Comparative Performance of Common Fecal Immunochemical Tests : A Cross-Sectional Study.

Quantitation of Hemoglobin Improves Fecal Immunochemical Tests for Noninvasive Screening

Optimizing Colorectal Cancer Screening by Getting FIT Right

COVID-19: An Opportunity to Reimagine Colorectal Cancer Diagnostic Testing—A New Paradigm Shift

<h3>Context:</h3> Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. Fecal immunochemical tests (FITs) are currently the most used strategy for population-based CRC screening in Europe and some Asian countries. Positive FIT results should be followed by colonoscopy. <h3>Objective:</h3> To identify the factors associated with false positive FIT results. <h3>Study Design and Analysis:</h3> Each participant completed five different FITs from a single stool sample prior to their colonoscopy. Colonoscopy and associated pathology reports were reviewed. Based on the pathology results, we dichotomized patients as having advanced colorectal neoplasia (ACN) or not. ACN was defined as adenomatous ≥ 10mm or sessile serrated polyps ≥ 10mm; any polyps with villous or tubulovillous pathology, or traditional serrated adenomas; any lesion with high grade dysplasia, or any stage of adenocarcinoma. FITs were false positive if no ACN was found on pathology reports. We used PROC GLIMMIX models in SAS to assess variables associated with false positive FIT results. <h3>Setting:</h3> Three academic medical centers in Iowa, North Carolina, and Texas. <h3>Population Studied:</h3> Participants ages 50-85 years undergoing a screening or surveillance colonoscopy. Participants who did not meet the definition for ACN were included in the current analysis. <h3>Instruments:</h3> Participant self-reported health questionnaire and colonoscopy/pathology review form. <h3>Results:</h3> Of the 3,759 participants, 3,440 did not have ACN and were included in this analysis. The mean age was 62.1 (±7.8) years; 64% were women, 86% White, and 29% Hispanic. The multivariable model showed the odds ratio of having a false positive FIT result vs. a true negative FIT result was 1.02 (95% CI, 1.01-1.03) for every year increase in age, 1.04 (95% CI, 1.03-1.06) for every one unit increase in BMI, 1.82 (95% CI, 1.29-2.56) for current smoker vs. never smoker, 1.33 (95% CI, 1.10-1.60) for regular aspirin use, and 2.12 (95% CI, 1.45-3.10) for blood thinner use, after controlling for the five FITs and other variables in the model. <h3>Conclusion:</h3> Several risk factors were associated with an increased odds for false positive FIT results. These findings were similar to other studies. Clinicians should be aware of these factors which may lead to false positive FITs in FIT-based colorectal cancer screening programs. <h3>Funding:</h3> NIH Grant R01CA215034

<h3>Context:</h3> Colorectal cancer (CRC) is the second leading cause of cancer death worldwide; it is largely preventable with appropriate screening. Fecal immunochemical tests (FIT) followed by colonoscopy, if positive, is a cost-effective option for CRC screening. There are limited data on the performance of various FITs for detecting advanced colorectal neoplasia (ACN). <h3>Objective:</h3> To compare the performance of five commonly used FITs for detecting ACN, using colonoscopy as the gold standard. <h3>Methods:</h3> Patients aged 50-85 years undergoing screening or surveillance colonoscopy were recruited from three academic medical centers in the United States. Each patient completed five FITs on a single stool sample prior to colonoscopy. FITs were analyzed according to manufacturer instructions and the subsequent colonoscopy and pathology reports were abstracted. ACN was defined as any advanced pre-cancerous lesion (adenomatous or sessile serrated polyps 10 mm or greater); villous, tubulovillous, or traditional serrated adenoma of any size, any lesion with high-grade dysplasia, or any stage adenocarcinoma. Based on histology, we calculated the test characteristics for each FIT for ACN. We used PROC GLIMMIX models in SAS to compare sensitivity and specificity across the different brands, accounting for within-patient correlation. <h3>Results:</h3> For the 3759 participants enrolled, the mean (SD) age was 62 (7.8) years, 63% were women, 86% white, and 29% Hispanic. Based on colonoscopy, 319 patients (8.5%) had ACN, including 9 participants (0.2%) with CRC and 310 (8.2%) with advanced adenomas. The positivity rates for each test were 4%, 13%, 16%, 11%, and 6%. The sensitivity for detecting ACN was 10%, 27%, 37%, 30%, and 19%; and the corresponding specificities were 97%, 89%, 85%, 91%, and 96%. Positive predictive values were 21%, 18%, 20%, 23%, and 29%; and the corresponding negative predictive values were 92%, 93%, 93%, 93%, and 93%. We found statistically significant differences in sensitivity (p&lt;.0001) and specificity (p&lt;.0001) across FITs. <h3>Conclusion:</h3> There were substantial variations in test performance among different FITs when used for single-sample stool testing. The ideal test for population-based screening should have a high sensitivity without a substantial loss of specificity and depends on resources for colonoscopy. These differences could impact regulatory policy and FIT selection by healthcare providers. <h3>Funding:</h3> NIH R01 CA215034

