Refer to domain search and domain methodology section.

We have not identified any study that compares FIT vs gFOBT in terms of mortality. The identified studies that provided mortality information compared screening using FIT vs no screening and reported only colorectal cancer specific mortality. A randomised controlled trial {3} and four observational studies {4, 5, 6, 7} examined the effect of the use of FIT for colorectal cancer screening versus no screening on colorectal cancer mortality or incidence, but not on overall mortality. Tables 1 to 6 and Figure 1 {EFF Appendix 1} extract and evaluate the most important results of the five above mentioned studies. Because of the lack of direct evidence to answer the research question a GRADE profile has not been elaborated.

Refer to domain search and domain methodology section.

We have not identified any study that compares FIT vs gFOBT in terms of mortality. The identified studies that provide mortality information compared screening using FIT vs no screening. A controlled trial {3} and three observational studies {4, 6, 7} examined mortality effect of the use of FIT for colorectal cancer screening versus no screening. Therefore no direct evidence comparing FIT vs gFOBT in the context of a population based colorectal cancer screening program is available. Because of the lack of direct available evidence to answer the research question a GRADE profile has not been elaborated.

The tables 1 to 5 extract and evaluate the most important results of the four above mentioned studies. Only one of them is a randomised controlled trial{3}, two are case-control studies {6, 7} and one is an observational and comparative retrospective study{4}. The randomised controlled trial compares the use of one round Reverse Passive Hemagglutination (RPHA) immunochemical test along with an individual attribute degree value score versus no screening. This trial, which analyses the screening program conducted in Jiashan (China), presents several bias risks and it is no focused on our specific research question.

First at all, the index test differs from the test consider in our research question because the FIT was used together with a quantitative individual risk assessment method (Attributive Degree Value). On the other hand, the reference standard was initially sigmoidoscopy and colonoscopy only for positive sigmoidoscopies and for positive FIT for those who FIT was repeated. Individuals with a positive FOBT were asked to undergo flexible sigmoidoscopy (FS). If FS failed to detect colorectal lesions, the participants were asked to repeat the FOBT. Those without a lesion found by FS but with a positive repeated FOBT were re-examined by 150-cm colonoscopy to confirm the results. The no use of colonoscopy for all the positive FIT could lead to an underestimation of the colon cancer cases and may explain the better results for detection of rectal but no for colon cancer. Double reference standard can lead to a differential verification bias. That occurs when some of the index test results are verified by a different reference standard. This usually occurs when patients testing positive on the index test receive a more accurate, often invasive, reference standard than those with a negative test result. In this case, the results are overestimated.

The controlled trial is a cluster randomized trial based on townships allocation, with a high risk of bias in several key domains of the Cochrane risk of bias table (randomization, allocation concealment and blinding). Twenty one townships were matched by population size and age distribution into 10 pairs. In each pair, a table of random digits was used to allocate to the screening or to the control group. The unit of analysis was individuals, but there was no inter-cluster correction that would minimize the selection bias risk. On the other hand, there was no participant and personnel blinding, which implies a high risk of performance bias.

This trial obtained no significant differences for colorectal and colon, but significant for rectal cancer mortality, when compared those FIT based screened vs. those no screened. The 8 year cumulative colorectal cancer mortality rate per 1,000 was 2.08 for the FIT group (95% CI: 1.96-2.18) and 2.44 (95% CI: 2.33-2.55) for no screening (p=0.19). For the specific colon cancer mortality the 8 year cumulative mortality rate per 1,000 was 0.90 for the FIT group (95% CI: 0.83-0.97) and 0.83 for the no screening group (95% CI: 0.76-0.90) (p=0.222). The 8 year cumulative rectal cancer mortality rate per 1,000 was significantly different (p<0.05) for the FIT group (1.10; 95% CI: 1.02-1.18) vs the no screening group (1.61; 95% CI: 1.52-1.70).

