Esmée J. Grobbee

A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening

Objective Colorectal cancer screening programmes are implemented worldwide; many are based on faecal immunochemical testing (FIT). The aim of this study was to evaluate two frequently used FITs on participation, usability, positivity rate and diagnostic yield in population-based FIT screening. Design Comparison of two FITs was performed in a fourth round population-based FIT-screening cohort. Randomly selected individuals aged 50–74 were invited for FIT screening and were randomly allocated to receive an OC -Sensor (Eiken, Japan) or faecal occult blood (FOB)-Gold (Sentinel, Italy) test (March–December 2014). A cut-off of 10u2005µg haemoglobin (Hb)/g faeces (ie, 50u2005ng Hb/mL buffer for OC-Sensor and 59u2005ng Hb for FOB-Gold) was used for both FITs. Results In total, 19u2005291 eligible invitees were included (median age 61, IQR 57–67; 48% males): 9669 invitees received OC-Sensor and 9622 FOB-Gold; both tests were returned by 63% of invitees (p=0.96). Tests were non-analysable in 0.7% of participants using OC-Sensor vs 2.0% using FOB-Gold (p<0.001). Positivity rate was 7.9% for OC-Sensor, and 6.5% for FOB-Gold (p=0.002). There was no significant difference in diagnostic yield of advanced neoplasia (1.4% for OC-Sensor vs 1.2% for FOB-Gold; p=0.15) or positive predictive value (PPV; 31% vs 32%; p=0.80). When comparing both tests at the same positivity rate instead of cut-off, they yielded similar PPV and detection rates. Conclusions The OC-Sensor and FOB-Gold were equally acceptable to a screening population. However, FOB-Gold was prone to more non-analysable tests. Comparison between FIT brands is usually done at the same Hb stool concentration. Our findings imply that for a fair comparison on diagnostic yield between FITs positivity rate rather than Hb concentration should be used. Trial registration number NTR5385; Results.

Advances in Fecal Tests for Colorectal Cancer Screening

Opinion statementColorectal 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.

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

Background:The effectiveness of faecal immunochemical test (FIT)-based screening programs is highly dependent on consistent participation over multiple rounds. We evaluated adherence to FIT screening over four rounds and aimed to identify determinants of participation behaviour.Methods:A total of 23u2009339 randomly selected asymptomatic persons aged 50–74 years were invited for biennial FIT-based colorectal cancer screening between 2006 and 2014. All were invited for every consecutive round, except for those who had moved out of the area, passed the upper age limit, or had tested positive in a previous screening round. A reminder letter was sent to non-responders. We calculated participation rates per round, response rates to a reminder letter, and differences in participation between subgroups defined by age, sex, and socioeconomic status (SES).Results:Over the four rounds, participation rates increased significantly, from 60% (95% CI 60–61), 60% (95% CI 59–60), 62% (95% CI 61–63) to 63% (95% CI 62–64; P for trend<0.001) with significantly higher participation rates in women in all rounds (P<0.001). Of the 17u2009312 invitees eligible for at least two rounds of FIT screening, 12u2009455 (72%) participated at least once, whereas 4857 (28%) never participated; 8271 (48%) attended all rounds when eligible. Consistent participation was associated with older age, female sex, and higher SES. Offering a reminder letter after the initial invite in the first round increased uptake with 12%; in subsequent screening rounds this resulted in an additional uptake of up to 10%.Conclusions:In four rounds of a pilot biennial FIT-screening program, we observed a consistently high and increasing participation rate, whereas sending reminders remain effective. The substantial proportion of inconsistent participants suggests the existence of incidental barriers to participation, which, if possible, should be identified and removed.