In the UK, patients with one or two adenomas, of which at least one is ≥ 10 mm in size, or three or four small adenomas, are deemed to be at intermediate risk of colorectal cancer (CRC) and referred for surveillance colonoscopy 3 years post polypectomy. However, colonoscopy is costly, can cause discomfort and carries a small risk of complications. To determine whether or not annual faecal immunochemical tests (FITs) are effective, acceptable and cost saving compared with colonoscopy surveillance for detecting CRC and advanced adenomas (AAs). Diagnostic accuracy study with health psychology assessment and economic evaluation. Participants were recruited from 30 January 2012 to 30 December 2013 within the Bowel Cancer Screening Programme in England. Men and women, aged 60-72 years, deemed to be at intermediate risk of CRC following adenoma removal after a positive guaiac faecal occult blood test were invited to participate. Invitees who consented and returned an analysable FIT were included. We offered participants quantitative FITs at 1, 2 and 3 years post polypectomy. Participants testing positive with any FIT were referred for colonoscopy and not offered further FITs. Participants testing negative were offered colonoscopy at 3 years post polypectomy. Acceptibility of FIT was assessed using discussion groups, questionnaires and interviews. The primary outcome was 3-year sensitivity of an annual FIT versus colonoscopy at 3 years for detecting advanced colorectal neoplasia (ACN) (CRC and/or AA). Secondary outcomes included participants' surveillance preferences, and the incremental costs and cost-effectiveness of FIT versus colonoscopy surveillance. Of 8008 invitees, 5946 (74.3%) consented and returned a round 1 FIT. FIT uptake in rounds 2 and 3 was 97.2% and 96.9%, respectively. With a threshold of 40 µg of haemoglobin (Hb)/g faeces (hereafter referred to as µg/g), positivity was 5.8% in round 1, declining to 4.1% in round 3. Over three rounds, 69.2% (18/26) of participants with CRC, 34.3% (152/443) with AAs and 35.6% (165/463) with ACN tested positive at 40 µg/g. Sensitivity for CRC and AAs increased, whereas specificity decreased, with lower thresholds and multiple rounds. At 40 µg/g, sensitivity and specificity of the first FIT for CRC were 30.8% and 93.9%, respectively. The programme sensitivity and specificity of three rounds at 10 µg/g were 84.6% and 70.8%, respectively. Participants' preferred surveillance strategy was 3-yearly colonoscopy plus annual FITs (57.9%), followed by annual FITs with colonoscopy in positive cases (31.5%). FIT with colonoscopy in positive cases was cheaper than 3-yearly colonoscopy (£2,633,382), varying from £485,236 (40 µg/g) to £956,602 (10 µg/g). Over 3 years, FIT surveillance could miss 291 AAs and eight CRCs using a threshold of 40 µg/g, or 189 AAs and four CRCs using a threshold of 10 µg/g. Annual low-threshold FIT with colonoscopy in positive cases achieved high sensitivity for CRC and would be cost saving compared with 3-yearly colonoscopy. However, at higher thresholds, this strategy could miss 15-30% of CRCs and 40-70% of AAs. Most participants preferred annual FITs plus 3-yearly colonoscopy. Further research is needed to define a clear role for FITs in surveillance. Evaluate the impact of ACN missed by FITs on quality-adjusted life-years. Current Controlled Trials ISRCTN18040196. National Institute for Health Research (NIHR) Health Technology Assessment programme, NIHR Imperial Biomedical Research Centre and the Bobby Moore Fund for Cancer Research UK. MAST Group Ltd provided FIT kits.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high‐risk CRC individuals defined as having positive risk‐adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT‐sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT‐sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT‐sDNA test was 91.9% (95% CI, 86.8–95.3), compared with 62.4% (95% CI, 54.9–69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3–68.3) for FIT‐sDNA test, compared with 30.9% (95% CI, 26.3–35.6) for FIT (P < 0.001). Multitarget FIT‐sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT‐sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

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.