The rest of the studies are observational retrospective studies with high risk of bias in most of the domains of the Cochrane risk of bias table. Two case-control studies compare, in the context of two different screening programs performed in two Japanese counties, the Odds Ratio of dying due to colorectal cancer for those screened within 1 to 5 years of case diagnosis vs. those no screened. The last one is a retrospective observational study that compares the five years survival rate of 194 screened detected colorectal cancer subjects versus 352 routinely detected (no screening) colorectal cancer at Hirosaki Hospital (Japan). Any of these observational studies provided high quality evidence of the effect of FIT versus gFOBT on the mortality caused by colorectal cancer in the context of a population based colorectal cancer screening program.

We have observed a similar reduction in CRC mortality in RCT of FIT versus no screening and in RCT of gFOBT vs no screening. If we compare the only one randomized clinical trial on CRC mortality in a population invited to FIT versus no screening {3} with the meta-analysis of four RCT on CRC mortality of gFOBT versus no screening {8}, we observe similar results but with a wide confidence interval. The meta-analysis used the Peto method and effect fixed modelization for obtaining an Odds Ratio of 0.84 (IC 95%: 0.78-0.9). Using the same method for estimating the effect of the unique RCT that compared FIT versus no screening the Odds Ratio would be 0.85 (CI 95%: 0.70-1.03). Table 7 {EFF Appendix 3}.

Refer to domain search and domain methodology section.

We have not identified any study that compares FIT vs gFOBT in terms of mortality. The identified studies that provided mortality information compared screening using FIT vs no screening and reported only colorectal cancer specific mortality. A controlled trial {3} and three observational studies {4, 5, 7} examined the effect of the use of FIT for colorectal cancer screening versus no screening on colorectal cancer mortality but not on overall mortality. Tables 1 to 5 {EFF Appendix 3} extract and evaluate the most important results of the above mentioned studies. Because of the lack of direct evidence to answer the research question a GRADE profile has not been elaborated.

Refer to domain search and domain methodology section.

A recent Italian screening programme by biennial immunochemical FOBT reported a retrospective comparison of cancer rate and stages between average risk screening participants and those who did not participate in the screening programme. Although the overall cancer rate was similar in the two populations (1.23 versus 1.20 per 1000 person-years), there were significant differences in TNM stage distribution between the two groups (stage III–IV cancers 0.24 versus 0.74 per 1000 respectively, p = 0.009).

This large cross-sectional study reported that colorectal cancers detected by immunochemical FOBT screening are identified at an earlier pathological stage, with significant prognostic and economic advantages to the populations screened {9}.

Refer to domain search and domain methodology section.

Compared with standard gFOBT, current evidence from systematic reviews and clinical trials indicates a higher sensitivity for the detection of CRC and advanced adenomas, and higher rates of detection for CRC and advanced adenomas (refer to EFF 12, EFF 20, EFF 22) {10,15,16,17,18}. A superior sensitivity and detection rate of adenomas is a distinguishing performance characteristic of FIT compared with gFOBT, thus proving a greater preventive capacity. If all advanced adenomas and CRC detected are removed progression of lesions could be avoided. The endoscopic removal of pre-malignant lesions also reduces the incidence of CRC by stopping the progression to cancer.

TNM stage distribution of CRC detected in screening programmes using FIT shows an early detection, and early treatment of colorectal lesions before they become symptomatic can reduce morbidity and mortality associated to CRC. 

A recent Italian screening programme by biennial immunochemical FOBT reported a retrospective comparison of cancer rate and stages between average risk screening participants and those who did not participate in the screening programme. Although the overall cancer rate was similar in the two populations (1.23 versus 1.20 per 1000 person-years), there were significant differences in TNM stage distribution between the two groups (stage III–IV cancers 0.24 versus 0.74 per 1000 respectively, p = 0.009). This large cross-sectional study reported that colorectal cancers detected by immunochemical FOBT screening are identified at an earlier pathological stage, with significant prognostic and treatment cost advantages to the populations screened {9}. A major goal of a colorectal cancer mass screening programme is to diagnose cancer at an earlier stage, thus permitting curative treatment at lower cost, as the prognosis and cost of late-stage cancer at diagnosis are quite different. In this screening programme most of the screen-detected cancers were diagnosed at a very early stage; 81 per cent were TNM stage I or II and were therefore treated with curative intent, compared with only44·0 per cent of cancers detected within the same age range in the non-screened population.

