advanced neoplasia were defined as CRC, adenomas ≥ 10 mm, adenomas with high-grade dysplasia, or adenomas with a villous component of at least 25%. RESULTS: The cumulative participation rate was significantly higher for FIT screening (73%) than for flexible sigmoidoscopy (31%; P < .001) or colonoscopy (24%; P < .001). The percentage of colonoscopies among invitees was higher for colonoscopy (24%) compared to FIT (13%; P < .001) or flexible sigmoidoscopy (3%; P < .001). In the intention to screen analysis, the cumulative diagnostic yield of advanced neoplasia was higher with FIT screening (4.5%; 95% CI 4.2-4.9) than with colonoscopy (2.2%; 95% CI, 1.8-2.6) or flexible sigmoidoscopy (2.3%; 95% CI, 2.0-2.7). In the as-screened analysis, the cumulative yield of advanced neoplasia was higher for endoscopic screening with colonoscopy (9.1%; 95% CI, 7.7-10.7) or flexible sigmoidoscopy (7.4%; 95% CI, 6.5-8.5) than with the FIT (6.1%; 95% CI, 5.7-6.6). All 3 screening strategies detected a similar proportion of patients with CRC. Follow-up times differed for each test (median 8.3 years for FIT and flexible sigmoidoscopy and 5.8 years for colonoscopy). Proportions of patients that developed interval CRC were 0.13% for persons with a negative result from FIT, 0.09% for persons with a negative result from flexible sigmoidoscopy, and 0.01% for persons with a negative result from colonoscopy. CONCLUSIONS: Mailed multiple-round FITs detect significantly more advanced neoplasia, on a population level, compared with once-only flexible sigmoidoscopy or colonoscopy screening. Significantly fewer colonoscopies are required by individuals screened by multiple FITs. Trialregister.nl numbers: first round, NTR1096; second round and additional invitees, NTR1512; fourth round, NTR5874; COCOS trial NTR1829.

Multiple rounds of one sample versus two sample faecal immunochemical test-based colorectal cancer screening: a population-based study.

BACKGROUND: Faecal immunochemical test (FIT)-based colorectal cancer screening requires successive rounds for maximum preventive effect. Advanced neoplasia can bleed intermittently and thus might be missed by single faecal sampling. Few studies have been done on two sample FIT (2-FIT) screening over multiple rounds. Therefore, we compared multiple rounds of one sample FIT (1-FIT) with 2-FIT screening with respect to participation, positive predictive value (PPV), diagnostic yield, and interval colorectal cancer. METHODS: In this population-based study, a random selection of asymptomatic individuals aged 50-74 years in the Rotterdam-Rijnmond region, Netherlands, were invited by post for four rounds (every 2 years) of 1-FIT or 2-FIT screening. Key exclusion criteria were a history or colorectal cancer or inflammatory bowel disease, colon imaging in the previous 2 years, and life expectancy of less than 5 years. Per round, invitees received one or two FITs to sample either one or two consecutive bowel movements. OC-Sensor Micro (Eiken Chemical Co., Ltd, Japan) FITs were used by all participants, except the fourth round of screening for the 1-FIT cohort, for which participants used either an OC-Sensor or a FOB-Gold (Sentinel Diagnostics, Milan, Italy). A faecal haemoglobin cutoff concentration of 10 µg/g of faeces in at least one test was used for referral for colonoscopy. FINDINGS: Between 2006 and 2015, of 10 008 invited individuals for the 1-FIT cohort, 9787 were eligible for inclusion, of whom 7310 participated at least once in four successive rounds. Of 3197 invited individuals for the 2-FIT cohort, 3131 were eligible for inclusion, and 2269 participated at least once in four successive rounds. In the 1-FIT screening cohort, 74·7% (7310 of 9787) of invitees participated at least once versus 72·5% (2269 of 3131) of invitees in the 2-FIT cohort (p=0·013). Among participants who participated at least once, the cumulative positivity rate over four rounds was 19·2% (1407 of 7310) for the 1-FIT cohort versus 28·5% (647 of 2269) for the 2-FIT cohort (p<0·0001). The cumulative PPV for advanced neoplasia was 33·0% (432 of 1308 colonoscopies) for the 1-FIT cohort versus 24·2% (147 of 607 colonoscopies) for the 2-FIT cohort (p<0·0001). The cumulative diagnostic yield of advanced neoplasia among invited individuals was 4·4% (432 of 9787) for 1-FIT versus 4·7% (147 of 3131) for 2-FIT screening (p=0·46)). FIT interval colorectal cancers were detected in eight (0·1%) of 7310 participants in the 1-FIT cohort and two (0·1%) of 2269 with 2-FIT screening (p=1·00). INTERPRETATION: Four rounds of 2-FIT screening with a low faecal haemoglobin cutoff level did not result in a significant increase in diagnostic yield or a decrease in interval colorectal cancers compared with 1-FIT, despite higher colonoscopy demand. Therefore, 1-FIT colorectal cancer screening programmes should be preferred. FUNDING: None.

