Research ArticleClinical Studies
Open Access

Diagnostic Accuracy of Fecal Immunochemical Test (FIT) in Bleed-positive and Bleed-negative Colorectal Cancer (CRC) Among a Cohort of 5,090 Subjects who Participated in the Colorectal Neoplasia (CRN) Screening in Brazil

MAARET ESKELINEN, JANNICA MEKLIN, DENISE PEIXOTO GUIMARAES, TUOMAS SELANDER, KARI SYRJÄNEN and MATTI ESKELINEN
Anticancer Research April 2023, 43 (4) 1569-1580; DOI: https://doi.org/10.21873/anticanres.16307

Abstract

Background/Aim: This study assessed the diagnostic accuracy (DA) of fecal immunochemical test (FIT) ColonView (CV) and guaiac-based fecal occult blood test (HemoccultSENSA) among bleed-positive (history or signs of intestinal bleeding) and bleed-negative participants (no history or signs of intestinal bleeding) (n=5,090) in colorectal neoplasia (CRN) screening in Brazil. Patients and Methods: The eligible patients for the study (n=506) collected three consecutive stool samples, to be analyzed by both assays (CV, SENSA). Finally, 421/5090 (8.3%) patients returned both samples, which were subjected to final analysis. Receiver operating characteristic (ROC) analysis with different cut-offs was performed to assess the DA. Results: The area under curve (AUC) values for i) visually analyzed (VA) CV for bleed-positive CRC, ii) automatically analyzed (AA) CV for bleed-positive CRC, iii) VA CV for bleed-negative CRC, and iv) AA CV for bleed-negative CRC as endpoints were as follows: i) AUC=0.864, ii) AUC=0.933, iii) AUC=0.836, and iv) AUC=0.892. In roccomp analysis, the differences in AUC values were: between i) and ii) p=0.068; between i) and iii) p=0.497; between i) and iv) p=0.488; between ii) and iii) p=0.0058; between ii) and iv) p=0.229; and between iii) and iv) p=0.138. Conclusion: This is the first investigation where two modes of CV test, VA, and AA, for bleed-positive and bleed-negative CRC patients were used as the endpoint. The AA reading of the CV test showed higher DA in bleed-positive than in bleed-negative CRC patients.

Key Words:

Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the Western World (1). Patients diagnosed at an early stage of CRC have a much better survival rate compared with those with widespread disease at the time of diagnosis. International estimates (2-5) based on recent randomized cohorts suggest that stool-based screening is associated with a 15-33% reduction in CRC mortality rates (2, 6-8).

Many stool-based tests are available for colorectal neoplasia (CRN) screening, including guaiac-based fecal occult blood tests (gFOBTs), fecal immunochemical tests (FITs), and multitarget stool DNA tests (1-8). A recent gold-standard test, the FIT test, requires only one stool sample and does not have restrictions to medications or diet prior to sampling; unlike in gFOBTs, foods with peroxidase activity do not produce false-positive results in the FIT test.

The principles of the immunochemical assay for human hemoglobin (Hb) were described by Suovaniemi, who investigated an antibody specific to human globin, the protein component of Hb (9). The developed FITs enable specific detection of occult human blood in the fecal samples at significantly lower concentrations of Hb than gFOBTs. The modern development in this area represents a second-generation FIT test (ColonView®, CV), which has the advantage of detecting two components of fecal occult blood (FOB): Hb and hemoglobin/haptoglobin (Hb/Hp) complex (10).

The diagnostic accuracy (DA) of FITs depends on the bleeding in the intestinal tract, as discussed in recent reviews (1-8). This is the first study where the DA of the CV test was investigated in the detection of bleed-positive and bleed-negative CRCs among patients who participated in a systematic screening of CRN in Barretos City, Brazil. Also, receiver operating characteristic (ROC) analysis with different cut-offs (CO) was used to assess the DA of the CV test in these patients.