It could be a case of lead time bias. Those participants who do not participate in the screening programme are diagnosed after they have signs and symptoms of cancer, so they are in advances TNM stages. If the screening program does not modify the progression, the increase in survival time makes it seem as though screened patients are living longer when that may not be happening (the date of diagnosis is earlier for screened patients).

Refer to domain search and domain methodology section.

We have not identified clinical trials or systematic reviews comparing FIT vs gFOBT in terms of the effectiveness of subsequent interventions (colonoscopy and surgery) in the context of population based colorectal cancer screening.  

Refer to domain search and domain methodology section.

A high-quality level systematic review studying differences in detection rates between FIT and gFOBT has been detected {10). This systematic review selected five randomized controlled trials comparing detection rate of advanced neoplasm of FIT vs gFOBT for screening of CRC. The five trials were combined in a meta-analysis using random effects. Colonoscopy was the reference standard. The Pooled detection rates intended to screen cancers and significant adenomas were achieved in 2.23% of individuals with FIT and 1.24 % of individuals with gFOBT. The pooled Odds Ratio of detection with FIT vs. with gFOBT was 1.50 (IC 95%: 0.94-2.39). Hence, the FIT have a 50%, but not significant, higher detection rate in comparison with gFOBT for advanced adenomas and cancer. The existence of heterogeneity (I2: 70.7%) led to use random effects model.

Refer to domain search and domain methodology section.

We have not identified clinical trials or systematic reviews comparing FIT vs gFOBT in terms of other health effects or clinical conditions not included in the project scope and requiring subsequent clinical management decisions. Therefore no direct evidence on other potential health conditions comparing FIT vs gFOBT in the context of a population based colorectal cancer screening program is available. 

Refer to domain search and domain methodology section.

All the systematic reviews and available RCTs included reported statistically significantly higher participation rates for FIT compared with gFOBT {10, 11, 15}. This means a higher charge of diagnostic colonoscopies in the population. With respect to FIT performance, compared with standard gFOBT, current evidence indicates a higher sensitivity for the detection of CRC and advanced adenomas, and higher rates of detection for CRC and advanced adenomas. These advantages of FIT are offset by a higher positivity rate (depending on the used cut-off level), which in turn may require a greater number of colonoscopies. A superior sensitivity and detection rate of adenomas is a distinguishing performance characteristic of FIT compared with gFOBT. These performance characteristics change when the cut-off level in hemoglobin concentration is changed, allowing a screening program to select the optimal cut-off for the program (more cancers and pre-malignant lesions detected with the minimum number of colonoscopies required).

Positive rates varies among randomized clinical trials from FIT 5.5% to gFOBT 3.2% {11}; FIT 4.8% to gFOBT 2.8%{12}; FIT 11.2% to gFOBT 7.9% {13} and FIT 3.2% to gFOBT 10.1%{14}. Differences in positive predictive values for CRC or advanced adenoma were no statistically significant.