Incidence of faecal occult blood test interval cancers in population-based colorectal cancer screening: a systematic review and meta-analysis.

OBJECTIVE: Faecal immunochemical tests (FITs) are replacing guaiac faecal occult blood tests (gFOBTs) for colorectal cancer (CRC) screening. Incidence of interval colorectal cancer (iCRC) following a negative stool test result is not yet known. We aimed to compare incidence of iCRC following a negative FIT or gFOBT. DESIGN: We searched Ovid Medline, Embase, Cochrane Library, Science Citation Index, PubMed and Google Scholar from inception to 12 December 2017 for citations related to CRC screening based on stool tests. We included studies on FIT or gFOBT iCRC in average-risk screening populations. Main outcome was pooled incidence rate of iCRCs per 100 000 person-years (p-y). Pooled incidence rates were obtained by fitting random-effect Poisson regression models. RESULTS: We identified 7 426 records and included 29 studies. Meta-analyses comprised data of 6 987 825 subjects with a negative test result, in whom 11 932 screen-detected CRCs and 5 548 gFOBT or FIT iCRCs were documented. Median faecal haemoglobin (Hb) positivity cut-off used was 20 (range 10-200) µg Hb/g faeces in the 17 studies that provided FIT results. Pooled incidence rates of iCRC following FIT and gFOBT were 20 (95% CI 14 to 29; I2=99%) and 34 (95% CI 20 to 57; I2=99%) per 100 000 p-y, respectively. Pooled incidence rate ratio of FIT versus gFOBT iCRC was 0.58 (95% CI 0.32 to 1.07; I2=99%) and 0.36 (95% CI 0.17 to 0.75; I2=10%) in sensitivity analysis. For every FIT iCRC, 2.6 screen-detected CRCs were found (ratio 1:2.6); for gFOBT, the ratio between iCRC and screen-detected CRC was 1:1.2. Age below 60 years and the third screening round were significantly associated with a lower iCRC rate. CONCLUSION: A negative gFOBT result is associated with a higher iCRC incidence than a negative FIT. This supports the use of FIT over gFOBT as CRC screening tool.

Risk of Oral and Upper Gastrointestinal Cancers in Persons With Positive Results From a Fecal Immunochemical Test in a Colorectal Cancer Screening Program.

