The effectiveness of FOBT vs. FIT: A meta-analysis on colorectal cancer screening test.

BACKGROUND: After lung and prostate cancers, colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women after breast cancer worldwide. Every year, more than one million people are diagnosed with colorectal cancer worldwide and half of these patients die from this disease, making it the fourth leading cause of death in the world. This systematic review aimed to assess the effectiveness of the two colorectal diagnostic tests of FOBT (fecal occult blood test) and FIT (fecal immunochemical test)) in terms of technical performance.
METHODS: To retrieve the relevant evidence, appropriate medical databases such as Cochrane library, NHSEED, Scopus and Google scholar were searched from February 2013 to July 2014, using free-texts and Mesh. In this study, inclusion/exclusion criteria of the papers, randomized controlled trials, economic evaluations, systematic reviews, meta-analyses and meta-syntheses of the effectiveness of FIT versus FOBT tests in moderate-risk populations (age: 50 to 70 years), which had reported the least of such outcomes as sensitivity, specificity and clinical outcomes were reviewed. The analyses of the effectiveness outcomes were performed in the form of meta-analysis.
RESULTS: Five papers were eligible to be included in the final phase of the study for synthesis. FIT showed a better performance in participation and positivity rate. Moreover, in terms of false positive and negative rate, FIT showed fewer rates compared to FOBT (RR:-4.06; 95% CI (-7.89-0.24), and NN-scope (Number need to scope) (2.2% vs. 1.6%), and NN-screen (Number need to screen) (84% vs. 31-49% in different cut off levels) showed significant differences in FOBT vs. FIT, respectively.
CONCLUSION: In the five included studies (3, 11-14), the acceptability of FIT was more than FOBT. However, in our meta-analysis, no difference was found between the two tests. FIT was significant in positivity rate and had a better performance in participation rate, and a fewer false negative numbers compared to FOBT.

Introduction

After lung and prostate cancers, colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women after breast cancer worldwide. Every year, more than one million people are diagnosed with colorectal cancer worldwide and half of these patients die from this disease, making it the fourth leading cause of death in the world (1). An appropriate population-based screening program in the early stages of precancerous lesions including early detection and removal of polyps and adenoma will reduce and prevent the incidence and mortality of CRC (2). According to the medical guidelines of the Western countries for screening people at average risk, the first-line screening stool-based method is recommended because of its cost effectiveness, non-invasive nature, good accessibility and patient compatibility (3). Gaiac (FOBT) and safety-chemical method (FIT) are two types of routine stool tests used for initial screening (4). Among the available options, screening with guaiac-based fecal occult blood test (g-FOBT) was associated with a 13–18% CRC-mortality reduction in major randomized studies (5). This mortality reduction was primarily resulted from detecting CRC in early stages (6-7). The immunochemical fecal occult blood test (FIT) has a better sensitivity than g FOBT and a similar specificity to g-FOBT for detecting advanced neoplasia and it specifically uses human hemoglobin for detection(8). Fecal tests have the advantages of being relatively simple and safe screening tests, suitable for a mass screening programs. However, because of the poor sensitivity for premalignant lesions, fecal test needs to be repeated every 1–2 years. Therefore, a high compliance to repeat testing is required to achieve long-term effectiveness with fecal tests (5). The effectiveness of the screening tests depends not only on the sensitivity for colorectal neoplasia, but also on population attendance. Low participation rates of CRC screening tests resulted in weakening of the true efficiency of the test and reducing the overall productivity for advanced neoplasia in the community. The impact of adherence on the eventual effectiveness of any screening strategy has been confirmed by simulation modeling in which showing apparently large differences in efficacy is reversed by small gradients in adherence rates (9-10). Therefore, a societal decision maker confronted with the choice of alternative tests to prevent the CRC incidence and/or mortality, and stated that one should choose the strategy with the most efficient compromise between adherence and efficacy, i.e., the highest effectiveness. Uncertainty in this choice will appear to be mainly related to the technical and procedural differences among the available tests, primarily between the fecal tests on the one hand and endoscopic strategies on the other.

Research Question

Which one of these tests (FOBT vs. FIT) is effective in term of different diagnostic validity indexes?

Study Objectives

This study aimed to assess the effectiveness of colorectal diagnostic tests (FOBT versus FIT) in terms of technical performance and to examine the ethical, organizational, social and legal aspects of this technology in those Iranians at moderate-risk of colorectal cancer.

