Number of stool specimens

Several studies have now examined the influence of the number of samples used for testing on clinical sensitivity and specificity. Allison takes any positive result from 3 stool samples measured using FlexSure OBT as an indication for referral and shows higher sensitivity for cancer than studies using single stool samples (Allison et al. 2007). Unsurprisingly other studies show agreement with that conclusion (St John et al. 1993; Allison et al. 1996; Knaani & Samuel 1997; Nakama et al. 1999; Greenberg et al. 2000; Nakama, Zhang & Fattah 2000; Rozen, Wong et al. 2003). Nakama et al. using Monohaem, showed sensitivities of 89% for cancer with 3 stools compared with 56% for a single stool (Nakama et al. 1999).

Using Hem-SP, Morikawa showed low sensitivity for cancer using a single-day sample (Morikawa et al. 2005). Rozen et al. (2006) used 3 stools for the OC-Sensor which contrasts with 2-day samples used in Japan (Nakama, Zhang & Fattah 2000) and 1-day biennial testing performed in Italy (Castiglione et al. 2002). The relative insensitivity in the Italian study to lesions in the proximal bowel (16.3 vs 30.7%) raises further doubts about the use of a single-day sample. In a study using OC-Sensor in an at-risk population, Levi et al. (2007) took numeric measurements from three samples and used the highest concentration of the three as the discriminating factor. Recent studies have taken the average concentration from 2 stool measurements as the discriminating parameter, an approach that reduces the positivity rate. 

The use of different cut-off limits and different numbers of stool samples illustrates how programme algorithms can manipulate clinical sensitivities and specificities for the lesions of interest. Chen describes the use of a cost-effectiveness model as a method of determining the optimal cut-off concentration for an iFOBT (Chen et al. 2007). In the study by Levi et al. (2007) using an iFOBT OCMicro, a scatter plot of 2 consecutive samples showed that of those with cancer or adenomas, 21 of 91 had elevated or markedly elevated faecal blood in one sample but were normal in the other. This is further evidence of intermittent or variable bleeding, sample heterogeneity or poor sample technique that will reduce clinical sensitivity. Imperiale (2007) commenting on the paper by Levi in his editorial in Annals of Internal Medicine (Levi et al. 2007), speculated that concentration-related clinical sensitivity and specificity could be used to determine post-test risk. If risk was related to subject age or sex, this would provide more sophisticated criteria for colonoscopy referral than is currently used. 

Optimising clinical performance using test cut-off limits & algorithms

Cut-off limits 

Until recently it has not been possible to adjust the analytical sensitivity of FOBT tests. This is still not possible for existing gFOBTs, with the exception of the simple adjunct of hydrating the specimen prior to testing with Hemoccult SENSA. With Hemoccult SENSA, hydration increases test sensitivity at the expense of specificity, thereby increasing the false positive rate (Mandel et al. 1993; Ransohoff & Sandler 2002). Hemoccult and Hemoccult SENSA have been compared in two large studies (Mandel et al. 1993). As a result of rehydration, the rate of positive results increased more than fourfold, from 2.4 to 9.8%. Sensitivity increased from 80.8% to 92.2% while both specificity and PPV decreased (specificity: 90.4% rehydrated and 97.7% non-rehydrated. PPV: 2.2 rehydrated and 5.6 non-rehydrated). In the study by Levin, Hess & Johnson (1997) the positivity rates were 5% and 14.6% and PPV 14% and 7% respectively for the non-rehydrated and the rehydrated. Rehydration using Hemoccult SENSA increases clinical sensitivity and decreases specificity and positive predictive value. The high positivity rate of this approach renders it unsuitable for population screening.

With iFOBTs that provide a numeric result, it is possible to adjust the cut-off limit to obtain an acceptable compromise between clinical sensitivity and specificity. This manipulation can provide an adequate detection rate from an acceptable cohort of subjects invited for colonoscopy. Several recent papers have addressed the issue of modifying the faecal haemoglobin cut-off limit of iFOBTs including the following studies (Sieg et al. 1999; Castiglione et al. 2000; Nakama, Zhang & Zhang 2001; Castiglione et al. 2002; Launoy et al. 2005; Vilkin et al. 2005; Rozen et al. 2006; Chen et al. 2007; van Rossum et al. 2009). The data are summarised in Table 4.5. By increasing the positive cut-off limit, the test sensitivity and positivity rate decreases and specificity and positive predictive values for colorectal cancer detection increase. It must be appreciated that these studies used different commercial products with different analytical characteristics, and therefore simple comparisons can be misleading. 

