New stool tests for colorectal cancer screening: a systematic review focusing on performance characteristics and practicalness

New stool tests may be promising tools for future colorectal cancer (CRC) screening. The aim of this review was to summarize current evidence of performance characteristics and practicalness in a population-based screening setting of recently developed stool tests. The MEDLINE database was searched for relevant articles published until July 2004. Studies were included if they comprised more than 10 cases and more than 10 controls. Details on study population, performance characteristics and stool collection procedure were taken into account. Overall, 29 studies, mostly retrospective, were included, investigating 17 different stool markers or marker combinations. Underlying study populations were very heterogeneous and mostly very small. Half of the studies reported sensitivity for adenomas in addition to sensitivity for CRC, and fewer than half reported sensitivity by tumor stage or location. Performance characteristics of stool tests varied to a large extent. For most DNA-based markers, specificity was about 95% or higher, but sensitivity was mostly low even for invasive CRC. More studies with larger sample sizes were done for protein-based markers, which typically had lower specificity. In most studies, stool samples were frozen within a rather short time period after defecation. While promising performance characteristics have been reported for some tests, more pervasive evidence from larger, prospectively designed studies, which also consider aspects of practicalness, e.g., the possibility of mailing the samples, is needed.     

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer

Proliferating cells, especially tumour cells, express a special isoenzyme of pyruvate kinase, termed M2-PK, which can occur in a tetrameric form with a high affinity to its substrate, phosphoenolpyruvate (PEP), and in a dimeric form with a low PEP affinity. In tumour cells, the dimeric form is usually predominant and is therefore termed Tumour M2-PK. The levels of Tumour M2-PK within tumours and in EDTA-plasma correlate with staging and the ability of the tumour cells to metastasise. Since most colorectal tumours grow intraluminally, it appeared interesting to determine whether Tumour M2-PK is detectable in the faeces of tumour patients. Stool samples were tested by ELISA from controls without colorectal cancer and colorectal cancer patients. Whereas Tumour M2-PK levels were low in the control group (mean value+/-s.e.m.: 3.3+/-0.4, n=144), they were high in the case of colorectal cancer (56.1+/-15.3, n=60). At a cutoff value of 4 U ml(-1), the sensitivity was 73%. TNM and Dukes' classification of the tumours revealed a strong correlation between faecal Tumour M2-PK levels and staging. The determination of Tumour M2-PK in faeces provides a new promising screening tool for colorectal tumours.     

Cancer‐associated fecal microbial markers in colorectal cancer detection

Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case–control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa‐C+ diffusely adherent Escherichia coli harboring the afa‐1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a “high‐risk” microbial pattern to other further diagnostic procedures such as colonoscopy.     

Impact of time between faecal immunochemical tests in colorectal cancer screening on screening results: A natural experiment

Repeated rounds of faecal immunochemical testing (FIT) for occult blood is a common method for screening for colorectal cancer (CRC). However, the time interval between FIT rounds is not thoroughly investigated. In a CRC screening trial in South-Eastern Norway, individuals were invited for biennial FIT between 2012 and 2019. The positivity threshold was >15 mcg haemoglobin/g faeces (mcg/g). Due to organizational challenges, the interval between screening rounds randomly varied between 1.5 and 3.5 years, forming a natural experiment. We investigated the detection rate of CRC and advanced neoplasia (AN: CRC or advanced adenoma) at the subsequent round (FIT₂), according to the faecal haemoglobin concentration (f-Hb) at the initial screening round (FIT₁), and time between the two screening rounds. 18 522 individuals with negative FIT₁ who attended FIT₂ were included in this study. 245 AN were detected at FIT₂, of which 34 were CRC. The CRC detection rate at FIT₂ for participants with FIT₁ = 0 mcg/g was 0.09% while it was 0.28% for participant with 0 > FIT₁ ≤ 15 mcg/g; odds ratio (OR) 3.22, 95% CI 1.49-6.95. For each 3 months' increment between FITs, the OR for detecting CRC was 1.33 (95% CI 0.98-1.79), while the OR was 1.13 (1.02-1.26) for AN. Individuals with FIT₁-value of 0 mcg/g, had a lower AN detection rate compared with participants with 0 > FIT₁ ≤ 15 mcg/g, irrespective of time between tests. Although CRC and AN detection rates increase with increasing time interval between FITs, individuals with undetectable f-Hb at first screen have substantially lower risk of CRC at the next screening round compared with individuals with detectable f-Hb.     