ObjectiveTo compare the screening efficacy of colonoscopy and pathologically confirmed single and combined Asia-Pacific colorectal screening (APCS), faecal immunochemical testing (FIT) and stool deoxyribonucleic acid (sDNA) testing protocols.MethodsFrom April 2021 to April 2022, 842 volunteers participated in primary colorectal cancer (CRC) screenings using APCS scoring, FIT and sDNA testing and 115 underwent a colonoscopy. One hundred high-risk participants were then identified from the results of both processes. The differences in the three CRC screening tests in combination with the colonoscopy pathology diagnostics were evaluated using Cochran’s Q test, the Dunn–Bonferroni test and area under the receiver operating characteristic curve (AUC) value analysis.ResultsBoth FIT and sDNA testing demonstrated a 100% performance in detecting CRC. For advanced adenoma, the sensitivity of the FIT + sDNA test scheme (double positive) was 29.2%, and the sensitivities of the combined FIT + sDNA test and APCS scoring + sDNA test schemes were 62.5% and 95.8%, respectively. The FIT + sDNA testing kappa value of advanced colorectal neoplasia was 0.344 (p = 0.011). The sensitivity for nonadvanced adenoma of the APCS score + sDNA test scheme was 91.1%. In terms of positive results, the sensitivity of the APCS score + FIT + sDNA detection protocol was significantly higher than that of the APCS score, FIT, sDNA detection, and FIT + sDNA detection methods (adjusted p < 0.001, respectively). For the FIT + sDNA test, the kappa value was 0.220 (p = 0.015) and the AUC was 0.634 (p = 0.037). The specificity of the FIT + sDNA test scheme was 69.0%.ConclusionThe FIT + sDNA test scheme demonstrated superior diagnostic efficacy, and the combined APCS score + FIT + sDNA test scheme demonstrated remarkable improvements in CRC screening efficiency and sensitivity for detecting positive lesions.

Reduced Incidence of Colorectal Cancers With Repeated Screening With Fecal Immunochemical Tests

ObjectivesQuantitative faecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening in the Western countries, whereas qualitative FITs are preferred in China. The present study aimed to compare...