Chen found an analytical cut-off limit range of 100–150 ng/mL faecal haemoglobin in an iFOBT to provide an acceptable balance between sensitivity and specificity (Nakama, Zhang & Zhang 2001; Chen et al. 2007). Increasing the cut-off limit to 300 ng/mL brought an increase in specificity that was small for the corresponding decrease in sensitivity and detection of cancers. A recent study by Rossum of 6157 50–75 year old Dutch participants and using a single OC-Sensor collection and OC-Micro analyser concluded that dropping from the standard 100 ng/mL cut-off to 75 ng/mL brought ‘optimal’ results and may be recommended for population screening in the Netherlands (van Rossum et al. 2009). This study also concluded that where colonoscopy capacity is insufficient, a cut-off up to 200 ng/mL would result in minimal false negatives for cancer although more for advanced adenoma. Policy makers are faced with an arbitrary decision based on the balance between missed cancers/advanced adenomas and the cost of colonoscopy 

European guidelines for quality assurance in colorectal cancer screening and diagnosis

Comparative clinical performance - gFOBT and iFOBT

In the USA, Allison et al. (2007) prospectively compared two types of FOBTs, a sensitive gFOBT (Hemoccult SENSA) and a manual iFOBT (Flexsure). A large number of patients (7394 subjects were eligible for the study) were requested to perform both tests. All patients positive for either FOBTs were invited to have a total colonoscopy, whereas all patients negative to FOBT were advised to have a sigmoidoscopy. All cancers occurring during the two years following the test were identified, so that it was possible to estimate the absolute sensitivity and specificity for detecting advanced neoplasms in the left colon within two years after the FOBT screening for the two tests administered separately and in combination. The sensitivity for detecting cancer was 81.8% (95% CI = 47.8% to 96.8%) for the iFOBT and 64.3% (95% CI = 35.6% to 86.0%) for the gFOBT. The sensitivity for detecting distal advanced adenomas was higher for gFOBT than for iFOBT 41.3% (95% CI = 32.7% to 50.4%) vs 29.5% (95% CI = 21.4% to 38.9%). PPV was much higher for iFOBT than for gFOBT for distal cancer (5.2% and 1.5% for iFOBT and gFOBT respectively) and for advanced adenomas (19.1 and 8.9% for iFOBT and gFOBT respectively). The authors concluded that iFOBT has high sensitivity and specificity for detecting left-sided colorectal cancer and that it may be a useful replacement for the gFOBT.

The study by Dancourt et al. (2008) compared the performance of a 3-day gFOBT and 2-day iFOBT in 17 215 subjects. For 1205 subjects who participated and had colonoscopy, the PPV for the guaiac and immunochemical test was respectively 5.9% v 5.2% for cancer and 27.2% and 17.5% for adenoma.  

The study by van Rossum et al. (2008) represents a milestone in the comparison of gFOBT with iFOBT, being the first randomised trial in a population based screening setting. A large number of people (20 623) aged 50–75 years were randomised to either gFOBT (Hemoccult II, Beckman Coulter Inc. Fullerton, CA, USA) or iFOBT (OC-Sensor). For iFOBT, the standard cut-off of 100 ng/mL was used. iFOBTs showed higher compliance than did gFOBTs (56.9% vs 46.9% respectively p<.01). The positivity rate was significantly higher in iFOBTs compared to gFOBTs (5.0% vs. 2.4% respectively, p<0.01). Cancer or advanced adenomas were found, respectively, in 11 and 46 of gFOBTs and in 24 and 121 of iFOBTs. The detection rate per 1000 examinations for cancer was 71% higher in iFOBT compared to gFOBT; the detection rate per 1000 examinations for advanced adenomas was 106% higher in iFOBT as compared to gFOBT. The number-to-scope to find 1 cancer or 1 adenoma was comparable between the tests, with the PPV not statistically different. In conclusion, iFOBT compared to gFOBT demonstrated a higher detection rate with a similar PPV.

The results of these five studies are consistent with data from the first European screening programmes. The UK Pilot study adopted Hema-screen, a conventional non-rehydrating gFOBT, using duplicate samples on 3 consecutive stools extended to 2 further sets of 3 stools if indicated. This UK pilot study gave a positivity rate during the first round of 1.9%. The Detection Rates (DR) for cancer and neoplasia (cancer and advanced or non-advanced adenoma) were 1.62 in 1000 and 6.91 in 1000 respectively. The PPV for neoplasia was 46.9% in England and 47.3% in Scotland (UK Colorectal Cancer Screening Pilot Group 2004). 

Comparative clinical performance - gFOBT and iFOBT

Many studies comparing iFOBT and gFOBT have been performed in the last 8 years, and several systematic reviews of the literature have been undertaken more recently. 

In 2007 Kerr published a systematic review by the Health Technology Assessment (NZHTA) of New Zealand which had the aim of identifying the international evidence for the clinical and cost effecttiveness of screening tests for colorectal cancer (Kerr et al. 2007). This review included all primary research published as full original reports and secondary research, systematic reviews and meta-analyses published since November 2004. It also included seven eligible primary research papers (Rozen, Knaani & Samuel 1997; Rozen, Knaani & Samuel 2000; Saito et al. 2000; Zappa et al. 2001; Cheng et al. 2002; Cole et al. 2003; Ko, Dominitz & Nguyen 2003) and five eligible secondary research papers; Australian Health Technology Advisory Committee (AHTAC) (1997), Conseil d'Évaluation des Technologies de la Santé du Quebec (2000), Canada, Craven UK (Craven 2001), Young World Health Organization and World Organization for Digestive Endoscopy (Young et al. 2002), Piper Blue Cross Blue Shield Association Technology Evaluation Center US

The review concluded that “there is limited definitive evidence regarding superior immunochemical FOBT performance over the guaiac tests. However, evidence from cross-sectional studies suggests that the immunochemical test HemeSelect, Beckman Coulter Inc. Fullerton, CA, USA… is comparable, or superior, to guaiac testing… The conclusions on this topic should be revisited if further reliable evidence on the comparative performance of screening FOBTs becomes available”.