Methods

Literature Search

This was a systematic review of the literature. Fourteen electronic reference databases were searched. Most major search sites in appropriate medical databases such as Cochrane library, NHSEED, Scopus and Google scholar were searched by proper keywords such as "neoplasm", fecal occult blood test", fecal immunochemical test" from February 2013 to July 2014 using free-texts and Mesh (Appendix 2). Gray literatures were searched via Google, the web sites of the Trial Registers Current Controlled Trial, the National Research Register, and Clinicaltrials.gov. In addition, references of all the included papers were searched to identify any additional relevant studies. Studies without control groups and non-English language studies were excluded. The titles and abstracts of the identified papers were checked to exclude non-relevant studies. The full texts of the remaining articles were checked against the inclusion-exclusion criteria. Papers were controlled independently by two reviewers. The risk of bias was checked by two reviewers independently.

The two reviewers independently screened the articles by title, abstract and full text and they then extracted the full texts of the articles, using a standard data extraction form and consulted a third investigator in cases of any disagreement. Data were extracted by identifying the formation of articles, the study objectives, study design, inclusion and exclusion criteria of the studies, the intervention and control groups, joint interventions, covert interventions, method of randomization, blinding, potential confounding, outcome of the study, statistical analysis, baseline characteristics of patients and outcome events.

Scope

In this study, the inclusion/exclusion criteria of the papers, randomized controlled trials, economic evaluations, systematic reviews, meta-analyses and meta-syntheses of the effectiveness of FIT versus FOBT were reviewed.

PICO Question

Which of the two stool-based colorectal cancer screening tests (FOBT vs. FIT) is more effective to be used for an average-risk population (age: 50 to70 years) in terms of technical performance rates?

Comparators: FOBT or FIT

Study Design: A Meta- analysis

Outcomes: The performance rate of the diagnostic test (sensitivity, specificity, positive predictive value, negative predictive value).

Quality Appraisal Method

The quality appraisal of the included RCTs was performed using JADAD checklist to evaluate the confounding factors used for RCTs apart from the clinical trials (Oxford quality scoring system, and independent evaluation of methodological quality of clinical trials). The analysis of technical performance outcomes was performed in the form of meta-analysis via the Rev Man software (Version 5.3).

Results

In the first phase, 1,737 papers were retrieved; of them, 333 were duplicated, so they were excluded. From the 1,404 remaining papers, after checking the titles and abstracts, 1,339 articles did not meet the inclusion/exclusion criteria, so only 65 papers remained. After reviewing the full texts, 44 articles were excluded because of their poor study design and inadequate control groups, and 21 papers remained in the final phase. All of the 21 articles were assessed with jaded checklist and 16 articles were excluded after reviewing their full texts because their quality was unclear due to not reporting the outcomes and existence of deficiencies both in sequence generation and allocation concealment. Finally, five articles were selected for the final analysis (3,11-14) (Fig. 1) (Appendix 3).

Fig. 1

Literature Search Results with PRISMA Flowchart

Four papers got 5 points and one study got 3 based on JADAD items (randomization, blinding and adequate sample size of patients) (Table 1). The five selected studies have been conducted from 2005 to 2013 in the Netherlands, Australia, Germany and France. In all the included studies, population-based screening was performed on the basis of FOBT and FIT kits in men and women in the age range of 75-50 years. Some studies reported test positive if at least one of the six kits had a color change (each panel contains two cards). FIT was positive at different cut off levels of fecal hemoglobin concentration per ml of sample buffer in case the color changed (in response to the hemoglobin molecule present in fecal samples). Most of the studies used FOBT in the form of hem occult non-rehydrated type (Beckman Coulter Inc. USA), and different brands were used for FIT.