The objectives of this session are to: 1) review the new guidelines for average-risk colorectal cancer (CRC) screening; 2) review recent selected studies of CRC screening for currently recommended tests, and; 3) review recent decision analyses and a cost-effectiveness analysis on screening. Guidelines: Less than 2 years ago, colorectal cancer (CRC) screening guidelines were highly concordant and flexible. New guidelines issued by the American Cancer Society/American College of Radiology/Multisociety Task Force in March 2008 (1), the U.S. Preventive Services Task Force in November 2008 (2) and the American College of Gastroenterology in March 2009 (3) are now disparate, with two of three organizations implicitly or explicitly preferring colonoscopy despite the absence of published evidence supporting this preference. Two decision analyses, commissioned by the USPSTF, show four screening strategies with equivalence in CRC mortality reduction and life-years gained: colonoscopy every 10 years; a sensitive guaiac-based fecal occult blood test (FOBT) annually; fecal immunochemical testing (FIT) annually, and; the combination of flexible sigmoidoscopy every 5 years with a mid-interval sensitive FOBT or FIT. (4) Screening tests: For fecal DNA, a large screening study comparing a multi-component panel to Hemoccult II with colonoscopy as the reference standard showed that fecal DNA detected 52% of CRCs compared to 13% for Hemoccult II; the two tests had comparable specificity. Recent case-control studies of fecal DNA using somewhat different markers show a single application cancer sensitivity of 83–88% and specificity of 82%.(5) Yet another version of fecal DNA showed cancer sensitivity and specificity of 58% and 84%, respectively; sensitivity for adenomas 1 cm or larger was 46%.(6) The main issues limiting wider use of fecal DNA are its uncertain test interval and greater cost compared to other non-invasive tests. Computer tomographic colonography (CTC or “virtual colonoscopy”) continues to demonstrate good-to-excellent test characteristics for CRC and large (1 cm or larger) adenomas. The ACRIN trial reaffirmed CTC's test characteristics, and may have enhanced prospects for generalizability of test performance. (7) Ongoing issues for CTC include deciding on which CTC colonic findings should be reported and which should lead to colonoscopy (polyp size, number); radiation dose; the clinical and economic impact of extracolonic findings; cost-effectiveness of CTC; and whether it would increase population adherence to CRC screening. Immunochemical FOBTs (or FITs) were developed to enhance the test characteristics of guaiac-based tests. FITs use monoclonal or polyclonal antibodies to detect the intact portion of human hemoglobin and are specific for occult bleeding from a lower GI source. Several FITs are currently available for CRC screening as qualitative tests. Few studies of FITs use colonoscopy as a reference standard; the few that do show widely varying test characteristics for cancer and advanced adenomas, although these are generally better than those of guaiac-based FOBTs. (8) Studies comparing guaiac-based FOBTs with FITs show higher acceptance rates as well as higher detection rates for cancer and advanced adenomas. (9) The real potential of FITs may be in their use as quantitative tests, as data from Levi and colleagues (10) suggest, although more investigation is required to determine the optimal number of single-application tests and the threshold for a positive test. A recent cost-effectiveness analysis by Parekh and colleagues (11) suggests that, as CRC treatment costs increase, screening with FIT may be cost-saving. This analysis also showed that annually FIT screening dominated colonoscopy screening every ten years, meaning that it was both less costly and more effective, suggesting that annual FIT may be “better than” colonoscopy when FIT adherence is high. Until just a few months ago, the effectiveness of sigmoidoscopy was supported only by high-quality case-control studies. Seven-year interim findings from NORCCAP, one of 4 ongoing trials of sigmoidoscopy, were published earlier this year. (12) Study findings included no difference in cancer incidence (not unexpected given the relatively short follow-up); no difference in CRC mortality by intention-to-treat; and a 60% per protocol reduction in overall CRC mortality, including a 75% mortality reduction from recto-sigmoid cancer. Colonoscopy is currently the most “popular” CRC screening test, despite an absence of data demonstrating its superiority over other tests. Within gastroenterology, much attention is focused on monitoring the performance of colonoscopy through parameters such as the extent of examination (to the cecum and by which landmarks?); withdrawal time spent examining the mucosa; and adenoma detection rate. Evidence for the effectiveness of colonoscopy in reducing CRC incidence and mortality is indirect. Follow-up of the National Polyp Study cohort suggests a 76–90% reduction in CRC incidence when compared to 3 reference populations. (13) Kahi and colleagues compared the observed CRC rate in a cohort of screened persons with a median of 7 years follow-up and found a significant reduction in CRC incidence of 67% (95% CI, 38–90%) when compared with SEER data; CRC mortality was reduced by 65%, though this finding was not statistically significant. (14) The degree and duration of protection of colonoscopy from CRC has been questioned in two recent studies. In a population-based case-control study, Baxter and colleagues found that colonoscopy reduced CRC mortality by 37% overall. Colonoscopy reduced left-sided CRC mortality by 67%, but reduced right-sided mortality by just 1%, a non-significant result. (15) In a population-based retrospective cohort study, Lakoff and colleagues looked at risk of CRC after a “negative” colonoscopy, finding that colonoscopy was protective later and less consistently for the proximal colon than for the distal colon. (16) Both technical and biological factors may explain the apparent and relative ineffectiveness of colonoscopy in the right colon in the Baxter and Lakoff studies, respectively. What's coming? Future studies are expected on how colonoscopy can improve detection of adenomas; on FIT test performance, both qualitative and quantitative; on CT colonography performance and acceptance, the latter of which would be enhanced by use of a “virtual prep”; on test performance and logistics of fecal DNA; and on blood-based biomarkers for CRC/advanced adenomas. Finally, we might also expect tailoring of both screening and surveillance based on improved risk stratification. Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN14-06.