A similar conclusion was reached in a systematic review commissioned by the UK NHS and undertaken by the Centre for Reviews and Dissemination of the University of York in 2007 (Burch et al. 2007) which examined the literature until 2004. The review included 59 studies 39 evaluated gFOBTs, 35 evaluated iFOBTs and one evaluated sequential FOBTs. It concluded that there was no clear evidence from direct or indirect comparisons to suggest that guaiac or immunochemical FOBTs performed better. However amongst iFOBTs, Immudia-HemSP (now Hem-SP) appeared to be the most sensitive and specific. 

In the four years since 2004, six studies comparing the performance of gFOBT and iFOBT have been published (Levi et al. 2006; Smith et al. 2006; Allison et al. 2007; Guittet et al. 2007; Dancourt et al. 2008; van Rossum et al. 2008). Some further studies have investigated the accuracy of iFOBTs which, although without a direct comparison with gFOBTs, confirmed the performance of iFOBTs which was reported in the following studies 

In Australia, Smith et al. (2006) performed a paired comparison of an iFOBT (InSure) with a sensitive gFOBT (Hemoccult SENSA); 2351 asymptomatic and 161 symptomatic subjects were requested to perform both FOBTs. iFOBT returned a true-positive result significantly more often in cancer (n = 24; 87.5% vs. 54.2%) and in significant adenomas (n = 61; 42.6% vs. 23.0%) while the false-positive rate for any neoplasia was marginally higher with the iFOBT than the gFOBT (3.4% vs. 2.5%; 95% CI of difference, 0–1.8%): the PPV for cancer and significant adenomas was slightly better for iFOBT (41.9% vs 40.4%). 

Description of terms used to describe test effectiveness

Where, a are true positive, b are false positive, c are false negative and d are true negative

Sensitivity = a/(a+c) 

Specificity = d/(b+d) 

PPV = a/(a+b) 

“True” in true positive, is an abstract concept because in practice a reference standard must be adopted. For colorectal cancer screening, true is usually defined by the outcome of total colonoscopy, the best practical diagnostic procedure we have though it does not have a sensitivity of 100%. In a clinical setting it is not always possible to perform a total colonoscopy on all subjects who have negative screening tests, so it is difficult to estimate the number of false negatives (c) and true negatives (d). The difficulty of estimating false negative has a great impact on sensitivity but much less so on specificity. In fact (c) is a number much lower than (d), so that the sum c+d (i.e. the number of negatives to the test) is a small overestimate of d.

For sensitivity, (c) is a significant proportion of (a+c), so that it is necessary to have a direct estimate of the number of false negatives. Very often this estimate is obtained by measurement of the interval cancers (i.e. the number of colorectal cancers that are diagnosed in subjects negative to the test during defined interval of time). Clearly the reliability of the estimated number of false negatives will depend on the time interval, and that will increase as time elapses. It is therefore important when comparing estimates of sensitivity obtained in this way to verify that the time interval used is the same.

The ideal theoretical approach to estimating cancer-screening performance would be to obtain the disease status using a “gold-standard” method that is independent of the screening method. For colorectal cancer, the disease status is usually determined from a histological examination of biopsy specimens of those with positive test results, because it is not ethically acceptable to collect biopsies from all individuals undertaking a screening test. The sensitivity and specificity of screening test are therefore usually estimated using interval cancers. As initially described by Day (1985) interval cancers will not include slow-growing cancers missed by the test and not evident between two screening events (therefore clinical sensitivity will be overestimated). Conversely, interval cancers will include fastgrowing cancers not present at the time of the screening test, but developing during the interval period (thus underestimating clinical sensitivity). This limitation is common to all screening procedure evaluations. 

Clinical performance

Description of terms used to describe test effectiveness 

gFOBT screening has been proven to be effective in reducing colorectal cancer mortality (Hewitson et al. 2007). In randomised trials the reduction in cause-specific mortality ranged from 15% (Hardcastle et al. 1996) to 33% (Mandel et al. 1993). Such a large variance in mortality can be explained by test differences, different numbers of faecal samples, different intervals between invitation cycles (one-year or two-year) and different responses to invitation associated with the characteristics and composition of the population screened. The sensitivity and specificity quoted for a test will therefore be influenced both by the test’s analytical characteristics and the context in which the test is used and evaluated.

gFOBTs come in two forms, the conventional form with normal sensitivity and the more sensitive variety, Hemoccult SENSA, in which the sample is hydrated before analysis. Hemoccult SENSA performs quite differently from the gFOBTs used in European trials (Hardcastle et al. 1996; Kronborg et al. 1996) and is both more sensitive and less specific. Comparison of the clinical performance of gFOBT and iFOBT is complex because iFOBTs can have different levels of specificity and sensitivity indeed they may have variable positive cut-off concentrations. Changes in cut-off concentrations result in different clinical performance characteristics.