BACKGROUND & AIMS: European guidelines recommend screening for colorectal cancer (CRC) using the fecal immunochemical test (FIT), with follow-up colonoscopies for individuals with positive test results. However, more than half of participants with positive results from the FIT are not found to have advanced neoplasia in the colonoscopy examination. Fecal occult blood might also come from the upper gastrointestinal (GI) tract, so perhaps we should consider esophagogastroduodenoscopy (EGD), to detect upper GI cancers. We aimed to determine how many individuals are found to have oral or upper GI cancers (oral cavity, throat, esophageal, gastric, or small bowel cancer) within 3 years after a positive or negative result from a FIT in a CRC screening program. METHODS: We performed a retrospective analysis of data from a pilot study of 3 rounds of biennial FIT-based screening for CRC in 2 regions in the west of the Netherlands, from 2006 through October 2012. Participants who developed oral or upper GI cancers were identified through linkage with the National Cancer Registry. We classified these cancers into 3 groups: those that developed in individuals with a positive result from a FIT but negative findings from colonoscopy (no advanced neoplasia), those that developed in individuals with a positive result from a FIT and a positive finding from colonoscopy (advanced neoplasia), and those that developed in individuals with negative results from a FIT. We compared oral and upper GI cancer incidence among groups. RESULTS: Among 16,165 screening participants, linkage identified 52 persons who developed an oral or upper GI cancer within 3 years after a FIT. We found no significant difference in incidence values between individuals with a positive vs a negative FIT result: 8 cancers developed in individuals with a positive result from a FIT (0.37%; 95% CI, 0.19-0.76) and 44 developed in individuals with a negative result from a FIT (0.31%; 95% CI, 0.23-0.42) (P = .65). Of the 8 individuals with a positive result from a FIT and an oral or upper GI cancer, 6 were diagnosed after negative findings from colonoscopy and 2 after positive findings from colonoscopy. We found that only 0.14% of all persons with a positive result from a FIT were diagnosed with a gastric or esophageal cancer within 3 years. CONCLUSION: In a study of individuals in the Netherlands undergoing screening for CRC by FIT, we found fewer than 1% of patients with a positive result from the FIT to receive a diagnosis of upper GI cancers within 3 years. Routine EGD investigation of individuals with positive results from a FIT and negative findings from colonoscopy is therefore not recommended. TrialRegister.nl, Number: NTR5385.

Association Between Concentrations of Hemoglobin Determined by Fecal Immunochemical Tests and Long-term Development of Advanced Colorectal Neoplasia.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening using quantitative fecal immunochemical tests (FITs) is rapidly gaining ground worldwide. FITs are invariably used in a dichotomous manner using pre-specified cut-off values. To optimize FIT-based screening programs, we investigated the association between fecal hemoglobin (fHb) concentrations below the FIT cut-off value and later development of colorectal advanced neoplasia (AN). METHODS: We analyzed data collected from a population-based study of 9561 average-risk subjects (50-74 years old) in the Netherlands who were offered 4 rounds of FIT screening for CRC from November 2006 through December 2014. We analyzed data from 7663 participants screened at least once and found to have a negative FIT result at baseline (below the cut-off value of 10 µg Hb/ g feces). Participants were followed for a median of 4.7 years (interquartile range, 2.0-6.1 years); CRCs diagnosed outside the screening program were identified from the Dutch Comprehensive Cancer Centre database. Hazard ratios for AN were determined using Cox proportional hazard regression analyses. Logistic regression techniques were used to calculate risks of AN after consecutive fHb concentrations below the cut-off value. RESULTS: After 8 years of follow-up, participants with baseline concentrations of 8-10 µg fHb/g had a higher cumulative incidence of AN (33%) than participants with 0 µg fHb/g (5%) (P < .001). Multi-variate hazard ratios increased from 1.2 for subjects with concentrations of 0-2 µg fHb/g to 8.2 for subjects with concentrations of 8-10 µg fHb/g (P < .001). Participants with 2 consecutive fHb concentrations of 8 µg Hb/g had a 14-fold increase in risk of AN compared with participants with 2 consecutive fHb concentrations of 0 µg Hb/g (P < .001). CONCLUSIONS: In a population-based study of average-risk individuals with a FIT result below the cut-off value, we associated baseline concentrations of 8-10 µg fHb/g with an increased risk of AN compared with baseline concentrations of 0 µg fHb/g. Baseline and consecutive fHb concentrations are independent predictors for incident AN. This information might be used in designing personalized strategies for population-based CRC screening and reduce unnecessary repeat tests. Trialregister.nl no: first round, NTR1096; second round and additional invitees, NTR1512.

Fecal immunochemical test-based colorectal cancer screening: The gender dilemma.

