One-sample quantitative and two-sample qualitative faecal immunochemical tests for colorectal cancer screening: a cross-sectional study in China

Quantitation of Hemoglobin Improves Fecal Immunochemical Tests for Noninvasive Screening

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

To the Editor: Fecal immunochemical tests (FITs) are immunoassays that are designed to detect human hemoglobin to indicate the occurrence of colonic neoplasia, which have been widely used in global colorectal cancer (CRC) screening programs. Previous diagnostic studies demonstrated that strong gradient in site-specific sensitivity existed with typically higher rate for advanced adenoma located in distal colon/rectum than that in the proximal parts, which may be explained by the colonic transition time affecting the degradation of hemoglobin, and the shape of adenoma (pedunculated, flat, and sessile) in different anatomic regions.[1] In addition, questionnaire-based risk assessment (QRA) using the established CRC-related risk factors has been proposed to identify high-risk populations for CRC screening.[2] However, previous studies demonstrated that site-specific differences existed for several risk factors.[3,4] In a CRC screening setting, whether and to what extent the FIT and QRA would affect the site-specific detection rate of colorectal neoplasia have not been evaluated. Therefore, we aimed to empirically evaluate the site-specific variations of the detection rates of adenomas for the FIT- and QRA-based screening based on a population-based CRC screening trial (TARGET-C). The study was conducted in the context of an ongoing TARGET-C trial consisted of 19,546 participants, aiming to evaluate the effectiveness of colonoscopy, FIT, and risk-adapted screening approaches in CRC screening in China, and the detailed study protocol has been previously published.[5,6] For the present study, we included 3825 subjects aged 40 to 74 years undertaking colonoscopy in the baseline screening in 2018–2019, of which 1665 were for screening purpose (colonoscopy arm), 1436 were for diagnostic purpose following positive-FIT (FIT arm or risk-adapted screening arm), and 724 were for diagnostic purpose following positive-QRA (risk-adapted screening arm). This study was approved by the Ethics Committee of the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences and Peking Union Medical College (No. 18-013/1615). All participants provided written informed consent. For the QRA use in the present study, the modified Asian-Pacific colorectal screening (APCS) score was used for risk stratification, including five risk factors of CRC (age, sex, family history of CRC among first-degree relatives, smoking, and body mass index [BMI]). Each factor is allocated a score, as followed described: age (0 point: 50–54 years; 1 point: 55–65 years; 2 points: 65–74 years); sex (0 point: female; 1 point: male); family history of CRC among first-degree relatives (0 point: absent; 1 point: present); smoking (0 point: non-smoker; 1 point: current or past smoker); and BMI (0 point: <23; 1 point: ≥23). The cumulative score was calculated. Subjects with scores ≥4 were defined as high-risk and were referred for colonoscopy; those with scores <4 were defined as low-risk and were referred for FIT screening. A self-administered qualitative FIT for hemoglobin (Pupu Tube, New Horizon Health Technology, Hangzhou, China) was used in this trial. The FIT enabled visual interpretation of the test results as positive or negative by eye if the fecal hemoglobin concentration exceeded the threshold specified by the manufacturer (100 ng Hb/mL, equivalent to 4 μg Hb/g feces). Participants with confirmed positive-FIT results were scheduled for subsequent diagnostic colonoscopy. Additional information regarding the study design is provided in the Supplementary File, https://links.lww.com/CM9/A447. The primary outcome of interest was the detection rate for advanced adenoma or non-advanced adenoma, which was calculated by numbers of the carriers with disease divided by the total number included participants. Advanced adenoma was defined as high-grade dysplasia, villous or tubular-villous histologic features, measuring 1 cm or more in diameter. Regarding the location of the neoplasm, the proximal colon was considered to include the splenic flexure and all segments proximal to it, and the rest was considered distal colon/rectum. For subjects having multiple adenomas, the outcome and anatomic location were defined according to the most advanced one. Site-specific detection rate was therefore calculated and compared between the three groups of subjects undertaking colonoscopy, that is, screening purpose, diagnostic purpose either of positive-FIT or positive-QRA. For the 3825 included subjects, the mean (standard deviation) age was 60.5 (6.3) years and slightly more men (n = 1977, 51.7%) were included. Overall, among the subjects undertaking screening colonoscopy and diagnostic colonoscopy after positive-FIT, no significant differences regarding the distribution of sociodemographic factors were observed. For subjects undertaking diagnostic colonoscopy after positive-QRA, the distribution of these factors was significantly different than the other two groups, because factors of age, sex, BMI, cigarette smoking, and history of CRC among the first-degree relatives were included in the risk assessment [Supplementary Table 1, https://links.lww.com/CM9/A447]. For subjects undertaking screening colonoscopy, the detection rates of advanced adenoma located in the distal colon/rectum and proximal colon were 3.12% (95% CI: 2.39–4.07%) and 2.52% (95% CI: 1.87–3.39%), the rate ratio distal vs. proximal was 1.24 (95% CI: 0.83–1.85), and the rate difference distal vs. proximal was 0.60% (95% CI: −0.52 to 1.73%). As