Although only one population-based RCT has been described with iFOBT (van Rossum et al. 2008), the many published diagnostic accuracy studies provide information on the comparative ability of current tests to distinguish subjects with or without colorectal cancer and adenoma and can be considered an acceptable indication of the satisfactory performance of iFOBT in population screening (Burch et al. 2007). 

Quality Assurance

 Quality assurance of gFOBT testing  

Whilst an immunochemical test is recommended, programmes that adopt a traditional guaiac test need to apply additional laboratory quality procedures. To minimise variability and error associated with visual test reading, including manual results input, the following procedures should be considered

o Use of appropriate temperature for artificial lighting and neutral-coloured walls in the reading laboratory; 

o Use of a national laboratory training programme to prosper consistency of interpretation; 

o A blinded internal QC check each day for each analyst prior to commencing testing;

o Adoption of a monitoring programme to identify operator related analytical performance (e.g. positivity variability and bias); and 

o Double entry of test results 

 Quality assurance of iFOBT testing  

Consistency in analytical performance must be assured by the adoption and application of rigorous quality assurance procedures. Manufacturer’s Instructions for Use must be followed. Laboratories should perform daily checks of analytical accuracy and precision across the measurement range with particular emphasis at the selected cut-off limit. Rigorous procedures need to be agreed and adopted on how internal quality control data is interpreted and how the laboratory responds to unsatisfactory results. Performance data, both internal quality control and external quality assessment data, should be shared and reviewed by a Quality Assurance team working across the programme. Sufficient instrumentation should be available to avoid delays in analysis due to instrument failure or maintenance procedures

External quality assessment  

A European external quality assessment scheme should be developed to facilitate Europe-wide quality assurance of occult blood testing and enhance the reproducibility of testing within and between countries providing population screening

 Outcome monitoring  

All aspects of laboratory performance in respect of the screening test should be part of a rigorous quality assurance system. Uptake, undelivered mail, time from collection to analysis, analytical performance (internal QC and external QA), positivity rates, lost & spoilt kits and technical failure rate, technician performance variability and bias should each be subject to rigorous monitoring

Quality of information 

 The proportion of unacceptable tests received for measurement is influenced by the ease of use of the test kit and the quality of the instructions for use. This proportion should not exceed 3% of all kits received; less than 1% is desirable  

FAECAL OCCULT BLOOD TESTING

Guaiac-based faecal occult blood tests 

 Guaiac-based faecal occult blood tests have proven characteristics that make them suitable for population screening. They lack the analytical specificity and sensitivity of immunochemical tests, their analysis cannot be automated and the concentration at which they turn from negative to positive cannot be adjusted by the user. For these reasons guaiac-based tests are not the preferred test for a modern population screening programme, although depending on local labour costs, the mechanism of kit distribution and collection and reduced sample stability in immunochemical testing, they might prove more practicable and affordable than immunochemical testing 

Immunochemical faecal occult blood tests

Immunochemical tests have improved test characteristics compared to conventional guaiac-based tests. They are analytically and clinically more sensitive and specific, their measurement can be automated and the user can adjust the concentration at which a positive result is reported. Immunochemical tests are currently the test of choice for population screening; however, individual device characteristics including, ease of use by the participant and laboratory, suitability for transport, sampling reproducibility and sample stability are all important when selecting the iFOBT most appropriate for an individual screening programme

DNA and other related new markers  

Only tests for blood in faeces have been demonstrated to have the necessary characteristics to be suitable for population screening. DNA and other related new markers are currently unsuitable for screening, either singly or as members of a panel of tests

Sample stability between collection and analysis  

Whilst a maximum period of 14 days between collection and analysis is quoted for many guaiac faecal occult blood tests, that quoted for immunochemical tests is significantly shorter. Until more stability data are published, screening programmes should adopt the conditions and period of storage described in manufacturer’s Instructions for Use having determined that they are appropriate for local conditions which might expose samples to high temperatures for long periods of time

CRC mortality rates

It will be several years before the impact of population screening on CRC mortality becomes observable, and many more years before the full effect is achieved. The timing of a reduction depends on the natural history of the disease, and the ‘lead time’ due to screening (i.e. the time by which screening advances the date of diagnosis) as well as on the time taken to cover the target population. It will also depend on the quality of screening. 

Methods to evaluate the impact of screening on CRC mortality include analyses of population trends, cohort studies (aggregated or individual-based) and case-control studies.