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

BACKGROUND & AIMSnAmong subjects screened for colorectal cancer (CRC) by the guaiac fecal occult blood test, interval cancers develop in 48% to 55% of the subjects. Data are limited on how many persons screened by fecal immunochemical tests (FIT), over multiple rounds, develop interval cancers. In the Netherlands, a pilot FIT-based biennial CRC screening program was conducted between 2006 and 2014. We collected and analyzed data from the program on CRCs detected during screening (SD-CRC) and CRCs not detected within the screening program (non-SD-CRC; such as FIT interval cancers, colonoscopy interval cancers, and cancer in nonparticipants).nnnMETHODSnScreenees with a negative FIT result received a letter explaining that no blood had been detected in the stool sample and were re-invited, if eligible, for screening biennially. Screenees with a positive FIT result (hemoglobin concentration of 10 μg Hb/g feces) were invited for consultation and scheduled for colonoscopy; results were collected. After the fourth round of FIT screening, the cohort was linked to the Netherlands Cancer Registry, through March 31, 2015; participant characteristics, data on tumor stage, location (at time of resection), and survival status were collected for all identified CRC cases. A reference group comprised all persons with CRC diagnosed in the Netherlands general population during the same period, in the same age range (50-76 years), who had not been offered CRC screening. The median time between invitations (2.37 years) was used as a cutoff to categorize participants within the FIT interval cancer category. We compared participant characteristics, tumor characteristics, and mortality among subjects with SD-CRC and with non-SD-CRC.nnnRESULTSnA total of 27,304 eligible individuals were invited for FIT screening, of whom 18,716 (69%) participated at least once. Of these, 3005 (16%) had a positive result from the FIT in 1 of the 4 screening rounds. In total, CRC was detected in 261 participants: 116 SD-CRCs and 145 non-SD-CRCs (27 FIT interval cancers, 9 colonoscopy interval cancers, and 109 CRCs in nonparticipants). The FIT interval cancer proportion after 3 completed screening rounds was 23%. Participants with SD-CRC had more early-stage tumors than participants with non-SD-CRCs (P < .001). Of persons with SD-CRC and FIT interval cancers, significantly higher proportions survived (89% and 81%, respectively) compared withxa0persons with colonoscopy interval cancers (44% survival) and nonparticipants with CRC (60% survival) (P < .001).nnnCONCLUSIONSnIn an analysis of data from a pilot FIT-based biennial screening program, we found that among persons screened by FIT, 23% developed FIT interval cancer. FIT therefore detects CRC with 77% sensitivity. The proportion of FIT interval cancers in FIT screening appears to be lower than that with guaiac fecal occult blood testing. Clinical trial registry: yes, www.trialregister.nl, trial number: NTR5385.

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.

Second-look colonoscopies and the impact on capacity in FIT-based colorectal cancer screening

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

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

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

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

Objective Colorectal cancer (CRC) screening programmes based on faecal immunochemical testing for haemoglobin (FIT) typically use a screening interval of 2u2005years. We aimed to estimate how alternative FIT strategies that use a lower than usual positivity threshold followed by a longer screening interval compare with conventional strategies. Methods We analysed longitudinal data of 4523 Dutch individuals (50–74u2005years at baseline) participating in round I of a one-sample FIT screening programme, of which 3427 individuals also participated in round II after 1–3u2005years. The cohort was followed until 2u2005years after round II. In both rounds, a cut-off level of ≥50u2005ng haemoglobin (Hb)/mL buffer (corresponding to 10u2005µg Hb/g faeces) was used, representing the standard scenario. We determined the cumulative positivity rate (PR) and the numbers of subjects diagnosed with advanced adenomas (N_AdvAd) and early stage CRC (N_earlyCRC) in the cohort over two rounds of screening (standard scenario) and compared it with hypothetical single-round screening with use of a lower cut-off and omission of the second round (alternative scenario). Results In the standard scenario, the cumulative (ie, round I and II combined) PR, N_AdvAd and N_earlyCRC were 13%, 180% and 26%, respectively. In alternative scenarios using a cut-off level of respectively ≥11 and ≥22u2005ng/HbmL buffer (corresponding to 2 and 4u2005µg Hb/g faeces), the PRs were 18% and 13%, the N_AdvAd were 180 and 162 and the N_earlyCRC ranged between 22–27 and 22–26. Conclusions The diagnostic yield of FIT screening using a lowered positivity threshold in combination with an extended screening interval (up to 5u2005years) may be similar to conventional FIT strategies. This justifies and motivates further research steps in this direction.

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

BACKGROUND & AIMSnColorectal 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 valuexa0and later development of colorectal advanced neoplasia (AN).nnnMETHODSnWe 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 thexa0screening 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 ANxa0after consecutive fHb concentrations below the cut-off value.nnnRESULTSnAfter 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%) (Pxa0< .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). Participantsxa0with 2 consecutive fHb concentrations of 8 μg Hb/g had a 14-fold increase in risk of AN compared with participantsxa0with 2 consecutive fHb concentrations of 0 μg Hb/g (P < .001).nnnCONCLUSIONSnIn 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.

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 100u2009000 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 11u2009932 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 100u2009000 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.