Table 1

Quality Appraisal of the Included RCTs

Title	Study Design	Screening Test	Comparator	JADAD Checklist
				Randomization 2	Blinding 2	An account of all patients 1	score
Screening for colorectal cancer: Random comp-arison of guaiac and immunochemical faecal occult blood testing at different cut-off levels	Diagnostic (RCT)	Hem occult (Beckman coulter ,Inc .Fullerton, CA, USA) non re hydration	OC-sensor (micro e liken chemical co, Tokyo. Japan)	√	√	√	5
Guaiac versus immunochemical tests: faecal occult blood test screening for colorectal cancer in a rural community	Diagnostic (RCT)	Hem occult(Beckman coulter, Inc. Fullerton, CA, USA) non re hydration	!form(enter ix)	√	X	√	3
Superior diagnostic performance of faecal immunochemical tests for haemoglobin in a head-to-head comparison with guaiac based faecal occult blood test among 2235 participants of screening colonoscopy	Diagnostic (RCT)	Hem occult, Beckman coulter, Krefeld, Germany)	1) Rid a screen haemo globin2) Rid a screen haemo-/ hapto globin complex, R- Biopharm AG, Darmstadt, Germany3) OC SENSOR,Tokyo, Japan	√	√	√	5
Random comparison of guaiac and immuno-chemical fecal occult blood tests for colorectal cancer in a screening population	Diagnostic (RCT)	Hem occult l I (Beckman coulter)	OC- sensor (e liken chemical Co.)	√	√	√	5
Immunochemical faecal occult blood tests are superior to guaiac-based tests for Detection of colorectal neoplasms	Diagnostic (RCT)	Hem occult II. beck man coulter inc ,fuller ton CA.USA (without rehydration)	Instant. view, alpha scientific designs, Poway, CA, USA	√	√	√	5

A) Analysis of Common Indicators in Final Studies with the Rev Man Software

In this analysis, the significance cut off point was set at 0.05 for the p-value, and normal distribution and random effects model were also assumed.

A-1) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, three studies were included in which the specificity of the two tests was not significantly different in ruling out colorectal cancer(Appendix 4).

A-2) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, two studies were included in which specificity of the two tests was not significantly different in ruling out advanced adenoma (Appendix 4).

A-3) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, three studies were included in which the positive predictive value of the two tests was not significantly different in existence of colorectal cancer (Appendix 4).

A-4) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, three studies were included in which the positive predictive value of the two tests was not significantly different in the existence of advanced adenoma (Appendix 4).

A-5) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, two studies were included in which the positive predictive value of two tests was not significantly different in the existence of non-advanced adenoma (Appendix 4).

A-6) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, two studies were included in which participation rates of the two tests were not significantly different (Appendix 4).

A-7) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, four studies were included in which the positivity rate of the two tests with heterogeneity tau²=0.00 (p=0.04, MD=-4.06, 95% CI: -7.89, -0.24) was significantly different (Appendix 4).

A-8) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, three studies were included in which detection rates of the two tests were not significantly different for colorectal cancer (Appendix 4).

A-9) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 50Ng/ml, three studies were included in which the detection rates of the two tests were not significantly different for advanced adenoma (Appendix 4).

A-10) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 100ng/ml, two studies were included in which the specificity of the two tests was not significantly different for colorectal cancer (Appendix 4).

A-11) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 100Ng/ml, two studies were included in which the specificity of the two tests was not significantly different for advanced adenoma (Appendix 4).

A-12) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 100Ng/ml, two studies were included in which the positive predictive value of the two tests was not significantly different for colorectal cancer (Appendix 4).

A-13) In the comparative approach of FOBT vs. FIT at hemoglobin cut off level of 100Ng/ml, two studies were included in which the positive predictive value of the two tests was not significantly different for advanced adenoma (Appendix 4).