Population trends 

Mortality from CRC has been decreasing in many European countries since the mid 1990’s, (Karim-Kos et al. 2008). Analyses of the routinely produced age-gender specific population rates over time will be subject to limitations due to the dilution of the effect of screening from deaths occurring in cases diagnosed prior to the introduction of screening, and/or at an age below which invitations begin. This can be overcome by use of refined CRC mortality rates in which such deaths are excluded. However, the rates will also be confounded by other factors such as cohort effects on underlying incidence, and by the effects of improvements in treatment and/or the stage of diagnosis of symptomatic disease on survival and mortality. Thus whilst a lack of any reduction in population mortality rates several years after the introduction of a screening programme should be a cause for concern, it is difficult to use such trends to quantify the effect, and attempts to do so should take account of the factors discussed above. 

Cohort studies 

In some settings, the introduction of population screening will have been phased in such a way as to facilitate comparisons of populations invited at different time points. Such a model has been used in Finland (see Ch. 2, Sect. 2.6.4). In the absence of such a system, comparisons can be made between geographical areas (regions invited/not invited to screening) or between the same population in different time periods before and after the introduction of screening. Both types of comparison are liable to possible bias due to underlying differences in the risk in the populations/time-periods. This may – under certain circumstances – be compensated for by including also a comparison group from geographic areas where no invitational program existed from before the introduction of screening. Cohort studies using aggregated data need estimates of incidence in order to avoid dilution effect discussed above. 

These biases can be avoided by individual-based cohort studies in which deaths and cancer registrations are linked to screening histories.

Performing the test: dietary restrictions and number of samples

In order to reduce the probability of a false positive result, dietary restrictions are usually recommended when guaiac-based tests are used. Retesting of subjects with a positive test (possibly with dietary restrictions being recommended) represents an alternative option adopted in some programmes to deal with this problem. A review of 5 trials (10 359 participants overall) comparing Guaiac FOBT with and without dietary restriction found a significant difference in compliance in favour of testing without dietary restrictions only in the trial where restrictions were particularly extensive. Authors concluded that advice to restrict the diet and avoid NSAIDs and vitamin C does not substantially reduce completion rate except perhaps when the dietary restrictions are particularly extensive (Pignone et al. 2001). More recent randomised trials (Cole et al. 2003; Federici et al. 2005; van Rossum et al. 2008) have demonstrated that better compliance can be achieved using iFOBT compared to a guaiacbased test. These results are not explained by the nature of the test but by lack of dietary and drug restrictions and easier and more pleasant sampling methods. Indeed, dietary restriction was associated with a significant decrease in participation also among people offered iFOBT test, compared to controls receiving the same test who where not advised to control their diet

Summary of evidence 

 Compliance is affected by dietary restriction and number of stool samples to be collected. Compliance is found to be consistently higher when the test adopted does not require modification of a subject’s diet and sampling is limited to one bowel movement (I).  

Examination of the samples, test interpretation and reporting 

Detailed protocols on handling the stool samples must be available and followed. Identification and tracing of the sample through the entire process should be ensured by adopting appropriate labelling allowing the sample and patient’s ID code to be linked. Automated check protocols should be implemented in order to avoid mismatching of the results. All data, including test results, should have a regular backup system.

An operational definition for an inadequate screening test should be made explicit in the programme protocol, taking into account the characteristics of the test (i.e. the stability and the storage requirements of the tests) as well as the testing procedure adopted

Protocols should be in place to define the appropriate test and the algorithm used to classify a test result (as negative or positive). For quantitative or semi-quantitative iFOBTs, an explicit definition of cut-off levels for haemoglobin concentration should be defined. Protocols or rules for combining results when using multiple samples, the number of samples that are needed to evaluate the test result, etc. must be in place. When using a quantitative test, provision should be made to record the information concerning the actual amount of haemoglobin, both for tests classified as negative and for those classified as positive.

Some people may present with clinical conditions such as inflammatory bowel disease (Crohn’s disease or haemorrhagic recto-colitis), which may explain a positive FOBT result. In such cases, if no cancers were detected, then the screening result should be classified as negative for the purposes of the screening programme. These patients should then be referred for treatment in the appropriate clinical setting.  

Testing protocol

FOBT 

Delivery of kits and collection of stool samples

The test kit may be delivered by mail, at GPs’ offices or outpatient clinics, by pharmacists, or in other community facilities, and in some cases with the support of volunteers. There is no evidence that any of these strategies may have an impact on the proportion of inadequate samples, provided that clear and simple instruction sheets are included with the kit

The choice of the provider should aim to maximise accessibility, taking into account local conditions, settings and cultural factors. 

Mailing of the FOBT kit with instructions, together with the invitation letter and the information leaflet, is effective in increasing participation rates (Church et al. 2004; Segnan et al. 2005). These results are consistent with previous reports indicating that the GP’s letter and mailing of FOBT kits represent the most important factors for improving compliance (King et al. 1992). Mailing of the FOBT kit might not always represent a cost-effective strategy, if the baseline participation rate and the expected increase in participation are low. Compared to mailing a second FOBT kit to all non-responders, mailing a recall letter with a test order coupon resulted in a substantial decrease in the programme costs, but also in a significant decrease in participation (Tifratene et al. 2007). The authors of the trial suggested, however, that the spared costs might be allocated more efficiently to communication interventions that might have a higher impact on compliance. 