expected, the detection rates of advanced adenoma increased for subjects with either positive-FIT (proximal vs. distal: 8.64% [95% CI: 7.29–10.20%] vs. 3.90% [95% CI: 3.01–5.03%]) or positive-QRA (proximal vs. distal: 6.91% [95% CI: 5.28–8.99%] vs. 4.70% [95% CI: 3.38–6.49%]), however, the rate ratiodistal vs. proximal increased to 2.21 (95% CI: 1.63–3.00; PFIT vs. colonoscopy = 0.025) and 1.47 (0.96–2.24; PQRA vs. colonoscopy = 0.567), respectively; and the rate differencedistal vs. proximal increased to 4.74% and 2.21%, respectively. Regarding detection for non-advanced adenoma and any adenoma, there were no significant differences in detection rates among the subjects of either positive-FIT or positive-QRA compared with the subjects undertaking screening colonoscopy. Detailed results are shown in Table 1. Table 1 - Differences in detection rate of colorectal adenoma among subjects performing colonoscopy with different indications (n=3825) Outcome Site Detected cases (n) Detection rate (%, 95%CI) Rate ratio P value ∗ Rate difference (%, 95% CI) Advanced adenoma Colonoscopy (n = 1665) Distal 52 3.12 (2.39–4.07) 1.24 (0.83–1.85) Reference 0.60 (–0.52–1.73) Proximal 42 2.52 (1.87–3.39) Reference Reference FIT (n = 1436) Distal 124 8.64 (7.29–10.20) 2.21 (1.63–3.00) 0.025 4.74 (2.97–6.50) Proximal 56 3.90 (3.01–5.03) Reference Reference QRA (n = 724) Distal 50 6.91 (5.28–8.99) 1.47 (0.96–2.24) 0.567 2.21 (–0.20–4.62) Proximal 34 4.70 (3.38-6.49) Reference Reference Non-advanced adenoma Colonoscopy (n = 1665) Distal 207 12.43 (10.93–14.10) 1.35 (1.11–1.64) Reference 3.24 (1.14–5.35) Proximal 153 9.19 (7.89–10.67) Reference Reference FIT (n = 1436) Distal 228 15.88 (14.08–17.86) 1.37 (1.14–1.65) 0.915 4.32 (1.81–6.83) Proximal 166 11.56 (10.00–13.32) Reference Reference QRA (n = 724) Distal 105 14.50 (12.13–17.26) 1.21 (0.93–1.58) 0.514 2.49 (–1.01–5.98) Proximal 87 12.02 (9.85–14.59) Reference Reference Any adenoma Colonoscopy (n = 1665) Distal 259 15.56 (13.89–17.38) 1.33 (1.12–1.58) Reference 3.84 (1.52–6.17) Proximal 195 11.71 (10.25–13.35) Reference Reference FIT (n = 1436) Distal 352 24.51 (22.36–26.80) 1.59 (1.37–1.85) 0.125 9.05 (6.15–11.96) Proximal 222 15.46 (13.68–17.42) Reference Reference QRA (n = 724) Distal 155 21.41 (18.58–24.54) 1.28 (1.03–1.59) 0.786 4.70 (0.66–8.74) Proximal 121 16.71 (14.17–19.60) Reference Reference FIT: Fecal immunochemical test; QRA: Questionnaire-based risk assessment. ∗P values were calculated comparing the differences of rate ratios between the examined group and the colonoscopy group using the Z-test proposed by Douglas G Altman and J Matrtin Bland (BMJ 2003;326: 219). In this retrospective analysis based on a population-based CRC screening trial, by setting the yield of screening colonoscopy as a reference reflecting the real-world prevalence of adenoma in different anatomic locations, we found that FIT- and QRA-based screening had large variations in terms of detection rates for proximal and distal located advanced adenoma, although the difference was only statistically significant for the FIT-based approach. There were several reasons that might explain the variations of the detection rates for advanced neoplasia located in the proximal and distal colon/rectum. First, most of the distal adenomas are pedunculated, which may therefore be more prone to be bleeding than the flat and sessile adenomas that are more likely to be detected in the proximal colon. Second, the degradation time for fecal hemoglobin is longer for proximal lesions than distal ones, which may therefore lead to the variation of the detection rate, although data to support this are sparse. Previous studies have suggested that lowering the positivity threshold of FIT may help to increase the sensitivity for detecting proximal neoplasm. The positivity threshold of FIT used in the present study was 4 μg Hb/g feces, which was lower than other FIT-based CRC screening programs.[8] Based on our results, such a strategy of lowering the positivity threshold of FIT may not aid such an issue. Another important finding of our study was that QRA also lead to divergent detection rates for proximal and distal neoplasms, although the differences were not statistically significant. Although the reasons behind this cannot be fully understood, we inferred that a series of factors such as smoking and BMI had different magnitudes of attributable risk in proximal and distal CRC, as demonstrated in a recently published study.[3,4] Further attention should be paid to this issue, since combining environmental and polygenic factors has been suggested in tailored risk-adapted CRC screening. Our study has limitations. First, the analysis was derived from a single round of screening, however, the current finding indicated that the differences between the detection rate for proximal and distal advanced adenoma may be even larger over multiple rounds of screening. Second, despite the overall large sample size of the trial, numbers of the advanced adenomas were still rather limited leading to rather wide confidence intervals, which should be addressed in further larger studies.[7] To sum up, we empirically demonstrated the divergent detection rates of proximal and distal advanced adenomas existed in FIT-based but not in the QRA-based CRC screening. Further efforts should be made to optimize the effectiveness of CRC screening by improving the lower detection rate of proximal advanced adenomas. Funding This work was supported by grants from the CAMS Innovation Fund for Medical Sciences (No. 2017-I2M-1-006), the National Natural Science Foundation of China (No. 81703309), Beijing Nova Program of Science and Technology (No. Z191100001119065), and the Natural Science Foundation of Beijing Municipality (No. 7202169). Conflicts of interest None.