The total number of colonoscopies needed to confirm positive test results is higher for FIT comparing to gFOBT. In one RCT{11} 20,623 individuals were invited; 10,301 received gFOBT and 10,322 FIT. Tests were returned by 10,993 individuals, 4836 (46.9%) in the gFOBT group and 6157 (59.6%) in the FIT group. To evaluate the outcome in the 456 positives results, a colonoscopy was performed in 383 (84%) patients. Total number of colonoscopies was 103 in the gFOBT group and 280 in the FIT group. Cancer was found in 11 of the G-FOBTs and in 24 of the FIT. Advanced adenomas were found in 46 of the gFOBT and in 121 of the FIT. The number of polyps found with gFOBT was 220 (of which 154 adenomas) and 679 with FIT (of which 470 adenomas). In this RCT the specificity of the FIT for advanced adenomas and cancer was lower compared with the gFOBT, but the detection rate for advanced adenomas and cancer with the FIT was significantly higher. Consequently, 3 times as many subjects tested with the FIT are referred for a negative colonoscopy. On the other hand, 3 times as many patients with advanced adenomas and 2 times more patients with cancer are left undetected in the gFOBT group compared with the FIT group, ultimately resulting in comparable Positive Predictive Values for both tests. 

We used both basic search done for the whole project and domain search (described in the Domain Methodology section). Furthermore test accuracy issues relative to Research Questions EFF 20, EFF 22, EFF 24, EFF 26, EFF 28, EFF 30 were selected from the above mentioned searches.

Inclusion criteria where: studies that report data on accuracy measures (sensitivity, specificity, positive and negative predictive values, likelihood ratios, SROC and other measures, detection rates), publication date after year 2000, FIT compared with gFOBT or alone, on asymptomatic average risk patients, age 50+ years, data on specific issues relative to selected research questions. Two investigators independently reviewed the titles and abstract. Disagreement was resolved by discussion. See Table 8 {EFF Appendix 3} for included articles. These articles were used, where pertinent, to answer all the above-mentioned Research Questions.

The quality assessment criteria for studies we used for all above mentioned Research Questions are R-AMSTAR {2}  {EFF Appendix 2} for systematic reviews and Cochrane risk of bias for observational studies {1}. Two independent reviewers assessed quality and bias. Disagreement was resolved by discussion.

Extraction tables where tailored to research questions issues. Articles covered by systematic reviews that were in our included list were not extracted.

Data was synthesized in tables were possible and research questions were answered starting from the best quality of available evidence.

Very few good quality diagnostic studies comparing FIT versus gFOBT use as reference standard colonoscopy or flexible sigmoidoscopy for all positive or negative results in the index test {10,15}.

Allison et al. {14} and Park et al. {13} studied participants that would receive screening in practice. The reference standards used for each study were different, with Allison et al comparing FIT with gFOBT, and with Park et al comparing FIT with colonoscopy. In both studies, the reference standard and the index test were performed in a short time. In Allison et al, colonoscopy was not used as the comparator to FIT, although participants with a positive test were referred for colonoscopy, and those with a negative test were referred for FS. In Park et al, FIT results were compared directly with colonoscopy results. The index test was independent of the reference standard used.

In the study conducted by Park et al, positivity was slightly higher for FIT (11.2%) than for gFOBT (7.9%), but this difference was not statistically significant. The sensitivity for detecting CRC was statistically significantly increased when using FIT compared with gFOBT (FIT 92.3% versus gFOBT 30.8% [P<0.01]). The sensitivity of FIT (33.9%) compared with gFOBT (13.6%) for detecting advanced adenoma (AA) was significantly higher (P<0.05).

The difference in specificity for both CRC and AA was not statistically significant when comparing FIT (CRC 90.1%; AA 90.6%) with gFOBT (CRC 92.4%; AA 92.4%). The difference in PPV for both CRC and AA was not statistically significant when comparing FIT (CRC 12.8%; AA 23.3%) with gFOBT (CRC 6.7%; AA 13.1%).