1University of Dundee, Nethergate, Dundee, DD1 4HN, Scotland, UK *Author for correspondence: r.j.c.steele@dundee.ac.uk The most commonly used strategy in colo­ rectal cancer (CRC) screening pro grams involves the use of stool tests to detect occult blood, and guaiac fecal occult blood tests (gFOBTs) are, to date, the only fecal tests shown to reduce CRC mortality in population­based randomized trials [1]. However, gFOBTs also carry disadvantages. A major concern is that interval cancers account for around 50% of cancers detected in gFOBT screened populations [2] and recent data show that gFOBTs are less sensitive in women than in men, and in both rectal and right­sided cancers when compared with left­sided disease [2,3]. In addition, the test is associated with a high false­positive rate with no neoplasia detected in around half of colonoscopies performed following a positive gFOBT [2,3]. This may be, in part, explained by the fact that gFOBTs are not specific for human hemoglobin (Hb) and are subject to possible dietary interference from, for example, red meat and high­peroxidase fruits and vegetables. As a result, it has been common practice to instruct participants to adhere to dietary restrictions ahead of sample collection, although this may act as a barrier to screening and affect participation rates [4]. However, data from a meta­analysis did not support dietary restrictions with gFOBTs, leading to recommendations that restrictions are abandoned to improve adherence rates [5]. Fecal immunochemical tests (FITs) are now available and are increasingly being used in screening programs. Unlike gFOBTs, FITs are specific for the detection of human Hb, eliminating any potential for dietary interference, and are also more specific than gFOBT for lower gastrointestinal bleeding. In addition, modern FITs generally allow a more convenient method of sample collection, and are associated with better participation rates [6]. Another major advantage of FIT is that automated versions not only eliminate interobserver variability, but also the quantitative nature of these tests allow provision of a measured fecal Hb concentration. Screening program “...the adoption of fecal immunochemical tests in colorectal cancer screening programs has potential to address participation, appropriate positivity rates and the problem of false‐negative results.” EDITORIAL

Introduction: Colonoscopy is the preferred test for colorectal cancer (CRC) screening and prevention, but it is resource intensive. Fecal immunochemical testing (FIT) is an alternative strategy for average risk screening, but it has less impact on cancer prevention, primarily identifying individuals with prevalent cancer. The aim of our study was to test the hypothesis that one time qualitative FIT reliably identifies patients with advanced colorectal neoplasia and those at highest risk for CRC in a VA screening population. Methods: FIT and colonoscopy are often ordered simultaneously by referring providers for screening purposes at our institution. We retrospectively analyzed data from the year 2014 of 48 consecutive patients with a (+)FIT who underwent diagnostic colonoscopy by two experienced endoscopists and compared findings to 100 consecutive age and endoscopist matched controls who underwent screening colonoscopy during the same time period with a (-)FIT obtained within a year of their examination. Findings were recorded for FIT (+) and (-) groups, including adenoma detection rates (ADR), proximal colon adenoma detection rates (pADR), mean adenomas per colonoscopy (APC), adenoma multiplicity, presence of advanced adenomas (≥1cm, villous histology or high grade dysplasia), cancer and detection of clinically significant serrated lesions (sessile serrated polyps, proximal colon serrated lesions, serrated lesions in any location ≥1cm). Results:Table 1 compares results. Patient age, ADR, pADR, adenoma multiplicity (≥3 adenomas) and clinically significant serrated lesion detection rates were similar in both groups. No invasive cancer was diagnosed in either group. Advanced adenomas (33% v. 9%, p=0.0007) and high-risk adenoma multiplicity (≥3 adenomas with at least one ≥1cm or ≥5 adenomas) (39.6% v. 16%, p=0.003) were significantly more common in the FIT(+) group. FIT failed to detect 35% of individuals with advanced lesions (advanced adenoma or ≥3 adenomas), including 16% with high-risk adenoma multiplicity.Table 1Conclusion: Patients with a (+)FIT have a significantly higher likelihood of advanced colorectal neoplasia, but a (-)FIT does not reliably exclude patients with clinically significant colorectal neoplasia and those at increased risk for advanced lesions. FIT(+) patients should be prioritized for access to colonoscopy, but colonoscopy should be advocated as the test of choice for CRC screening and prevention, even after (-)FIT, in a VA population.

Screening and Surveillance Colonoscopy and COVID-19: Avoiding More Casualties