BACKGROUND: Despite differences between men and women in incidence of colorectal cancer (CRC) and its precursors, screening programs consistently use the same strategy for both genders. OBJECTIVE: The objective of this article is to illustrate the effects of gender-tailored screening, including the effects on miss rates of advanced neoplasia (AN). METHODS: Participants (age 50-75 years) in a colonoscopy screening program were asked to complete a fecal immunochemical test (FIT) before colonoscopy. Positivity rates, sensitivity and specificity for detection of AN at multiple cut-offs were determined. Absolute numbers of detected and missed AN per 1000 screenees were calculated. RESULTS: In total 1,256 individuals underwent FIT and colonoscopy, 51% male (median age 61 years; IQR 56-66) and 49% female (median age 60 years; IQR 55-65). At all cut-offs men had higher positivity rates than women, ranging from 3.8% to 10.8% versus 3.2% to 4.8%. Sensitivity for AN was higher in men than women; 40%-25% and 35%-22%, respectively. More AN were found and missed in absolute numbers in men at all cut-offs. CONCLUSION: More AN were both detected and missed in men compared to women at all cut-offs. Gender-tailored cut-offs could either level sensitivity in men and women (i.e., lower cut-off in women) or level the amount of missed lesions (i.e., lower cut-off in men).

Interval Colorectal Cancer Incidence Among Subjects Undergoing Multiple Rounds of Fecal Immunochemical Testing.

BACKGROUND & AIMS: Among subjects screened for colorectal cancer (CRC) by the guaiac fecal occult blood test, interval cancers develop in 48% to 55% of the subjects. Data are limited on how many persons screened by fecal immunochemical tests (FIT), over multiple rounds, develop interval cancers. In the Netherlands, a pilot FIT-based biennial CRC screening program was conducted between 2006 and 2014. We collected and analyzed data from the program on CRCs detected during screening (SD-CRC) and CRCs not detected within the screening program (non-SD-CRC; such as FIT interval cancers, colonoscopy interval cancers, and cancer in nonparticipants). METHODS: Screenees with a negative FIT result received a letter explaining that no blood had been detected in the stool sample and were re-invited, if eligible, for screening biennially. Screenees with a positive FIT result (hemoglobin concentration of 10 µg Hb/g feces) were invited for consultation and scheduled for colonoscopy; results were collected. After the fourth round of FIT screening, the cohort was linked to the Netherlands Cancer Registry, through March 31, 2015; participant characteristics, data on tumor stage, location (at time of resection), and survival status were collected for all identified CRC cases. A reference group comprised all persons with CRC diagnosed in the Netherlands general population during the same period, in the same age range (50-76 years), who had not been offered CRC screening. The median time between invitations (2.37 years) was used as a cutoff to categorize participants within the FIT interval cancer category. We compared participant characteristics, tumor characteristics, and mortality among subjects with SD-CRC and with non-SD-CRC. RESULTS: A total of 27,304 eligible individuals were invited for FIT screening, of whom 18,716 (69%) participated at least once. Of these, 3005 (16%) had a positive result from the FIT in 1 of the 4 screening rounds. In total, CRC was detected in 261 participants: 116 SD-CRCs and 145 non-SD-CRCs (27 FIT interval cancers, 9 colonoscopy interval cancers, and 109 CRCs in nonparticipants). The FIT interval cancer proportion after 3 completed screening rounds was 23%. Participants with SD-CRC had more early-stage tumors than participants with non-SD-CRCs (P < .001). Of persons with SD-CRC and FIT interval cancers, significantly higher proportions survived (89% and 81%, respectively) compared with persons with colonoscopy interval cancers (44% survival) and nonparticipants with CRC (60% survival) (P < .001). CONCLUSIONS: In an analysis of data from a pilot FIT-based biennial screening program, we found that among persons screened by FIT, 23% developed FIT interval cancer. FIT therefore detects CRC with 77% sensitivity. The proportion of FIT interval cancers in FIT screening appears to be lower than that with guaiac fecal occult blood testing. Clinical trial registry: yes, www.trialregister.nl, trial number: NTR5385.

Immunochemical faecal occult blood testing to screen for colorectal cancer: can the screening interval be extended?