Fecal occult blood screening for colorectal cancer: open issues.

Data from seven case-control and--mainly--three randomized clinical trials consistently indicate that biennial fecal occult blood screening (FOBT) can reduce colorectal cancer (CRC) mortality by approximately 20% after 10-18 years. The reduction may be greater in compliant subjects. In the long-term, incidence also appears to be reduced. There are suggestions that the effect of annual screening may be greater, although data are inadequate to quantify the potential advantages of annual versus biennial screening. The issue of the effectiveness of FOBT in the general population and, more important, of comparative cost-effectiveness with other possible screening tests for CRC, however, remain open to discussion.     

Effectiveness of a clinic-based colorectal cancer screening promotion program for underserved Hispanics

BACKGROUND:

Hispanics in the United States are less likely than other groups to receive screening services for colorectal cancer.

METHODS:

The authors conducted a clinic‐based individual randomized trial that enrolled Hispanic patients ages 50 to 79 years who had been seen in the Seattle‐based community clinic in the past 5 years. A total of 501 patients met the eligibility criteria and were randomized to 1 of 3 conditions: 1) usual care; 2) mailed fecal occult blood test (FOBT) card and instructions on how to complete the test (mailed FOBT only); and 3) mailed FOBT card and instructions on how to complete the test, telephone reminders, and home visits (mailed FOBT and outreach). The authors assessed postintervention differences in rates of FOBT screening in intervention and usual care groups using computerized medical records reviewed from June 2007 to March 2008.

RESULTS:

Data analysis occurred between November 2008 and September 2009. Nine‐month postintervention screening rates were 26% among patients who received the mailed packet only intervention (P < .001 compared with usual care) and 31% in the group that received the mailed packet and outreach intervention (P < .001 compared with usual care). This compared with 2% in the group that received usual care. Screening rates in the mailed FOBT only group and in the mailed FOBT and outreach group were not significantly different (P = .28).

CONCLUSIONS:

Culturally appropriate clinic‐based interventions may increase colorectal cancer screening among underserved Hispanics. Cancer 2011. © 2010 American Cancer Society.     

Comparison and combination of blood-based inflammatory markers with faecal occult blood tests for non-invasive colorectal cancer screening

Background:

Faecal occult blood tests (FOBTs) are widely used for colorectal cancer (CRC) screening. Blood-based inflammatory markers have been suggested as alternative or supplementary non-invasive CRC screening tests.

Methods:

Among 179 CRC patients, 193 people with advanced adenoma and 225 people free of neoplasm, C-reactive protein (CRP), serum CD26 (sCD26), complement C3a anaphylatoxin and tissue inhibitor of metalloproteinases 1 (TIMP-1) levels in blood were measured by ELISA tests, and an immunochemical FOBT (iFOBT) and a guaiac-based FOBT were performed. Receiver operating characteristic curves were constructed and the areas under the curves (AUCs) were compared.

Results:

The blood levels of CRP, sCD26 and TIMP-1 showed statistically significant differences between CRC patients and neoplasm-free participants, and levels of TIMP-1 were furthermore significantly elevated in advanced adenoma patients. For the four inflammatory markers, AUCs ranged from 0.52 to 0.62 for CRC detection and from 0.50 to 0.58 for advanced adenomas detection, compared with AUCs of 0.90 and 0.68 for the iFOBT. At 97% specificity, blood markers showed much lower sensitivities than FOBTs. Combining inflammatory markers with the iFOBT increased the AUC for advanced adenomas.

Conclusion:

These blood-based markers do not seem to be an alternative to FOBT-based CRC screening. The potential use of these and other blood-based tests in combination with iFOBT might deserve further attention.     