In the study conducted by Allison et al, positivity was statistically significantly lower for FIT than the sensitive gFOBT used in the study (FIT 3.2% versus gFOBT 10.1% [P<0.01]). The difference in sensitivity for detecting CRC and AA was not statistically significant for FIT (CRC 81.8%; AA 29.5%) compared with gFOBT (CRC 64.3%; AA 41.3%).The specificity for both CRC and AA was statistically significantly higher for FIT than for gFOBT (CRC FIT 96.9% versus gFOBT 90.1% [P<0.01]; AA FIT 97.3% versus gFOBT 90.6% [P<0.01]). The PPV for both CRC and AA was also statistically significantly higher for FIT compared with gFOBT (CRC FIT 5.2% versus gFOBT 1.5% [P<0.01]; AA FIT 19.1% versus gFOBT 8.9% [P<0.01]). Positive likelihood ratio for distal cancer was 26.7 (95% CI 19.4-36.6) with FIT and 6.5 (4.3-9.6) with gFOBT. Positive likelihood ratio for distal adenomas ≥1 cm was 11.0 (7.9-15.3) with FIT and 4.4 (3.5-5.5) with gFOBT. This measure summarizes how many times more likely patients with the disease will test positive compared with patients without the disease.

In summary, the sensitivity and PPV of FIT for detecting CRC and AA compared with a standard gFOBT is superior. Differences on specificity are not so relevant. Positivity rates for FIT using the manufacturer’s standard cut-off level in hemoglobin concentration are higher than for gFOBT.

In a review and meta-analysis {10} seven diagnostic cohort studies in diagnostic patients scheduled for colonoscopy are included. The pooled PPV for detecting advanced colorectal neoplasm was significantly higher for FIT than for gFOBT (0.41 vs 0.29, P < 0.01). The sensitivity of FIT (0.67, 95% CI 0.61–0.73) was superior to that of gFOBT (0.54, 95% CI 0.48–0.60), as were the specificities (0.85, 95% CI 0.83–0.87 vs 0.80, 95% CI 0.78–0.82). Figure shows the SROC for FOBT in diagnosing advanced colorectal neoplasm of diagnosed patients, which indicates the mildly higher diagnostic accuracy of FIT.

Figure 1. Summary receiver operating characteristic curve (SROC) showing the diagnostic precision of guaiac-based fecal occult blood test (gFOBT) as Area Under the Curve (AUC) 0.7677, was lower than that of immunochemical fecal occult blood (iFOBT) as AUC 0.8241, for detecting advanced colorectal neoplasm in patients scheduled for colonoscopy.

From: Zhu MM, Xu XT, Nie F, Tong JL, Xiao SD, Ran ZH. Comparison of immunochemical and guaiac-based fecal occult blood test in screening and surveillance for advanced colorectal neoplasms: A meta-analysis.  Journal of Digestive Diseases, 2010; 11 (3): 148-60. 

Please refer to EFF 20

We identified 5 systematic reviews {10,15,16,17,18} and 3 additional diagnostic cohort trials {19,20,21} directly comparing FIT vs gFOBT and they are listed in table 9 with R-AMSTAR and risk of bias results. Data reported on accuracy measures are presented in the relative column of above mentioned table, starting from the more robust available evidence.

Overall 6 out of the 8 studies in the table conclude that FIT is more accurate and preferable to gFOBT for CRC screening.

The most recent and high quality review {15} analyses the performance characteristics of FIT compared with gFOBT, including two randomized control trials {11,12} and two observational studies{13,14}. In summary, the sensitivity of FIT for detecting CRC and AA compared with a standard gFOBT is superior. In the two randomized control trials, specificity was decreased for CRC and Advanced Adenoma when using FIT compared with gFOBT. On the other hand, these two studies reported higher advanced neoplasia detection rates for FIT compared with gFOBT. The PPV for detecting CRC and Advanced Adenoma using FIT is not different from the standard gFOBT. In general, the positivity rates for FIT using the manufacturer’s standard cut-off level in hemoglobin concentration are higher than for gBOBT. Please refer to Table 9 for values of accuracy measures.

Overall, FIT performance is superior to the standard gFOBT for the detection of CRC and adenomas. FIT has additional important advantages compared to gFOBT: higher screening participation rates, potential for automation in the laboratory and to select the cut-off level of hemoglobin concentration that defines a positive test. However, the following potential disadvantages are: greater specimen instability and possibly higher positivity rates.

No merging of available data has been performed do to the wide variability in settings and presented outcomes.