Patients and Methods

Study design and eligibility of study patients. The Barretos Cancer Hospital (BCH) CRN cohort included 5,090 patients between January 2014 and December 2016 (Figure 1). Potentially eligible patients (n=699) were identified among the total cohort of subjects originally screened (n=5,090). Every patient was asked to provide a written consent for participation in the study. Patients who accepted to participate in the study (n=506) were given a box containing all material for stool sampling of Hemoccult SENSA (SENSA) and CV tests including instructions for sample collection. Patients with unsatisfactory or missing stool samples were excluded (n=85), leaving 421/5,090 (8.3%) eligible for the study. Detailed description of all CRN lesions was recorded, including their number and size, as well as the symptoms and findings identified during the consultation. These data included a detailed history of bleeding; bleed-negative patients (no history or signs of intestinal bleeding) versus bleed-positive patients (history or signs of intestinal bleeding). Exclusion criteria of the study patients included: unsatisfactory colonoscopy, previous colon surgery, inflammatory bowel disease (IBD)/Crohn’s disease, radiation proctitis, missing/unsatisfactory stool sample and/or patients who presented with visible blood in the stools regularly (>one episode per week).

Figure 1.
Figure 1.

Flow-chart of the study.

Sample collection, processing, and interpretation of results. For the CV test, two optional reading modes are available: visual analysis (VA) and automatic analysis (AA)(11). For the AA mode, the Quick Test Reader (QTR) is needed. QTR is a mobile device for quantitative evaluation of Lateral Flow Assays and the protocol of this instrument, described in more detail recently (Chembio Diagnostics GmbH, Berlin, Germany), has been previously described (10, 11). The analytical sensitivity of the CV Hb is 15 ng/ml, and of the CV Hb/Hp complex, 4 ng/ml (10-12). The guaiac-based FOBT (Hemoccult SENSA, Beckman Coulter Inc., Pasadena, CA, USA) was used as the comparison test in this study.

Statistical analysis. STATA/SE version 17.0 (StataCorp, College Station, TX, USA) and MetaDiSc software 1.4 (Unit of Clinical Biostatistics team of the Ramón y Cajal Hospital, Madrid, Spain) were used for analysis. Conventional ROC analysis was used to graph for the sensitivity (Se) and specificity (Sp) and to find the optimal cut-off (CO) values for both Hb and Hb/Hp of the CV test (Figure 2). Meta-analytical technique (metaprop; Stata) was used to create separate forest plots for Se and Sp, with each set of data included. Hierarchical receiving operating characteristic (HSROC) curves using the CRC endpoint were created and roccomp test (Stata) was used to compare the statistical significance between the area under the curve (AUC) values of the AA and VA modes and separately for bleed-positive and bleed-negative CRC endpoints.

Figure 2.
Figure 2.

Receiver operating characteristic (ROC) curve for test optimization and finding optimal cut-off point for automatically analyzed (AA) ColonView (CV) Hb and Hb/Hp tests in bleed-positive and bleed-negative CRC endpoints.

Results

The study cohort. In the bleed-positive study group, 145 patients were included with 22 CRCs, whereas the bleed-negative study group consisted of 276 patients including 21 CRCs.

Bleed-positive CRC endpoint with VA tests. The Se, Sp, and efficiency (Ef) of the SENSA test for CRC were as follows: 91%, 72%, and 75% (Table I, Figure 3, and Figure 4). The Se, Sp, and Ef of the VA CV Hb and CV Hb/Hp tests for CRC were 95%/95%, 52%/51%, and 59%/58% (Table I, Figure 3, and Figure 4). The positive predictive value (PV+) of the CV Hb/Hp VA test was equal to that of the CV Hb VA test (Table I): 26.6% versus 26.9%. When CV Hb+Hb/Hp VA were used as a test panel for the CRC endpoint, the panel had 95% Se, 46% Sp, and 54% Ef (Table I, Figure 3, and Figure 4).

View this table:
Table I.

Visually analyzed screening tests for ‘blood in stool positive’ colorectal cancer endpoint.

Figure 3.
Figure 3.

Sensitivity values of visually analyzed (VA) screening tests for bleed-positive colorectal cancer endpoint. ES: Estimated sensitivity; CI: confidence interval.