False negative fecal occult blood tests due to delayed sample return in colorectal cancer screening

Delayed return of immunochemical fecal occult blood test (iFOBT) samples to a laboratory might cause false negatives because of hemoglobin degradation. Quantitative iFOBT's became increasingly more accepted in colorectal cancer screening. Therefore, we studied the effects of delay between sampling and laboratory delivery on iFOBT performance. IFOBT positivity (≥50 ng/ml hemoglobin) in colorectal cancer screening participants without delay between sampling and laboratory delivery (<5 days), was compared with positivity in participants with ≥5 and ≥7 days delay. Additionally, positive tests were stored at room temperature and retested 5 times within 10–14 days. The sampling date was reported by 61% (n = 3,767) of the participants: in 19% delay was ≥5 days and in 5% ≥7 days. Compared with no‐delay, the adenoma detection rate was already significantly decreased after ≥5 days delay (OR 0.6; 95%CI 0.4–0.9). We retested iFOBT samples of 170 positives of which 139 (82%) had a colonoscopy: 45 (32%) had advanced adenomas (not colorectal cancer) and 8 (6%) had colorectal cancer. Mean daily fecal hemoglobin decrease was 29 ng/ml (S.D. 38 and median 11 ng/ml). In patients with advanced adenomas, hemoglobin in the sample was <50 ng/ml in 5 (11%) 2–3 days after the initial test and in 16 (36%) after 10–14 days. Seven days after the initial test, 2 (25%) colorectal cancer patients became false negative. Both had stage I colorectal cancer and initial values below 100 ng/ml, where the average for stage I is 532 ng/ml. Delay in sample return increased false negative immunochemical FOBT's. Mainly precursor lesions, but also colorectal cancer, will be missed due to delayed sample return. © 2009 UICC     

The role of defensive information processing in population-based colorectal cancer screening uptake

Background

Internationally, colorectal cancer screening participation remains low despite the availability of home-based testing and numerous interventions to increase uptake. To be effective, interventions should be based on an understanding of what influences individuals’ decisions about screening participation. This study investigates the association of defensive information processing (DIP) with fecal immunochemical test (FIT)–based colorectal cancer screening uptake.

Methods

Regression modeling of data from a cross-sectional survey within a population-based FIT screening program was conducted. The survey included the seven subdomains of the McQueen DIP measure. The primary outcome variable was the uptake status (screening user or nonuser). Multivariable logistic regression was used to estimate the odds ratio (OR) for screening nonuse by DIP (sub)domain score, with adjustments made for sociodemographic and behavioral factors associated with uptake.

Results

Higher scores (equating to greater defensiveness) on all DIP domains were significantly associated with lower uptake in the model adjusted for sociodemographic factors. In the model with additional adjustments for behavioral factors, the suppression subdomains of “deny immediacy to be tested” (OR, 0.53; 95% confidence interval [CI], 0.43–0.65; p < .001) and “self-exemption” (OR, 0.80; 95% CI, 0.68–0.96; p < .001) independently predicted nonuse of FIT-based screening.

Conclusions

This is the first study outside the United States that has identified DIP as a barrier to colorectal cancer screening uptake, and it is the first focused specifically on FIT-based screening. The findings suggest that two suppression barriers, namely denying the immediacy to be tested and self-exempting oneself from screening, may be promising targets for future interventions to improve uptake.     

Toward standardizing and reporting colorectal cancer screening indicators on an international level: The International Colorectal Cancer Screening Network

The International Colorectal Cancer Screening Network was established in 2003 to promote best practice in the delivery of organized colorectal cancer screening programs. To facilitate evaluation of such programs, we defined a set of universally applicable colorectal cancer screening measures and indicators. To test the feasibility of data collection, we requested data on these variables and basic program characteristics from 26 organized full programs and 9 pilot programs in 24 countries. The size of the target population for each program varied considerably from a few thousand to 36 million. The majority of programs used fecal occult blood tests for primary screening, with more using guaiac than immunochemical tests. There was wide variation in the ability of screening programs to report the requested measures and in the values reported. In general, pilot programs were more likely to provide screening measure values than were full programs. As expected, detection rates for polyps and neoplasia were substantially higher in programs screening with endoscopy than in those using fecal occult blood tests. It is hoped that the screening measures and indicators, once revised in the light of this survey, will be adopted and used by existing programs and those in the early planning stages, allowing international comparison with the goal of improved colorectal cancer screening quality.     