Comparing Fecal Immunochemical Tests: Improved Standardization Is Needed

Is this the end of colonoscopy screening for colorectal cancer? An Asia-Pacific perspective.

Background:Fecal immunochemical tests (FITs) are the most widely used non-invasive tests in colorectal cancer (CRC) screening. However, evidence about the direct comparison of the test performance of the self-administered qualitative a laboratory-based quantitative FITs in a CRC screening setting is sparse.Methods:Based on a CRC screening trial (TARGET-C), we included 3144 pre-colonoscopy fecal samples, including 24 CRCs, 230 advanced adenomas, 622 non-advanced adenomas, and 2268 participants without significant findings at colonoscopy. Three self-administered qualitative FITs (Pupu tube) with positivity thresholds of 8.0, 14.4, or 20.8 μg hemoglobin (Hb)/g preset by the manufacturer and one laboratory-based quantitative FIT (OC-Sensor) with a positivity threshold of 20 μg Hb/g recommended by the manufacturer were tested by trained staff in the central laboratory. The diagnostic performance of the FITs for detecting colorectal neoplasms was compared in the different scenarios using the preset and adjusted thresholds (for the quantitative FIT).Results:At the thresholds preset by the manufacturers, apart from the qualitative FIT-3, significantly higher sensitivities for detecting advanced adenoma were observed for the qualitative FIT-1 (33.9% [95% CI: 28.7–39.4%]) and qualitative FIT-2 (22.2% [95% CI: 17.7–27.2%]) compared to the quantitative FIT (11.7% [95% CI: 8.4–15.8%]), while at a cost of significantly lower specificities. However, such difference was not observed for detecting CRC. For scenarios of adjusting the positivity thresholds of the quantitative FIT to yield comparable specificity or comparable positivity rate to the three qualitative FITs accordingly, there were no significant differences in terms of sensitivity, specificity, positive/negative predictive values and positive/negative likelihood ratios for detecting CRC or advanced adenoma between the two types of FITs, which was further evidenced in ROC analysis.Conclusions:Although the self-administered qualitative and the laboratory-based quantitative FITs had varied test performance at the positivity thresholds preset by the manufacturer, such heterogeneity could be overcome by adjusting thresholds to yield comparable specificities or positivity rates. Future CRC screening programs should select appropriate types of FITs and define the thresholds based on the targeted specificities and manageable positivity rates.