Discussion

Screening status for moderate-risk groups in Iran is unclear, and the trend of cancer occurrence is seen in a population of younger than40 years of age. Therefore, this study focused on comparing the performance of diagnostic tests to detect CRC based on fecal FOBT and FIT in the first line of treatment. According to the included studies, FIT compared to FOBT, has a better performance in specificity, positivity rate, NN-scope and NN-screening. The results of the five large trials were meaningful in measuring the performance of FOBT and FIT tests (3,11,12,14,15). Interpretation of the test results according to the manufacturers’ instructions may have been affected by the results of each RCT. In some studies, dietary restriction did not apply, or only a sample of three stool samples were used for analysis, and this may give rise to false positive rates and may impose costs and mental burden on the patients. However, some of the references listed in the dietary restrictions lead to a reduction in the amount of positive FOBT test and increase the specificity of FOBT (15). According to the manufacturers’ instructions and the restrictions imposed by The Food and Drug Organization, dietary restrictions impact on the sensitivity and specificity had been reported in various studies, and so the comparison with other studies were difficult. Since the samples were collected in plastic containers, freezed and then defrosted again to be prepared for the analysis process, it was impossible to compare the performance of the two tests for multiple stool samples. In addition, according to some studies, when colonoscopy capacity was limited, FOBT could reduce the demand by limiting the range and extensive screening intervals. Moreover, when colonoscopy capacity was unlimited, the best strategy to screen people at the age of 45 to 80 years was FIT with cutoff 50Ng/cc, and 50 Ng/cc cut off level was recommended for colonoscopy follow- ups for all people with positive adenoma. However, when faced with limited capacity of colonoscopy, the optimal strategy was using FIT with cutoff of 200nm/cc at the range of 50 to 75 years; and consequently, by reducing the follow up rounds of colonoscopy, the demand will decrease (16). The low hemoglobin cut off levels provided a higher detection of advanced neoplasia and it also reduced the number of false-positives, and those that were not in a priority for performing colonoscopy. False-positive results may impose concerns and additional costs for accurate diagnosis. An increase in hemoglobin cut off levels leads to reduction in the detection rate and thus reduces sensitivity. Thereby, increasing the false negatives can progress to metastatic diseases, making it more difficult to be treated and leading to higher costs of the treatment. In one of the included studies, the detection rate of FIT in the cut off of 75Ng/cc was two times higher than FOBT, suggesting that this cut- off point is more favorable in assessing the performance rate. However, the general conclusion based on the meta-analysis was not different between the two tests in terms of detection rate or sensitivity. Detection rate and false positive rate can be considered as an indicator of sensitivity and specificity. Therefore, in our study, no differences were observed between the two indicators. Since most studies used the 75ng/cc cut-off to assess FIT versus FOBT, it can be stated that the results of our study have a good validity for generalization. FIT, compared to FOBT, was more sensitive in detecting CRC, advanced and non-advanced adenomas, considering that it also may contain false positive numbers. Therefore, FIT may be less specific than FOBT. This result was similar to that of the study conducted by Dancourt et al. in 2008. Based on their results, the performance of FIT (sensitivity, specificity, PPV, NPV and likelihood ratios)was better than FOBT (3). In the five included studies (3,11-14), the acceptability of FIT was more than FOBT. However, in our meta-analysis, we detected no difference between the two tests. FIT, compared to FOBT, had fewer false negative rates, and NN-scope (Number need to scope) and NN-screen (Number need to screen) were significantly different between the two tests, but in the final meta-analysis, no significant difference was found between NN-screen and NN-scope.

Conclusion

FIT detected more positive results compared to FOBT and showed fewer false negatives. Also, FIT was a more acceptable test for the participants because it was easy to take because of short sampling times and no food restrictions.

Acknowledgements

This article was derived from a thesis titled: "The Effectiveness of FOBT vs. FIT, which is appropriate: A Meta-Analysis on colorectal cancer screening test" by Maryam Mousavinezhad supervised by Dr AliAkbari Sari and Dr RezaMajdzadeh, that was submitted to the Graduate Studies Office in partial fulfillment of the requirements for the degree of Master in Health Technology Assessment. This study was financially supported by the Vice Chancellor for Research at Tehran University of Medical Sciences (Contract no 240/1548).

Conflict of Interest

There was no conflict of interest.

Appendix 1.

Characteristics of the Included Trials

Study	Country	Population	Range age	Year	Setting	Intervention	Comparator	Outcome	(FIT vs. FOBT)	Jaded
Wilschut et al (11)	LH Netherlands	10011	50-75 years	2009	At home	FIT	GFOBT	Specificity PPV NNscope¹ NNscreen² Positivity rate Detection rate	Specificity 97.6% (cut off 50ng/cc) 92.9 % (cut off 75ng/cc) VS. FOBT 97.6% (p7lt;0.05) Positivity rate 8.1 (cut off 50 ng/cc) 5.7 (cut off 75 ng/cc) 4.8 (100 ng/cc) 4.1(125ng/cc) 4 (150ng/cc) 3.6 (175 ng/cc) 3.5 (200ng/cc) VS. FOBT 2.8% (p<0.05)	5
Hughes K et al (12)	Australia	3358	50-75 year	2005	At home	FIT	GFOBT	Sensitivity Participation rate Positivity rate	No difference	3
Brenner H et al (13)	Germany	2414	50-75 year	2013	At home	FIT	GFOBT	Specificity Sensitivity PPV NPV	No difference	5
Vanrossom LG et al (14)	Netherlands	20623	50-75 year	2008	At home	FIT	GFOBT	Specificity PPV Intention to screen Participation rate	Intention to screen 5 FIT 0.4% VS. FOBT 0.2% P<0.01 (95% CI 0.3-0.5)	5
Dancourt V et al (3)	France	17215	50-75 year	2008	At home	FIT	GFOBT	Positivity rate Detection rate PPV Positivity rate	No difference	5