Several test providers close to the target population should be available when the subject is required to reach health or community facilities to get the kit. A recent study (Federici et al. 2006) showed that the time required to reach the test provider was the strongest determinant of compliance: OR (<15 minutes versus 15–30 or >30 minutes):0.8 (0.5–1.3) and 0.3 (0.2–0.7) respectively.

Volunteers or non-health professionals may also be involved in the distribution and collection of kits. Delivery of kits may represent in this case an additional opportunity for counselling, for conveying information about the programme and for providing instructions for test utilisation. Subjects contacted at home by a trained non-health professional who delivered the kit and collected the sample from the participant’s home showed a substantially higher completion rate of iFOBT, as compared to the group who received the kit by mail with an invitation from their primary care physician, (Courtier et al. 2002). 

Community volunteers, who have received some general training by the programme staff, have been involved in the kit distribution in the context of ongoing organised programmes and their involvement has been consistently associated with high participation rates (Zorzi et al. 2007). As no randomised comparison is available, it is difficult to dissociate their specific effect from other characteristics of the communities or target populations involved. Sustainability over time represents an important issue to be taken into account when planning to use volunteer support. 

The modalities adopted for stool collection, storage and shipping of the sample to the laboratory are mainly dependent on the characteristics of the test adopted, i.e. its stability at environment temperature. Based on these considerations mailing of the samples may be an option that can be implemented more easily for guaiac than for immunochemical tests, which need to be processed faster. Accessibility of the collection facilities remains an important goal, but the logistics of the sample han-dling may promote reducing the number of collection facilities in order to ensure an appropriate storage or timely shipping to the laboratories. 

Summary of evidence 

 There is no evidence that the proportion of inadequate samples may be affected by the provider used to deliver the kit, if clear and simple instruction sheets are provided with the kit (II - V).

 The time required to reach the test provider represents a strong determinant of compliance (II). Sending the FOBT kit together with the invitation letter may be more effective than sending a letter alone, but this strategy may not be cost-effective (II). 

The role of primary care providers

Primary health care providers can be effective media for improving awareness of the risk of cancer and of the benefits of screening, for increasing confidence in the screening test method and for countering the reluctance to collect faecal samples. In many European countries this provider is the general practitioner (GP), but other trusted health professionals, such as community nurses for example, may play a similar role. 

Primary health care providers should be trained to deliver evidence-based information on screening and there should be a consensus on the programme protocol before starting the programme. 

Role of GPs/family physicians 

The involvement of GPs in screening can be very effective in improving compliance, according to the findings of several studies from different countries (Launoy et al. 1993; Tazi et al. 1997; Grazzini et al. 2000; Brawarsky et al. 2004; Federici et al. 2006; Sewitch et al. 2007; Seifert et al. 2008), but the effect is dependent upon the GP's own willingness to get involved. The findings of studies conducted in the context of opportunistic screening showed that the probability of not receiving a GP recommendation for CRC screening was highest among those with a low socioeconomic status (SES) (Brawarsky et al. 2004; Wee, McCarthy & Phillips 2005; Klabunde, Schenck & Davis 2006; Schenck, Klabunde & Davis 2006). These findings suggest that inadequate provider counselling represents an important determinant of the SES gradient in screening uptake. Compliance was shown to be closely linked to practitioner motivation also in the context of organised programmes

Knowledge of GP attitudes and preferences is therefore crucial in enhancing participation. A study based on semi-structured questionnaires addressed to 32 GPs in England (Woodrow et al. 2006) indicated that for GPs to effectively promote screening they must have adequate information prior to the start of a screening programme. The evidence should be based specifically on the effectiveness of the screening programme, and information on the proportion of false negatives and the proportion of false positives. 

Interventions aimed to promote provider involvement  

Provider education has been identified as a potentially effective intervention to promote CRC screening utilisation, even if the implementation of organisational measures may be necessary to achieve an impact of educational efforts (Stone et al. 2002). This conclusion is supported by the results of recent experimental studies: educational seminars offered to physicians did not show an effect on rates of CRC screening (Walsh et al. 2005), while a reminder note to the physician to direct his patients to perform an FOBT was more effective than a mail reminder and as effective as a phone reminder for the patients.

Even if GPs are not delivering kits, or not collecting or reading the test cards, they should be aware of how the programme, and in particular the invitation scheme, is structured. They can advise noncompliers about screening, which is important for older people, or for those with lower socio-economic status, and they can offer counselling for patients with positive tests. To facilitate this task, GPs should receive the results of screening and assessment tests performed by their patients 

Summary of evidence 

 Primary health care providers appear to be effective media for improving awareness of the risk of cancer and the benefits of screening, and increasing confidence in and countering the reluctance to take the screening test (I). 