Figure 4.
Figure 4.

Specificity values of visually analyzed (VA) screening tests for bleed-positive colorectal cancer endpoint. ES: Estimated specificity; CI: confidence interval.

Bleed-positive CRC endpoint with AA tests. The overall Se of the AA mode for bleed-positive CRC was 90% (95%CI=83-96%) (Table II, Figure 5, and Figure 6). The most sensitive AA tests (CV Hb AA at CO ≥11.80 and CV Hb/Hp AA at CO ≥9.71) showed 95% Se (Table II, Figure 5). The overall Sp of the AA mode for the bleed-positive CRC endpoint was 79% (95%CI=54-96%) (Figure 6). The most specific AA test (CV Hb AA at cut-off ≥298) in bleed-positive CRC diagnosis showed Sp of 98% (Figure 6).

View this table:
Table II.

Automatically analyzed screening tests for ‘blood in stool positive’ colorectal cancer endpoint.

Figure 5.
Figure 5.

Sensitivity values of automatically analyzed (AA) screening tests for bleed-positive colorectal cancer endpoint. ES: Estimated sensitivity; CI: confidence interval.

Figure 6.
Figure 6.

Specificity values of automatically analyzed (AA) screening tests for bleed-positive colorectal cancer endpoint. ES: Estimated specificity; CI: confidence interval.

Bleed-negative CRC endpoint with VA tests. The Se, Sp, and Ef of the SENSA test for bleed-negative CRC were as follows: 62%, 85%, and 83% (Table III, Figure 7, and Figure 8). The Se, Sp, and Ef of the VA CV Hb and CV Hb/Hp tests for distal CRC were as follows: 89%/89%, 62%/86%, and 64%/86% (Table III, Figure 7, and Figure 8). The PV+ of the CV Hb VA test was substantially lower than that of the CV Hb/Hp VA test (Table III): 15.3% versus 39.0%. When CV Hb+Hb/Hp VA were used as a test panel for the CRC endpoint, the panel had 89% Se, 57% Sp, and 60% Ef (Table III, Figure 7, and Figure 8).

View this table:
Table III.

Visually analyzed screening tests for ‘no blood in stool’ colorectal cancer endpoint.

Figure 7.
Figure 7.

Sensitivity values of visually analyzed (VA) screening tests for bleed-negative colorectal cancer endpoint. ES: Estimated sensitivity; CI: confidence interval.

Figure 8.
Figure 8.

Specificity values of visually analyzed (VA) screening tests for bleed-negative colorectal cancer endpoint. ES: Estimated specificity; CI: confidence interval.

Bleed-negative CRC endpoint with AA tests. The overall Se of the AA mode for bleed-negative CRC was 92% (95%CI=83-97%) (Table III, Figure 9). Three AA tests had Se of 95% (CV Hb AA at CO ≥8.35, CV Hb/Hp AA at CO ≥4.69 and CV Hb/Hp AA at CO ≥19.00) (Figure 9). The overall Sp of the AA reading mode for the bleed-negative CRC endpoint was 69% (95%CI=51-85% (Figure 10). The two most specific AA tests (CV Hb AA at CO ≥44.80 and CV Hb/Hp AA at CO ≥19.00) in distal CRC diagnosis showed Sp range of 77-88% (Figure 10).

Figure 9.
Figure 9.

Sensitivity values of automatically analyzed (AA) screening tests for bleed-negative colorectal cancer endpoint. ES: Estimated sensitivity; CI: confidence interval.

Figure 10.
Figure 10.

Specificity values of automatically analyzed (AA) screening tests for bleed-negative colorectal cancer endpoint. ES: Estimated specificity; CI: confidence interval.

ROC analysis and optimal COs of the CV for bleed-positive CRC endpoint. The ROC analysis (Figure 2) for bleed-positive CRC endpoint showed the optimal CO value of ≥11.80 for CV Hb AA (Table II) and ≥9.71 for CV Hb/Hp AA (Table II). Using these COs, the Se, Sp, and Ef of the CV Hb AA (Table II) and CV Hb/Hp AA (Table II) tests for CRC were 96%/96%, 58%/58%, and 64%/64%. The PV+ was the same in both tests (CV Hb AA versus CV Hb/Hp AA) (Table II); 29.6% versus 29.6%.