Need for further research:

• More well-designed randomized controlled studies directly comparing guaiac and FIT.
• The use the Standards for Reporting of Diagnostic Accuracy guidelines is recommended for reporting future diagnostic accuracy studies.
• Studies should ideally recruit a representative screening population, use colonoscopy to confirm diagnosis regardless of the FOBT result, measure the detection of CRC and adenomas and report the results separately and combined, and allow outcome assessors access to clinical information that would be available in practice, but blind them to other information.
• Specimen instability issue must be considered in each setting.
• The type of FIT and associated costs, the appropriate haemoglobin cut-off to use, and the capacity for follow-up by colonoscopy or flexible sigmoidoscopy may contribute to deciding if FIT is an appropriate CRC screening tool.

Please refer to EFF 20

The reference standard used in most reviews was colonoscopy {10,15,17,22}. Burch et al reported that one study was a diagnostic cohort study in which 3090 patients underwent colonoscopy and an unspecified immunochemical FOBT: for the detection of all neoplasms, sensitivity was 53% and specificity 99.6%; for the detection of CRC, sensitivity was 52.6% and specificity 87.2% {17}.

We found one systematic review reporting accuracy measures for colonoscopy among a total of five colorectal cancer screening methods {22}. It included 130 articles in total (of these 20 were relative to colonoscopy) and the reported mean ± standard deviation sensitivity of colonoscopy for cancer and for large polyps (≥10mm) was respectively 94.7 ± 4.6 % and 92.5± 6.2 % (compared to FOBTs 45.7 ± 26.5% and 18.5 ± 11.8%). Instead the overall specificity of colonoscopy for detecting CRC was 99.8 ± 0.2% (compared to FOBTs 87.6 ± 11.4%). Colonoscopy has the highest sensitivity and specificity of the selected screening methods.

In the remaining reviews the results were not clear. Nevertheless, one of them{15} reported results about one study also included in this review. Park 2010 et al{13} implemented a prospective study in a large population of average- risk people in which everyone underwent colonoscopy after having FIT and gFOBT: confirmed with better evidence the observations of others that FIT has a higher sensitivity for detecting advanced colorectal cancers than gFOBT, and has an acceptable specificity that significantly reduces the need for colonoscopic evaluation in the screened population. FIT results were compared directly with colonoscopy results: the positive rate of gFOBT in patients with adenomas did not differ from the patients with normal colonoscopies (8.0 % vs. 7.3 %); however, the positive rate of FIT at the 75 and 100 ng/ml thresholds was higher in patients with adenomas compared with that of patients with normal colonoscopies (16.9 % vs. 7.5 %, and 14.6 % vs. 7.3% ( P < 0.001 and P = 0.002), respectively.

Further literature research could be done on colonoscopy accuracy measures to gain a more comprehensive view, although most of the studies relative to accuracy measures of FOBTs refer to colonoscopy as the reference standard but do not report what these measures are for colonoscopy itself.

Please refer to EFF 20

We found a total of 7 studies relative to cut-off values for the amount of fecal blood that have attempted to define an optimal cut off value or have adopted producers indications and are here below described.

It is know that the positivity rate, specificity and the detection rate of advanced neoplasia varied with the cut-off level. A high-level quality review performed the analysis using different cut-off values in the meta analysis, and the superiority of FIT in the detection of advanced neoplasm was not significantly influenced. Ultimately, data extracted at a cut-off value of 75 ng/mL were considered as an acceptable trade-off between the detection rate and the number needed to scope {10}. Another review reported on 4 studies assessing FITs performances at multiple haemoglobin concentrations cut-off levels that differ from manufacture’s recommendations: in general, increasing the cut-off level of haemoglobin concentration the positivity rate decreased and the specificity and PPV increased {15}.