The second round of the Dutch colorectal cancer screening program: Impact of an increased fecal immunochemical test cut-off level on yield of screening

The Dutch colorectal cancer (CRC) screening program started in 2014, inviting the target population biennially to perform a fecal immunochemical test (FIT). We obtained prospectively collected data from the national screening information-system to present the results of the second round (2016) and evaluate the impact of increasing the FIT cut-off halfway through the first round from 15 to 47 μg Hb/g feces on outcomes in the second round. Second round screening was done with a 47 μg Hb/g feces FIT cut-off. Participants were classified based on first round participation status as either FIT (15,47) or FIT (47,47) participants, and previous nonparticipants. In total, 348,891 (75.9%) out of 459,740 invitees participated in the second round. Participation rates were 93.4% among previous participants and 21.0% among previous non-participants. FIT(47,47) participants had a significantly higher detection rate of AN (15.3 vs. 10.4 per 1,000 participants) compared to FIT(15,47) participants in the second round, while their cumulative detection rate of AN over two rounds was significantly lower (45.6 vs. 52.6 per 1,000 participants). Our results showed that participation in the Dutch CRC screening program was consistently high and that second round detection rates depended on the first round FIT cut-off. The cumulative detection over two rounds was higher among FIT(15,47) participants. These findings suggest that a substantial part of, but not all the missed findings in the first round due to the increased FIT cut-off were detected in the subsequent round.     

Long-term risk of colorectal cancer after screen-detected adenoma: Experiences from a Danish gFOBT-positive screening cohort

Fecal occult blood test (FOBT) screening for colorectal cancer (CRC) is implemented in several countries. Approximately half of all FOBT-positive persons have screen-detected adenomas. Despite removal of these, patients with large/multiple adenomas have increased risk of later developing new advanced adenomas and CRC. International guidelines exist for colonoscopic surveillance following adenoma removal. These divide patients into low-, intermediate- and high-risk groups. We followed 711 FOBT-positive patients with screening adenoma identified during population-based CRC screening in two Danish counties in 2005–2006. As reference population, we included 1,240,348 persons in the same age group from the rest of Denmark not included in the screening. We estimated the long-term CRC risk stratified by adenoma findings during screening and compared to the reference group. After 12 years follow-up, the CRC incidence among all adenoma patients was 322 cases per 100,000 person-years (95% confidence interval [CI]: 212–489) ranging from 251 (95% CI: 94–671) to 542 (95% CI: 300–978) cases per 100,000 person-years in the low- and high-risk groups, respectively. In the reference population, the CRC incidence was 244 (95% CI: 242–247) per 100,000. Patients with screen-detected high-risk adenomas after a positive FOBT had an almost doubled risk of CRC compared to the reference population (adjusted hazard ratio [aHR] 1.95, 95% CI: 1.08–3.51), and the incidence in those with no follow-up visits was over 3.6 (aHR 3.64, 95% CI: 1.82–7.29) times the incidence in the reference population. The increased CRC risk could be controlled if high-risk patients underwent follow-up colonoscopy (aHR 0.87, 95% CI: 0.28–2.69).     

Changes in colorectal cancer screening use after introduction of alternative screening offer in Germany: Prospective cohort study

In October 2002, screening colonoscopy was added to the German colorectal cancer (CRC) screening program as an alternative to fecal occult blood test (FOBT). We aimed to evaluate the change in CRC screening use after introduction of the dual screening offer and to assess determinants of screening use. Data were drawn from a population-based cohort study initiated during 2000–2002 in Germany (n = 5,845, age range at recruitment: 50–75 years). We conducted both cross-sectional and longitudinal analyses to obtain uptake rates of CRC screening based on four waves of data. Age-group specific proportions of participants having had FOBT within 2 years remained essentially unchanged at 61–67% between 2000 and 2002 (1st wave) and 2005–2007 (3rd wave). The proportions of participants having undergone screening colonoscopy within 10 years increased from 23–29% to 46–57%, leading to a substantial overall increase in being up-to-date with CRC screening from 66–68% to 77–80%. In 2008–2010 (4th wave), FOBT use declined and colonoscopy use continued to increase. Obesity was significantly associated with lower prevalence of being up-to-date with FOBT (odds ratio [OR] at 8-year follow-up 0.68; 95% confidence interval [CI], 0.58–0.80) and screening colonoscopy (OR, 0.73; 95% CI, 0.62–0.86). Also, smokers were less likely to have ever used FOBT (OR, 0.54; 95% CI, 0.40–0.75) or colonoscopy (OR, 0.75; 95% CI, 0.63–0.90) compared to nonsmokers. After the introduction of dual screening offer, the overall adherence to CRC screening steeply increased, mainly due to an increase in screening colonoscopy uptake. Screening tests kept being underused by obese people and smokers who are at elevated CRC risk.