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.

Population-Based Prevalence of Gastrointestinal Abnormalities at Colon Capsule Endoscopy.

BACKGROUND & AIMS: The population prevalence of gastrointestinal (GI) disease is unclear and difficult to assess in an asymptomatic population. The aim of this study was to determine prevalence of GI lesions in a largely asymptomatic population undergoing colon capsule endoscopy (CCE). METHODS: Participants aged between 50-75 years were retrieved from the Rotterdam Study, a longitudinal epidemiological study, between 2017-2019. Participants received CCE with bowel preparation. Abnormalities defined as clinically relevant were Barrett segment >3cm, severe ulceration, polyp >10 mm or ≥3 polyps in small bowel (SB) or colon, and cancer. RESULTS: Of 2800 invited subjects, 462 (16.5%) participants (mean age 66.8 years, female 53.5%) ingested the colon capsule. A total of 451 videos were analyzed, and in 94.7% the capsule reached the descending colon. At least 1 abnormal finding was seen in 448 (99.3%) participants. The prevalence of abnormalities per GI segment, and the most common type of abnormality, were as follows: Esophageal 14.8% (Barrett's esophagus <3 cm in 8.3%), gastric 27.9% (fundic gland polyps in 18.1%), SB abnormalities 33.9% (erosions in 23.8%), colon 93.3% (diverticula in 81.2%). A total of 54 participants (12%) had clinically relevant abnormalities, 3 (0.7%) in esophagus/stomach (reflux esophagitis grade D, Mallory Weiss lesion and severe gastritis), 5 (1.1%) in SB (polyps > 10 mm; n = 4, severe ulcer n = 1,) and 46 (10.2%) in colon (polyp > 10 mm or ≥3 polyps n = 46, colorectal cancer n = 1). CONCLUSIONS: GI lesions are very common in a mostly asymptomatic Western population, and clinically relevant lesions were found in 12% at CCE. These findings provide a frame of reference for the prevalence rates of GI lesions in the general population.

Applicability of colon capsule endoscopy as pan-endoscopy: From bowel preparation, transit, and rating times to completion rate and patient acceptance.

Background and study aims Colon capsule endoscopy (CCE) has the potential to explore the entire gastrointestinal tract. The aim of this study was to assess the applicability of CCE as pan-endoscopy. Patients and methods Healthy participants received CCE with bowel preparation (bisacodyl, polyethylene electrolyte glycol (PEG) + ascorbic acid) and booster regimen (metoclopramide, oral sulfate solution (OSS)). For each segment of the gastrointestinal tract, the following quality parameters were assessed: cleanliness, transit times, reading times, patient acceptance and safety of the procedure. When all gastrointestinal segments had cleansing score good or excellent, cleanliness of the whole gastrointestinal tract was assessed as good. Participants' expected and perceived burden was assessed by questionnaires and participants were asked to grade the procedure (scale 0-10). All serious adverse events (SAEs) were documented. Results A total of 451 CCE procedures were analyzed. A good cleansing score was achieved in the stomach in 69.6%, in the SB in 99.1 % and in the colon in 76.6 %. Cleanliness of the whole gastrointestinal tract was good in 52.8 % of the participants. CCE median transit time of the whole gastrointestinal tract was 583 minutes IQR 303-659). The capsule reached the descending colon in 94.7 %. Median reading time per procedure was 70 minutes (IQR 57-83). Participants graded the procedure with a 7.8. There were no procedure-related SAEs. Conclusions CCE as pan-endoscopy has shown to be a safe procedure with good patient acceptance. When cleanliness of all gastrointestinal segments per patient, completion rate and reading time will be improved, CCE can be applied as a good non-invasive alternative to evaluate the gastrointestinal tract.

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.

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.

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.

Effects of Increasing Screening Age and Fecal Hemoglobin Cutoff Concentrations in a Colorectal Cancer Screening Program.

BACKGROUND & AIMS: Several countries have implemented programs to screen for colorectal cancer (CRC) by using the fecal immunochemical test (FIT). These programs vary considerably in age of the population screened and the cutoff concentration of fecal hemoglobin (Hb) used to identify candidates for further evaluation; these variations are usually based on a country's colonoscopy resources. We calculated how increasing the Hb cutoff concentration and screening age affects colonoscopy yield, missed lesions, and demand. METHODS: We collected data from 10,008 average-risk individuals in The Netherlands, 50-74 years old, who were invited for an FIT in the first round of a population-based CRC screening program from November 2006 through December 2008. Fecal samples were collected, and levels of Hb were measured by using the OC-sensor Micro analyzer; concentrations ≥10 µg Hb/g feces were considered positive. Subjects with a positive FIT were scheduled for colonoscopy within 4 weeks. Logistic regression analysis was performed to evaluate the association between age and detection of advanced neoplasia. RESULTS: In total, 5986 individuals (62%) participated in the study; 503 (8.4%) had a positive test result. Attendance, positive test results, detection of advanced neoplasia, and the FIT's positive predictive value all increased significantly with age (P < .001). Detection of advanced neoplasia ranged from 1.3% in the youngest age group to 6.2% in the oldest group; the positive predictive value of the FIT was 26% in the youngest group and 47% in the oldest group. Increasing the starting age of invitees from 50-74 years to 55-74 years reduced the proportion of subjects who underwent colonoscopy evaluation by 14% and resulted in 9% more subjects with advanced neoplasia being missed. Increasing the cutoff concentration from 10 to 15 µg Hb/g feces reduced the proportion of subjects who underwent colonoscopy evaluation by 11% and resulted in 6% of advanced neoplasia being missed. CONCLUSIONS: In an analysis of an average-risk screening population in The Netherlands, we found that detection of advanced neoplasia by FIT increases significantly with age and fecal Hb cutoff concentration. Increasing the cutoff concentration or screening age reduces the numbers of patients who undergo colonoscopy evaluation in FIT-based CRC screening programs. Our findings provide insight in these effects per age category and cutoff concentration and the consequences in terms of missed lesions.

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.

Colorectal cancer screening: a global overview of existing programmes.

Colorectal cancer (CRC) ranks third among the most commonly diagnosed cancers worldwide, with wide geographical variation in incidence and mortality across the world. Despite proof that screening can decrease CRC incidence and mortality, CRC screening is only offered to a small proportion of the target population worldwide. Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. This review highlights issues to consider when implementing a CRC screening programme and gives a worldwide overview of CRC burden and the current status of screening programmes, with focus on international differences.