 Educational interventions are less effective than organisational changes in improving the impact of physicians’ counselling on their patients’ screening rates (I). 

Interventions to promote participation

A systematic review (Stone et al. 2002), assessed the effectiveness of the following on improving screening participation: regulatory and legislative actions (outside the medical care organisation), financial incentives for providers or patients, organisational change (changes in clinical procedures or facilities and infrastructures), reminders for providers and screenees, provider feedback, education and visual materials. The most effective was the implementation of organisational changes that made delivery of these services a routine part of patient care (establishing separate clinics devoted to screening, involving nursing or clerical staff in the delivery of services, adoption of monitoring and quality improvement approaches), reducing, or eliminating costs for the individual or establishing a system of reminders. 

Removing financial barriers

Experimental studies conducted in the context of breast cancer screening showed that reduced charges for screening are effective in encouraging uptake among disadvantaged groups (Jepson et al. 2000). Sending an FOBT with a postage-paid envelope for returning the sample resulted in a significantly higher uptake, compared to non-postage (Jepson et al. 2000). The return rate was highly significant for medically uninsured people in one of the studies (Miller & Wong 1993). Offering a free FOBT in addition to educational intervention was superior to the educational intervention alone in promoting completion of screening (Plaskon & Fadden 1995). Offering financial incentives to subjects invited for screening was not found to have an impact on participation 

Delivering information about screening 

Although the organisation of screening within health services emerges as the most important determinant of uptake, factors related to culture, values and beliefs may still play a role. Also, provision of information is clearly necessary to enable subjects to make an informed choice.

 Data from the National Health Interview Survey (NHIS) consistently indicate that lack of awareness of CRC represents one of the main determinants of the underutilisation of screening. 

Data from people recruited in the UK sigmoidoscopy trial (Wardle et al. 2004) who were requested to express their intention to attend screening suggest that part of the explanation of the socio-economic status (SES) gradient may be the difference in beliefs and expectations. Lower social groups evaluated the offer of a screening test, which had been publicised identically and was provided free of charge , at a convenient location and time, to all social groups, as being more frightening and less beneficial, than higher social groups. In England, with overall population participation at 60% despite free testing, the uptake rate of the FOBT programme is lower in deprived areas and among ethnic minorities (von Wagner et al 2009). Rural areas were shown to have a lower participation rate than urban areas (Launoy et al. 1993; Giorgi Rossi P. et al. 2005). 

Therefore, the way the population is informed about the potential benefits and harms of screening is of particular importance. Strategies aimed at improving population knowledge and awareness of CRC and screening should target health professionals as well as individuals

Information conveyed with the invitation 

A systematic review of methods aimed at enhancing screening rates concluded that educational interventions are less effective than organisational changes and should not be the first choice (Stone et al. 2002). Findings from more recent studies (Harris et al. 2000; Lipkus, Green & Marcus 2003; Robb et al. 2006; Costanza et al. 2007) support such a conclusion. When individuals interested in screening were requested to actively seek further information and a referral to screening from their providers, an information brochure was observed to have no impact, but the number of screening requests in-creased significantly when the GP delivered an FOBT request form together with the information pamphlet. 

 The content and format of the information material sent with the invitation may influence a subject’s decision to undertake screening.  An individually tailored interactive multimedia programme at the physician’s office seemed more efficacious in increasing readiness to undergo screening, as compared to the same intervention not individually tailored (Jerant et al. 2007). 

Interventions that use visual instruments to enhance appeal and clarity are more effective: adding illustrations about the polyp-cancer process and the removal of the polyps during FS to written material was associated with a significant increase in knowledge and understanding (Brotherstone et al. 2006). Culturally and linguistically appropriate approaches promoting FOBT can enhance screening practice in groups of low-income and less acculturated minority patients

Family history

People with a positive family history for CRC are sometimes considered for exclusion from screening programmes targeting average-risk people.

Implementing this option requires the adoption of procedures for identifying people with a positive family history and accurately collecting the information that is relevant to assess an individual’s level of risk. It is also necessary to ensure that an alternative organised programme is in place for this group of people.

Specific surveillance protocols based on colonoscopy at shorter intervals and starting at a younger age have been shown to be effective and are recommended for members of families with hereditary syndromes. However, it is still not clear if more intensive surveillance for people at moderate risk can achieve a favourable cost-benefit ratio (Sondergaard, Bulow & Lynge 1991; Benhamiche-Bouvier et al. 2000; Nakama et al. 2000; Johns & Houlston 2001; Church 2005; Baglietto et al. 2006; Butterworth, Higgins & Pharoah 2006; Menges et al. 2006; Cottet et al. 2007)

If an alternative option (i.e. access to a specific surveillance protocol) is not available, people with positive family history should not be excluded from a population-based screening programme as screening offers the opportunity of access to an intervention that may ensure protection for people who would not be otherwise be covered.