ROC analysis and optimal COs of the CV for bleed-negative CRC endpoint. The ROC analysis (Figure 2) for bleed-negative CRC endpoint showed the optimal CO value of ≥8.35 for CV Hb AA (Table IV) and ≥4.69 for CV Hb/Hp AA (Table IV). Using these COs, the Se, Sp, and Ef of the CV Hb AA (Table IV) and CV Hb/Hp AA (Table IV) tests for CRC were 95%/95%, 53%/54%, and 56%/57%. The PV+ of CV Hb AA (Table IV) was similar to that of CV Hb/Hp AA (Table IV); 13.4% versus 13.3%.

View this table:
Table IV.

Automatically analyzed screening tests for ‘no blood in stool’ colorectal cancer endpoint.

HSROC and AUC values. HSROC curves were used to visualize the pooled overall accuracy of VA and AA modes in bleed-positive and bleed-negative CRC detection. In the HSROC analysis, the AUC values for i) VA in bleed-positive CRC endpoint, ii) AA in bleed-positive CRC endpoint, iii) VA in bleed-negative CRC endpoint, and iv) AA in bleed-negative CRC endpoint were: i) AUC=0.864 (95%CI=0.830-0.898) (Figure 11), ii) AUC=0.933 (95%CI=0.901-0.964) (Figure 12), iii) AUC=0.836 (95%CI=0.760-0.920) (Figure 13), and iv) AUC=0.892 (95%CI=0.842-0.942) (Figure 14). In roccomp analysis, the differences in AUC values were as follows: between i) and ii) p=0.068; between i) and iii) p=0.497; between i) and iv) p=0.488; between ii) and iii) p=0.0058; between ii) and iv) p=0.229; and between iii) and iv) p=0.138.

Figure 11.
Figure 11.

Hierarchical summary receiver operating characteristic (HSROC) curve of the visually analyzed (VA) screening tests for bleed-positive colorectal cancer endpoint.

Figure 12.
Figure 12.

Hierarchical summary receiver operating characteristic (HSROC) curve of the automatically analyzed (AA) screening tests for bleed-positive colorectal cancer endpoint.

Figure 13.
Figure 13.

Hierarchical summary receiver operating characteristic (HSROC) curve of the visually analyzed (VA) screening tests for bleed-negative colorectal cancer endpoint.

Figure 14.
Figure 14.

Hierarchical summary receiver operating characteristic (HSROC) curve of the automatically analyzed (AA) screening tests for bleed-negative colorectal cancer endpoint.

Discussion

CRC is a highly prevalent disease with a well shown preclinical phase and CRN screening could therefore impact: i) the detection of adenomatous polyps that could later become malignant neoplasia (primary prevention), and ii) diagnose CRC as early as possible for effective treatment (secondary prevention) (2). The CRC patients diagnosed at an early stage of disease have a much better survival rate compared with those who have widespread disease at the time of diagnosis, as confirmed by the previous randomized cohorts implicating that FOB-based screening is associated with a 15-33% decrease in CRC mortality rates (2, 6-8).

Thus, a general consensus agrees that CRC screening reduces cancer-specific mortality, and many FOB-based tests are available for CRC screening, including gFOBTs, FITs, and multitarget stool DNA tests (7, 8). The use of proteomics in FOB-based CRC screening is based on the finding that mutant DNA present in CRN lesions is excreted in stools (17-19). In addition, RNA-based methods possess some promise in CRC screening; the test is non-invasive, 1 g of stool is enough, consecutive sampling is not required, stool samples can be mailed, and the test can be automated (18, 19). However, no current FOB-tests used for CRC screening are devoid of shortcomings, including potential flaws, and limited accessibility or acceptability to screening patients. Therefore, more research is needed to make the FOB-tests more accurate to further improve DA in CRC screening.