The faecal haemoglobin concentration at first screening predicts subsequent risk of incident colorectal neoplasia: the adjusted hazard ratios increased from 1.43 (95% CI 1.08–1.88) for baseline faecal haemoglobin concentration of 20–39 ng/mL, to 3.41 (2.02–5.75) for a baseline concentration of 80–99 ng/mL (trend test p<0·0001), relative to 1–19 ng/mL {23}. Nevertheless, findings needs to be validated for each kit separately, with a longer term follow-up, since colorectal neoplasia typically takes 10 years to develop, and using a large, population-based longitudinal follow-up study {23}.

Furthermore, f-Hb is related to severity of colorectal neoplastic disease: median f-Hb concentration was higher in those with cancer than those with no (p<0.002) or non-neoplastic (p<0.002) pathology, and those with LRA (p=0.0001); polyp cancers had lower concentrations than more advanced stage cancers (p<0.04). Higher f-Hb was also found in those with HRA than with LRA (p<0.006), large (>10 mm) compared with small adenoma (p<0.0001), and also an adenoma displaying high-grade dysplasia compared with low-grade dysplasia (p<0.009); f-Hb was significantly higher in those with a large compared with a small adenoma (p<0.0001){24}. Nevertheless, these results could be limited by the fact that false negative f-Hb were not taken into account and only participants with a positive result were referred for colonoscopy.

The cut-off level increases detection both for haemoglobin and haemoglobin-haptoglobin: when varying the cut-off level from 2 mcg/ g of stool (recommended by the manufacturer) to 14 mcg/g of stool, sensitivities for advanced adenomas and large adenomas ( ≥ 1 cm in diameter) ranged 40-24 % and 50-30 % for haemoglobin, and 33-12 % and 41-13 % for haemoglobin-haptoglobin, respectively, whereas specificities ranged 90–97 % for hemoglobin and 91–99 % for haemoglobin-haptoglobin; at cutoff values of 6 mcg/g of stool for hemoglobin and 4 mcg/g of stool for haemoglobin-haptoglobin, the specificity was ~ 95 % for both tests {25}.

A major advantage of FIT is recognized to be the automated and easier to interpret and furthermore, it measures the concentration of haemoglobin in the buffer, thus making it possible to choose the cut-off value. Nevertheless, the effect of different cut-off level in different FIT kit cannot be detected because manufacturers quote the concentration of haemoglobin not in the faeces, but in the buffer solution and this varies between different devices. Therefore, simple comparisons of cut-offs were not possible {19}.

Cut-off level detection is also linked to the colonoscopy capability: when colonoscopy capacity was unlimited, the optimal screening strategy was to administer an annual FIT with  a 50 ng/mL haemoglobin cut off level in individuals aged 45–80 years and to offer colonoscopy surveillance to all  individuals with adenomas. When colonoscopy capacity was decreasing, the optimal screening adaptation was to first increase the FIT haemoglobin cut-off value to 200 ng haemoglobin per mL and narrow the age range to 50–75 years, to restrict colonoscopy surveillance, and finally to further decrease the number of screening rounds {26}.

Please refer to EFF 20.

A high-quality review indicated that sensitivities were higher for the detection of CRC, and lower for adenomas, in both the diagnostic cohort and diagnostic case–control studies for both guaiac and immunochemical FOBTs {17}. Another review with lower quality due to unclear design and quality assessment of selected studies, compared sensitivity and specificity of the colorectal cancer mass screening methods: colonoscopy was reported as the one with best sensitivity and specificity while fecal occult blood test with the lowest. The mean ± standard deviation per patient sensitivities and specificity of colonoscopy respectively 94.7 ± 4.6 % and  99.8  ±  0.2% (compared to FOBTs 45.7 ± 26.5% 87.6 ± 11.4%) {22}.

