Mo1177 Participation, FIT-Result and Yield in Three Rounds of Biannual FIT-Based Screening in the Netherlands

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

Quantitation of Hemoglobin Improves Fecal Immunochemical Tests for Noninvasive Screening

Participation, yield, and interval carcinomas in three rounds of biennial FIT-based colorectal cancer screening

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

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

Colorectal cancer (CRC) screening has come of age in Canada, with every province now having a screening program either implemented or well underway. These programs are based on the detection of fecal occult blood, with positive results triggering colonoscopy for definitive diagnosis. This approach is supported by high-level evidence demonstrating a mortality benefit for individuals screened in this manner. Fecal occult blood testing (FOBT) uses indirect methods to test for&#13;\nthe presence of hemoglobin, which can be affected by chemicals, such as vitamin C, or heme from other sources such as red meat. In contrast, fecal immunochemical tests (FIT) use an antibody to detect human globin directly. These assays may offer advantages of greater specificity&#13;\nand sensitivity, and improved adherence. Most FITs produce a visual colour change on a strip to indicate a positive result, but some are analyzed using automated systems in a laboratory to provide a quantitative result.

A Quarter of Participants With Advanced Neoplasia Have Discordant Results From 2-Sample Fecal Immunochemical Tests for Colorectal Cancer Screening

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.

Optimizing Colorectal Cancer Screening by Getting FIT Right

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.

Background: The current guideline does not recommend upper gastrointestinal evaluation for patients with a positive fecal immunochemical test (FIT) and negative colonoscopy results. However, this indication was based on low-quality evidence as data on this issue are very limited. We assessed the risk of proximal cancers (oral or throat, esophageal, stomach, and small intestine cancers) after negative or positive FIT results in the Korean National Cancer Screening Program (NCSP). Methods: Using the NCSP databases, we collected data on participants who underwent FIT between 2009 and 2011. Participants were classified based on FIT results and colorectal cancer (CRC) diagnosed within 1 year after FIT as FIT− (n = 5,551,755), FIT+/CRC− (n = 368,553), and FIT+/CRC+ (n = 12,236). Results: The incidence rates of overall proximal cancers in FIT−, FIT+/CRC−, and FIT+/CRC+ patients within 1, 2, and 3 years after FIT were 0.38%, 0.68%, and 2.26%; 0.57%, 0.93%, and 2.74%; and 0.79%, 1.21%, and 3.15%, respectively. After adjusting confounding variables, the risks of esophageal, stomach, and small intestine cancers as well as overall proximal cancers within 1, 2, and 3 years after FIT were higher in FIT+/CRC− patients than those in FIT− patients. However, the risk of oral or throat cancer did not differ between FIT− and FIT+/CRC− patients. The risks for oral or throat cancer and small intestine cancer were higher in FIT+/CRC+ patients than those in FIT+/CRC− patients. Conclusions: In this population-based study, FIT+/CRC− patients were at higher risk for esophageal, stomach, and small intestine cancers than were FIT− patients, suggesting that positive FIT results were associated with these cancers.

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

The participation in the FIT-based colorectal cancer screening programme and subsequent compliance to colonoscopy after a positive FIT test was only slightly affected during the COVID-19 pandemic in Denmark.

BackgroundColorectal cancer (CRC) is the most common cancer in Europe with a mortality rate of almost 50%. The prognosis of patients is largely determined by the clinical and pathological stage at the time of diagnosis. Population screening has been shown to reduce CRC-related mortality rate. Most screening programs worldwide rely on fecal immunochemical testing (FIT). The effectiveness of a FIT screening program is not only influenced by initial participation rate, but also by program adherence during consecutive screening rounds. We aim to evaluate the participation rate in and yield of a third CRC screening round using FIT.Methods and designFour years after the first screening round and two years after the second round, a total number of approximately 11,000 average risk individuals (50 to 75 years of age) will be invited to participate in a third round of FIT-based CRC screening. We will select individuals in the same target area as in the previous screening rounds, using the electronic database of the regional municipal administration registrations. We will invite all FIT-negatives and all non-participants in previous screening rounds, as well as eligible first time invitees who have moved into the area or have become 50 years of age.FITs will be analyzed in the special technique laboratory of the Academic Medical Center of the University of Amsterdam. All FIT-positives will be invited for a consultation at the outpatient clinic. In the absence of contra-indications, a colonoscopy will follow at the Academic Medical Center or at the Flevohospital. The primary outcome measures are the participation rate, defined as the proportion of invitees that return a FIT in this third round of FIT-screening, and the diagnostic yield of the program.ImplicationsThis study will provide precise data on the participation in later FIT screening rounds. This enables to estimate the effectiveness of CRC screening programs that rely on repeated FIT- screening, such as the one that will be implemented in the Netherlands in 2013.