All FOB-tests are based on detection of intestinal bleeding. Several non-CRN related conditions cause intestinal bleeding, including IBD (i.e., Crohn’s disease and ulcerative colitis) and perianal lesions, and also most non-steroidal anti-inflammatory drugs produce occult blood loss. There are not many studies comparing the DA of any FOB-tests among bleed-positive and bleed-negative CRNs, and even fewer of those using FITs. Of all FITs, few tests detect the Hb/Hp complex, although the benefits of testing Hb/Hp have been confirmed (10). The advantages of using the test with both Hb and Hb/Hp complex have also been discussed in a recent review (7) and in a meta-analysis (8). The Hb/Hp complex has an important role in the recovery of Hb and this complex resists proteolytic degradation, which means that the Hb/Hp complex can persist in the intestine for substantially longer, thus increasing the chance that bleeding from even small CRCs could be detected in the stool samples (13, 14). Instead, the proteolytic degradation of Hb in the stool sample takes place within a few days, reducing the Hb concentration below the cut-off limit if the stool sample requires storage for several days (20). Therefore, efficient methods for stabilization of Hb in the stool are needed; one promising new tool with increased buffer stability being Hb Smart enzyme-linked immunosorbent assay (ELISA) (20).

In previous studies for Hb and Hb/Hp (CV), VA and AA modes were reported separately (15, 16). For the AA mode, the QTR device is needed (10, 15, 16). Eskelinen et al. (21) studied the applicability of the AA and VA modes of the CV test, and AA mode showed significantly better DA as compared to the VA reading (or SENSA), in detecting proximal CRC. In addition, the authors stratified the patients by the cancer site (proximal vs. distal) and found that the DA of both the AA and VA modes is clearly superior for CRCs in the distal site as compared with that in the proximal site. Because the detection of cancers through screening tends to occur 2-3 years before clinical symptoms, any FOB-based screening test for CRC precursor lesions, i.e., colorectal adenomas (CRA) is important. As compared with the CRC endpoint, the DA value of the CV test is far inferior for the CRA endpoint, as determined by the AUC values (22). Sieg et al. compared Hb and Hb/Hp tests in a cohort of 621 patients, and for detecting CRC the Se was 87% in both tests. Authors concluded that immuno-luminometric determination of the Hb and Hb/Hp complex in stool samples has a comparable Se for CRC patients, but significantly higher Se for CRA (Se for Hb versus Se for Hb/Hp; 54% versus 76%) (13).

Karl et al. (14) assessed six markers in a cohort of 551 patients (186 CRC, 113 CRA, and 252 control patients) to establish the DA of each marker and marker combinations. The best DA was found for S100A12 with an AUC of 0.95, followed by TIMP-1 (0.92), Hb/Hp (0.92), HB (0.91), calprotectin (0.90), and carcinoembryonic antigen (0.66). By using Bayes logistic regression, the highest Se (88%) for the detection of CRC at 95% Sp was obtained with the marker pair S100A12 and Hb/Hp. Increasing the Sp to 98%, the combination of S100A12, Hb/Hp, and TIMP-1 resulted in a Se of 82%, with the highest increase in Se found in tumor stage I: 74% Se versus 57% of the best single marker (14). A marker pair, S100A12 and Hb/Hp, or a triple combination including TIMP-1, allowed the diagnosis of CRC at significantly higher rates than those obtained with the Hb FIT test alone. These observations led us to assess, whether there is any difference between bleed-positive and bleed-negative CRC patients, because bleed-negative patients might be missed more easily than bleed-positive patients in organized CRN screening.