OBJECTIVE: Colorectal cancer (CRC) screening programmes based on faecal immunochemical testing for haemoglobin (FIT) typically use a screening interval of 2 years. We aimed to estimate how alternative FIT strategies that use a lower than usual positivity threshold followed by a longer screening interval compare with conventional strategies. METHODS: We analysed longitudinal data of 4523 Dutch individuals (50-74 years at baseline) participating in round I of a one-sample FIT screening programme, of which 3427 individuals also participated in round II after 1-3 years. The cohort was followed until 2 years after round II. In both rounds, a cut-off level of ≥50 ng haemoglobin (Hb)/mL buffer (corresponding to 10 µg Hb/g faeces) was used, representing the standard scenario. We determined the cumulative positivity rate (PR) and the numbers of subjects diagnosed with advanced adenomas (N_AdvAd) and early stage CRC (N_earlyCRC) in the cohort over two rounds of screening (standard scenario) and compared it with hypothetical single-round screening with use of a lower cut-off and omission of the second round (alternative scenario). RESULTS: In the standard scenario, the cumulative (ie, round I and II combined) PR, N_AdvAd and N_earlyCRC were 13%, 180% and 26%, respectively. In alternative scenarios using a cut-off level of respectively ≥11 and ≥22 ng/HbmL buffer (corresponding to 2 and 4 µg Hb/g faeces), the PRs were 18% and 13%, the N_AdvAd were 180 and 162 and the N_earlyCRC ranged between 22-27 and 22-26. CONCLUSIONS: The diagnostic yield of FIT screening using a lowered positivity threshold in combination with an extended screening interval (up to 5 years) may be similar to conventional FIT strategies. This justifies and motivates further research steps in this direction.

Variable Quality and Readability of Patient-oriented Websites on Colorectal Cancer Screening.

BACKGROUND & AIMS: The efficacy of colorectal cancer (CRC) screening is dependent on participation and subsequent adherence to surveillance. The internet increasingly is used for health information and is important to support decision making. We evaluated the accuracy, quality, and readability of online information on CRC screening and surveillance. METHODS: A Website Accuracy Score and Polyp Score were developed, which awarded points for various aspects of CRC screening and surveillance. Websites also were evaluated using validated internet quality instruments (Global Quality Score, LIDA, and DISCERN), and reading scores. Two raters independently assessed the top 30 websites appearing on Google.com. Portals, duplicates, and news articles were excluded. RESULTS: Twenty websites were included. The mean website accuracy score was 26 of 44 (range, 9-41). Websites with the highest scores were www.cancer.org, www.bowelcanceraustralia.org, and www.uptodate.com. The median polyp score was 3 of 10. The median global quality score was 3 of 5 (range, 2-5). The median overall LIDA score was 74% and the median DISCERN score was 45, both indicating moderate quality. The mean Flesch-Kincaid grade level was 11th grade, rating the websites as difficult to read, 30% had a reading level acceptable for the general public (Flesch Reading Ease > 60). There was no correlation between the Google rank and the website accuracy score (rs = -0.31; P = .18). CONCLUSIONS: There is marked variation in quality and readability of websites on CRC screening. Most websites do not address polyp surveillance. The poor correlation between quality and Google ranking suggests that screenees will miss out on high-quality websites using standard search strategies.

Adherence to colorectal cancer screening: four rounds of faecal immunochemical test-based screening.