A large population study found that the sensitivity of FIT for non-advanced adenomas, advanced adenomas, and cancer was 10.6%, 28.0%, and 78.6%, respectively. The sensitivity of FIT for advanced polypoid neoplasm (31.1%) was significantly higher than that of nonpolypoid ones (21.1%) (P <.001){27}. Furthermore, the sensitivity of FIT was in relation to neoplasm stage: FIT sensitivity showed stage-dependence and was 28.0% for advanced adenomas, 73.9% for invasive cancer, 66.7% for Tis plus T1 cancers, and 100% for T2 to T4 cancers (P for trend < .001){27}. The specificity was similar in relation with stage: 92.8% for invasive cancer, Tis plus T1 cancer and T2-T4 cancer.

Finally, the sensitivity of FIT for advanced neoplasms was in relation to location and morphology: the sensitivity was significantly lower for proximal polypoid advanced neoplasms compared with distal ones (27.7% vs 31.6%; P < .001) and proximal nonpolypoid advanced neoplasms compared with distal ones (16.2% vs 24.3%; P < .001) {27}. The trend was similar when proximal and distal, polypoid and nonpolypoid advanced adenomas were compared. For invasive cancers, although there was a trend toward lower sensitivity for proximal lesions, the result was not statistically significant {27}.

The I-FOBTs were significantly better than the G-FOBTs in detecting both cancers and advanced adenomas. The detection of cancers was at least twice as high with the I-FOBT as with the G-FOBT, and the number of advanced adenomas was about three to four times as high{19}. The same study also assessed detection according to stage of cancers at diagnosis: the proportion of Tis and stage 1 cancers was higher with I-FOBTs than with the G-FOBT. The differences between I-FOBTs and G-FOBTs, however, were not significant{19}. However, results need to be validated with cut off levels assessed in the faeces and not in the buffer solution {19}.

When applied on as second round test, the results reported here show that, despite a significant decrease in the PPV for CRC, a substantial number of significant lesions were detected; this applies more to advanced adenomas than to cancer cases and appears to be independent of the type of test used in the first round (guaiac FOBT or FIT) {28}.

FITs capability of reliably ruling in or out adenomas and CRC depends not only on its accuracy measures, but also on threshold and appropriate Mean Sejourn Time. Both of these issues need further research. Also refer to research question EFF15 for other factors influencing accuracy measures.

Please refer to EFF 20.

Many factors affecting the FITs accuracy have been studied. These are reported in the following table.

Effect of variations of different factors on fecal blood detection immunochemical screening 

* Grazzini G, Ventura L, Zappa M, et al. Influence of seasonal variation in ambient temperatures on performance of immunochemical faecal occult blood test for colorectal cancer screening: observational study from Florence district. Gut. 2010;59:1511– 1515.

Please refer to EFF 20.

The development of automated systems for the interpretation of the test has increased the advantage of FITs. Accurate interpretation of gFOBTs is not easy and requires well-run laboratories. An automated FIT is easier to interpret, and minimizes human error in test processing, thus making it a more objective laboratory test with excellent quality control. Furthermore, it measures the concentration of hemoglobin in the buffer, thus making it possible to choose the cutoff value. It is also possible to reinterpret the test in case of a technical problem {19}.

Direct comparison between quantitative and qualitative immunochemical fecal occult blood tests (FOBTs) has been studied. One cohort study reported that quantitative FITs offers advantages in terms of transparency and flexibility regarding the positivity threshold (e.g., specificity can be oriented toward available colonoscopy resources or personal risk profiles) and in terms of a higher level of standardization regarding test analysis and interpretation {25}.

These findings are also confirmed by another cohort study that reported a positivity rates of 8.1% for the qualitative and 2.5% for the quantitative FIT. The detection rate was 5.2% for the qualitative and 14.4% for the quantitative FIT. The odds ratio of a “suspicious cancer and cancer” versus a “normal” result was 2.73 (95% CI=2.22–3.35) for the quantitative compared to qualitative FIT {33}.

Another study about inter-observer variability in interpretation of 5 visually read FOBTs methods (standard guaiac-based method and four immunochemical methods)  reported  no cases of observer variability except for Hemoccult ITC test this was only minimal (on 1 sample 2 observers recorded a faint band at the cut off and one called the test negative){31}.