This study investigated the DA of the two modes of the CV test, for a bleed-positive versus bleed-negative CRC endpoint. It is of major interest to assess whether some of the test modes in the two categories (SENSA and CV) are particularly influential in this analysis, i.e., have a significant influence on the pooled summary estimates in the forest plots. This can be done by different approaches. The simplest way is to make a visual inspection of the forest plots depicting the pooled estimates of Se and Sp, separately for SENSA and CV tests (Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10). Using this approach, one can easily identify the test modes with the highest Se and Sp. Among both test categories, there are several test modes where the test Se is over 90%. As usual, this high Se is achieved at the expense of lower Sp. Importantly, there is no single study (or test brand) either using the SENSA or CV that is 100% specific to the CRC endpoint (Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10). As pointed out before (1-8), this is exactly what we can expect because of the simple reason that FOB detected by these tests is not specific to invasive CRC, but indeed, can be derived from various other (neoplastic or non-neoplastic) sources as well. In bleed-positive CRC endpoint, the overall Se of the AA reading mode 90% was lower to that of the VA reading 95%. However, the AA mode showed significantly higher Sp than the VA reading in the bleed-positive endpoint (79% versus 53%). Similarly, in the bleed-negative CRC endpoint, the overall Se of the AA reading mode 84% was lower than that of the VA reading 92%, with the pooled Sp of 69% and 70%, respectively.

While considering the strengths and weaknesses of the present study, it can be admitted that analyses of screening studies with a relatively small number of patients, as in this study that included only 50 patients, are always subject to detection and verification biases. Interestingly, there seems to be a seasonal variation in FIT test performance with lower positivity rates in hot weather, due to the degradation of Hb (23, 24). Use of a standard collection device/probe with a known buffer may also be subject to bias. However, at the moment, there is no accepted international quality control standard for the use of FITs (1-8).

Because the AA mode of the CV test provides quantitative results, we aimed to identify the optimal COs for Hb and Hb/Hp that give the best Se/Sp balance. This was neatly done by using conventional non-parametric ROC analysis (Figure 2) and selecting the coordinate points in the ROC curve as indicators of these CO values for Hb and Hb/Hp separately. The CO values have become increasingly important with the introduction of quantitative FITs in which it is possible to adjust the CO limit to obtain an acceptable compromise between the clinical Se and Sp. This adjustment of the CO values can provide an adequate detection rate from an acceptable cohort of CRN patients. By increasing the positive CO limit, the test Se and positivity rate decreases whereas the Sp and PPV for CRC detection increase. However, it is important to keep in mind that in any studies using different commercial products with different analytical characteristics, direct comparisons can be misleading. HSROC analysis (25, 26) is a convenient approach to evaluate the DA of various FOBTs, as here used to analyze the DA of the CV test with different COs. When applied to the present setting, HSROC curve for the AA mode in bleed-positive CRC showed an AUC=0.933, which is clearly superior to that obtained with the VA reading (AUC=0.864). Using the bleed-negative CRC endpoint, the DA of both AA and VA readings (AUC=0.892 versus AUC=0.836, respectively) was clearly inferior to that for the bleed-positive CRC.

Conclusion

CRC screening by FOB-tests is based on the intestinal bleeding from the CRN lesions. We were interested to see whether differences in the DA of the new-generation FIT exist between bleed-positive and bleed-negative CRC patients who participated in organized CRN screening. When stratified by the ‘blood in stool’ (as bleed-positive or bleed-negative endpoint), the DA of the CV test was clearly higher for bleed-positive than bleed-negative CRCs, and of the two modes of the CV test, the AA reading gave a higher DA in both bleed-positive and bleed-negative CRC patients.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the collection and analysis of data, drafting, and revising the manuscript, and read and approved the final article.

  • Conflicts of Interest

    The Authors have no conflicts of interest or financial ties to disclose in relation to this study.

  • Received January 20, 2023.
  • Revision received February 3, 2023.
  • Accepted February 6, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Diagnostic Accuracy of Fecal Immunochemical Test (FIT) in Bleed-positive and Bleed-negative Colorectal Cancer (CRC) Among a Cohort of 5,090 Subjects who Participated in the Colorectal Neoplasia (CRN) Screening in Brazil
MAARET ESKELINEN, JANNICA MEKLIN, DENISE PEIXOTO GUIMARAES, TUOMAS SELANDER, KARI SYRJÄNEN, MATTI ESKELINEN
Anticancer Research Apr 2023, 43 (4) 1569-1580; DOI: 10.21873/anticanres.16307
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