The aim of this study was to evaluate the performance of qualitative and quantitative fecal immunochemical tests (FITs) in population screening for colorectal neoplasm. A total of 9000 participants aged between 40 and 74 years were enrolled in this study. Each participant received two stool sampling tubes and was asked to simultaneously submit two stool samples from the same bowel movement. The stool samples of each participant were tested using an immunogold labeling FIT dipstick (qualitative FIT) and an automated fecal blood analyzer (quantitative FIT). Colonoscopy was performed for those who test positive in either FIT. The positive predictive values and population detection rates of the FITs for predicting colorectal neoplasm were compared. A total of 6494 (72.16%) participants simultaneously submitted two stool samples. The diagnostic consistency for a positive result between quantitative and qualitative FITs was poor (κ=0.278, 95% confidence interval=0.223-0.333). The positive predictive values of the quantitative FIT were significantly higher than those of the qualitative FIT for predicting large (≥1 cm) adenomas (23 cases, 14.29% and 16 cases, 6.72%, P=0.013) and colorectal cancer (10 cases, 6.21% and 5 cases, 2.10%, P=0.034); however, the population detection rate for advanced neoplasm of the quantitative FIT was not significantly different from that of the qualitative FIT. Quantitative FIT is superior to qualitative FIT in predicting advanced colorectal neoplasm during colorectal cancer screening. Further studies are needed to elucidate the causes of the predictive superiority.

Optimizing Colorectal Cancer Screening by Getting FIT Right

Objective. The National Cancer Screening Program (NCSP) has since 2004 provided annual colorectal cancer screening using the fecal immunochemical test (FIT) for individuals aged 50 years or older. The aim of this study was to examine the positivity and detection rates of the FIT and to compare the detection rates of the qualitative and quantitative FITs in participants in the 2009 NCSP. Methods. We analyzed positivity and detection rates according to FIT type (qualitative and quantitative). We used a multinomial logistic regression to analyze the odds ratio of “benign” or “suspicious cancer and cancer” compared to “normal,” adjusted for gender, age, health insurance type, region of residence, hospital type, and FIT type. Results. Of the 1,181,904 participants, 72.8% received a qualitative and 27.2% a quantitative FIT. The positivity rates were 8.1% for the qualitative and 2.5% for the quantitative FIT. The detection rate was 5.2% for the qualitative and 14.4% for the quantitative FIT. The odds ratio of a “suspicious cancer and cancer” versus a “normal” result was 2.73 (95% CI = 2.22–3.35) for the quantitative compared to qualitative FIT, after adjustment. Conclusions. The positivity rate of the qualitative FIT was around three times higher than that of the quantitative FIT. However, the odds ratio for detection of “suspicious cancer and cancer” versus “normal” of the quantitative FIT was about three times higher than that of the qualitative FIT. These findings suggest that quality control may be important, particularly for the qualitative FIT.