BACKGROUND: The effectiveness of faecal immunochemical test (FIT)-based screening programs is highly dependent on consistent participation over multiple rounds. We evaluated adherence to FIT screening over four rounds and aimed to identify determinants of participation behaviour. METHODS: A total of 23 339 randomly selected asymptomatic persons aged 50-74 years were invited for biennial FIT-based colorectal cancer screening between 2006 and 2014. All were invited for every consecutive round, except for those who had moved out of the area, passed the upper age limit, or had tested positive in a previous screening round. A reminder letter was sent to non-responders. We calculated participation rates per round, response rates to a reminder letter, and differences in participation between subgroups defined by age, sex, and socioeconomic status (SES). RESULTS: Over the four rounds, participation rates increased significantly, from 60% (95% CI 60-61), 60% (95% CI 59-60), 62% (95% CI 61-63) to 63% (95% CI 62-64; P for trend<0.001) with significantly higher participation rates in women in all rounds (P<0.001). Of the 17 312 invitees eligible for at least two rounds of FIT screening, 12 455 (72%) participated at least once, whereas 4857 (28%) never participated; 8271 (48%) attended all rounds when eligible. Consistent participation was associated with older age, female sex, and higher SES. Offering a reminder letter after the initial invite in the first round increased uptake with 12%; in subsequent screening rounds this resulted in an additional uptake of up to 10%. CONCLUSIONS: In four rounds of a pilot biennial FIT-screening program, we observed a consistently high and increasing participation rate, whereas sending reminders remain effective. The substantial proportion of inconsistent participants suggests the existence of incidental barriers to participation, which, if possible, should be identified and removed.

Advances in Fecal Tests for Colorectal Cancer Screening.

OPINION STATEMENT: Colorectal cancer (CRC) forms an important public health problem, especially in developed countries. CRC screening tests can be used to identify asymptomatic individuals with CRC precursors and (early) cancer. Removal of these lesions reduces CRC incidence and prevents CRC-related mortality. There are a range of screening tests available, each with advantages and disadvantages. Stool screening tests can broadly be divided into fecal occult blood tests (FOBTs) and molecular biomarker test, such as DNA/RNA marker tests, protein markers, and fecal microbiome marker tests. Guaiac fecal occult blood tests (gFOBT) have been demonstrated in large randomized screening trials to reduce CRC mortality. Fecal immunochemical tests (FIT) have superior adherence, usability, and accuracy as compared to gFOBT. Advantage of the use of quantitative FITs in CRC screening programs is the cut-off level that can be adjusted. Molecular biomarker DNA tests have shown to detect significantly more cancers than FIT. By combining biomarker DNA tests with FIT, sensitivity for advanced adenomas can be increased significantly. However, it has lower specificity thus demands more colonoscopy resources, is more cumbersome, and costly. The adherence has not been assessed in population screening trials. For these reasons, FIT is therefore at present regarded as the preferred method of non-invasive CRC screening. This chapter will review the current status of fecal test-based CRC screening.

Second-Look Colonoscopies and the Impact on Capacity in FIT-Based Colorectal Cancer Screening.

OBJECTIVES: Fecal immunochemical testing (FIT) and colonoscopy are tandem procedures in colorectal cancer (CRC) screening. A positive FIT predicts advanced neoplasia (AN) that requires endoscopic detection and removal. En bloc or piecemeal resection of AN is associated with a significant rate of residual or recurrent neoplasia. Second-look colonoscopies are indicated to assess completeness of removal of AN. These colonoscopies can make a substantial demand on colonoscopy capacity and health-care system. This study is the first to evaluate the demand and risk factors for second-look colonoscopy in FIT CRC screening. METHODS: All colonoscopies after a positive FIT, in subjects aged 50-74 years approached for 3 rounds of FIT screening, were prospectively registered. Second-look colonoscopies were defined as any colonoscopy within 1 year following a colonoscopy after positive FIT. RESULTS: Out of 1,215 FIT-positive screenees undergoing colonoscopy, 105 (8.6%) patients underwent a second-look colonoscopy, of whom 30 (2.5%) underwent more than one colonoscopy (range 2-9), leading to a total of 149 (12.3%) additional colonoscopies. Main reasons for second-look colonoscopies were assessment of complete AN removal (41.9%) and need for additional polypectomy (34.3%). Risk factors were advanced adenomas and poor bowel preparation (P<0.001). High fecal hemoglobin concentration was the only predictor of a second-look colonoscopy before index colonoscopy (P<0.001). CONCLUSIONS: Second-look colonoscopies have substantial impact on colonoscopy resources, increasing the demand with 12%. The main reasons for these second-look colonoscopies were previous incomplete polypectomy and control of completeness of removal of neoplastic lesions. A high fecal hemoglobin concentration as measured by FIT can help to identify patients at risk of a second-look colonoscopy.