Appendix 2

The Search Strategies

Search (((((((colorectal screening [Title/Abstract]) AND fecal occult blood[Title/Abstract]) OR fecal occult[Title/Abstract]) AND fecal immunochemical[Title/Abstract]) OR fecal occult blood test[Title/Abstract]) OR colorectal cancer screening[Title/Abstract]) OR FOBT[Title/Abstract]) OR fecal immonochemical test[Title/Abstract] Search fecal occult blood test[MeSH Terms] Search fecal immonochemical test [MeSH Terms] Search (((fecal immunochemical test) AND fecal occult blood test) AND ((((("Colorectal Neoplasms"[Mesh] OR "Colorectal Neoplasms, Hereditary Nonpolyposis"[Mesh] OR "Lynch Syndrome II"[Mesh])) OR colorectal cancer) OR colorectal neoplasia) OR colorectal neoplasms)) AND ((FIT ) OR "FOBT"[Mesh]) Sort by: Title Search (((("Colorectal Neoplasms"[Mesh] OR "Colorectal Neoplasms, Hereditary Nonpolyposis"[Mesh] OR "Lynch Syndrome II"[Mesh])) OR colorectal cancer) OR colorectal neoplasia) OR colorectal neoplasms

Appendix 3

Excluded Articles in the Final Step

Reason for Exclusion	Address of the Articles in References
Descriptive study	16-17-18-19
Review article	31-32-33-34-35
Mismatch with PICOD	42-43-44-45-46-47-48

A) Appendix 4

Meta-analysis of Common Indicators in Final Studies with the RevMan Software

Study	Strategy	Validity Index	MD. 95% CI	p
Wilschut LH Vanrossom LG	FOBT, FIT 50ng/dl	CRC specifity	1.16[-96.10,98.42]	0.98
Wilschut LH Vanrossom LG	FOBT, FIT 50ng/dl	Advanced adenoma specifity	2.11[-95.57,99.79]	0.97
Wilschut LH Vanrossom LG Dancourt V	FOBT, FIT 50ng/dl	CRC PPV	0.71[-5.25,6.66]	0.82
Wilschut LH Vanrossom LG Dancourt V	FOBT, FIT 50ng/dl	Advanced adenoma PPV	-5.48[-32.12,21.15]	0.69
Vanrossom LG Dancourt V	FOBT, FIT 50ng/dl	Non-Advanced adenoma PPV	-1.32[-17.32,14.69]	0.87
Hughes k Vanrossom LG	FOBT,FIT 50ng/dl	Participation rate	-9.74[-50.92,31.45]	0.64
Hughes k Vanrossom LG Wilschut LH Dancourt V	FOBT, FIT 50ng/dl	Positivity rate	-4.06[-7.89,-0.24]	0.04
Vanrossom LG Wilschut LH	FOBT, FIT 50ng/dl	CRC detection rate	-0.99[-2.08,0.09]	0.07
Vanrossom LG Wilschut LH	FOBT, FIT 50ng/dl Advanced adenoma	-1.00[-2.39,0.39]	0.16
Brenner H Wilschut LH	FOBT, FIT 100ng/dl	CRC specifity	1.15[-95.24, 96.55]	0.99
Brenner H Wilschut LH	FOBT, FIT 100ng/dl	Advanced adenoma specifity	-0.67[-97.90, 96.55]	0.99
Brenner H Wilschut LH	FOBT, FIT 100ng/dl	CRC PPV	-16.77[-61.12, 27.58]	0.46
Brenner H Wilschut LH	FOBT, FIT 100ng/dl	Advanced adenoma PPV	-24.53[-67.43, 18.37]	0.26