The optimal fecal occult blood test (FOBT) and hemoglobin (Hb) threshold for balancing diagnostic accuracy and endoscopic demand in colorectal cancer (CRC) screening among Chinese outpatients remained unclear. A prospective multicenter trial was conducted from January 2017 to April 2021 across eight tertiary hospitals. Eligible outpatients were enrolled, whose stool samples were analyzed using quantitative fecal immunochemical test (FIT), self-administered qualitative FIT, general qualitative FIT, and gFOBT. All participants underwent colonoscopy. The primary outcome was the sensitivity of FOBTs for CRC detection. A total of 2,930 participants were enrolled, with 2,618 participants meeting inclusion criteria and completing FOBTs and colonoscopies. At the threshold of 5.2µg/g, quantitative FIT demonstrated comparable sensitivity for CRC detection (90.1%) to self-administered qualitative FIT (87.1%), general qualitative FIT (91.1%), and gFOBT (82.2%) (all P > 0.05). The positive rate of quantitative FIT (12.4%) was significantly lower than that of self-administered qualitative FIT (27.5%), general qualitative FIT (24.2%), and gFOBT (23.0%) (all P < 0.05). Quantitative FIT showed superior specificity (93.9%) compared to self-administered qualitative FIT (79.5%), general qualitative FIT (83.6%), and gFOBT (80.7%) (all P < 0.05). Furthermore, quantitative FIT at 5.2µg/g exhibited higher PPV and LR + for CRC, advanced adenoma (AA) and advanced neoplasia (AN) than other FOBTs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) revealed excellent accuracy for CRC detection (AUC: 0.951, 95% CI: 0.920-0.981). The quantitative FIT with a threshold of 5.2µg/g demonstrated superior performance for early CRC screening in Chinese outpatients.

Screening for colorectal cancer (CRC) and its precursors by fecal occult blood test (FOBT) is widely recommended and is being applied more than ever [1–3]. Although annual or biennial guaiac fecal occult blood test (gFOBT) screening has been proved to reduce the mortality of CRC [4], the gFOBT has been faulted for its low sensitivity [5, 6]. More recently, the fecal immunochemical test (FIT) has been introduced as an alternative to the gFOBT. The FIT is currently preferred over the gFOBT due to its higher sensitivity and improved detection rate for advanced neoplasia [5, 7–10]. Besides its diagnostic performance, the FIT has several advantages over the gFOBT including no need for dietary restriction, easier stool collection method, and automated analysis [11]. Furthermore, quantitative FIT allows for the adjustment of the cutoff value for an abnormal result based on population characteristics and available colonoscopy resources. Due to these characteristics, quantitative FIT is more favored as a screening tool than qualitative FIT [11]. The FIT selectively reacts with the globin moiety of human hemoglobin [12]. Because globin is rapidly degraded by proteases in the upper gastrointestinal (GI) tract, the FIT dose not detect small amounts of blood in the upper GI tract and selectively recognizes occult bleeding of colorectal origin [12]. With regard to small bowel lesions, although there is a possibility that some small bowel occult bleeding could be identified by FIT, no data are currently available regarding this issue. In the current issue of Digestive Diseases and Sciences, Chiba et al. [13] present the results of their prospective study on small bowel evaluation in asymptomatic FIT-positive subjects with a negative colonoscopy. In this, the first study to evaluate the small bowel with capsule endoscopy (CE) in asymptomatic FIT-positive patients with a negative colonoscopy, 53 asymptomatic patients with FIT-positivity and a negative total colonoscopy and esophagogastroduodenoscopy underwent CE. The CE findings were classified into three categories: P0, no abnormalities or findings without potential for bleeding; P1, findings with uncertain potential for bleeding; and P2, findings with high potential for bleeding. The cecal completion rate was 92.5%. There were no cases of P2, 19 cases of P1, and 34 cases of P0. Moreover, no abnormalities were identified in five patients who underwent additional diagnostic evaluations that were considered necessary based on the individual clinical results. No clinically significant small bowel lesions were found in the asymptomatic FIT-positive patients with negative bidirectional endoscopy. Although FIT has been widely accepted as a CRC screening tool, 40–60% of subjects with a positive FIT are found to have no lesions in their colon or rectum to explain their positive status [5, 14, 15]. How then do we explain the discrepancy between the results of FIT and colonoscopy? There are several possible explanations for this discrepancy. First, this may reflect true false-positive results of FIT for advanced neoplasia. Quantitative FIT results are subjected to predetermined cut-off values for fecal hemoglobin; this methodology could inevitably yield some true false positives. Additionally, medications that can increase the likelihood of GI bleeding may cause false-positive FIT J. J. Park Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seoul, Korea

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.

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.

Colorectal Cancer Screening in Patients with Inherited Bleeding Disorders: High Cancer Detection Rate in Hemophilia Patients

Risk-Adapted Screening Shows Superior Diagnostic Efficacy than Fecal Immunochemical Test in Colorectal Cancer Screening: Baseline Results of a Multi-Center Randomized Controlled Trial (TARGET-C)