Furthermore, family history, in the absence of hereditary syndromes, does not represent an indication for changing standard surveillance protocols (see Ch. 9, Sect. 9.2.3.2, Rec. 9.13). In a recent study, the characteristics of the neoplasm rather than individual’s family history were found to be associated with the risk of recurrence among subjects not fulfilling the Amsterdam criteria. This suggests that these people could be considered at moderate risk of developing CRC and that surveillance intervals of more than five years may be appropriate in these cases (Dove-Edwin et al. 2005). Therefore, family history should not represent a criterion for exclusion from the screening programme, even for patients identified at the time of assessment. 

Barriers  

Several factors influencing participation have been identified related to individual’s characteristics, the setting and the organisation of the intervention and the knowledge, attitudes and practice of the provider (Vernon 1997; Jepson et al. 2000). The findings concerning the relative weight of these factors are not consistent across studies assessing determinants and barriers to participation. However, the variability of the reported findings is probably related to the different conditions under which the examined screening interventions have been implemented.

The organisation of screening within health services appears, in most countries, to be a major determinant of participation rate. Lack of insurance coverage and cost of the test have been identified as the main negative influences on participation for all screening interventions and tests. Also, lack of resources is the most likely explanation for the negative association of lower socio-economic status with completion of CRC screening tests

Knowledge and perceived benefits of screening, perceived risk of CRC and health motivation were associated with higher participation in most of the studies assessing the influence of these determinants. Worry about pain, discomfort, or embarrassment associated with the test, or fear of test results were also consistently associated with a lower attendance 

Gender and age differences in participation to CRC screening have also been reported; most studies have shown a trend to decreased participation among older people, although these findings have not been confirmed by all investigators. It has been reported that participation may be higher among women for FOBT screening and among men for endoscopy screening 

Support from a partner probably explains the positive association of marriage with screening uptake. This is more prominent in males. One reason for these findings could be that women have prior experience of screening (breast, cervix) and may therefore need less support to participate 

Implementing the screening programme

Organised CRC screening is a multi-step process including:

•  Identification of the target population; 
•  Recruitment of eligible subjects;
•  Delivery of screening test;
•  Reporting of screening test results; 
•  Reassurance of people with normal results and information on the timing of the next test;
•  Recall of people with unsatisfactory/inadequate screening test Follow-up of people with positive tests, i.e. diagnostic procedures and treatment needed, including a fail-safe system to make sure this actually happens; and
•  Registration, monitoring and evaluation of the entire programme.

Identifying and defining the target population 

Catchment areas and target populations must be clearly defined. The necessary data include unique identification for each person, such as name, date of birth, relevant health insurance or social security numbers, general practitioner (GP) where appropriate, and contact address. Population registers or registries can in general provide such data, but they must be updated regularly to account for population migration, deaths and changes in personal details. In those countries in which population registries are based on administrative areas of small size, communication between registries is essential. Suitable registries might include population, electoral, social security, screening programme, and health service registries. Incomplete or inaccurate registries can result in certain groups (such as transients or ethnic minorities) not being invited for screening.

If an accurate, complete and regularly-updated register of the whole target population does not exist, an administrative database that combines information from available registries for all people to be included in screening should be implemented for the purposes of the programme. The legal basis for access to such registries must be set up and all data protection measures should be implemented according to the national and European legislation. 

Inclusion and exclusion criteria  

The target population for a CRC screening programme includes all people eligible to attend screening on the basis of age and geographical area of residence. However, each programme may apply additional exclusion/inclusion criteria to identify the population eligible for screening. Potential reasons for excluding a subject from screening might include conditions in which offering the screening test is not appropriate, such as terminal illness (no benefit could be attained through screening), recent (the relevant period should be specified and justified) screening test (the expected benefit achievable by repeating the test might not outweigh the risks associated with the procedure), previous diagnosis of CRC or pre-malignant lesions (these patients should already be followed-up according to specific surveillance protocols, and their inclusion in screening might result in the offer of conflicting management options).

The extent to which such individuals can be identified and excluded from the target population will vary by screening programme: for some programmes it may not be feasible or desirable to identify every category of potential exclusion prior to invitation. 

The necessary information may be collected at the first personal contact with the screenee, i.e. at the time of a possible colonoscopy assessment in the case of FOBT programmes, or at the time of the screening exam for FS or colonoscopy programmes. 

Exclusion might alternatively be based on the information gathered through the GPs or other primary care providers, who may be requested to check the eligibility of their patients ear-marked for invitation.

If the screening policy allows for exclusions, the exact definition of the respective criteria should be given and exclusions should be carefully and routinely monitored for appropriateness and equity.  

CT colonography

CTC is a potential technique for CRC screening. With CTC, two- and three-dimensional digital images are constructed to investigate the presence of lesions in the colon and rectum. Studies on the impact of CTC screening on CRC incidence or mortality have not yet been conducted. Seven systematic reviews have been published between 2003 and 2008 on CTC performance characteristics in comparison to colonoscopy (Sosna et al. 2003; Halligan et al. 2005; Mulhall, Veerappan & Jackson 2005; Purkayastha et al. 2007; Rosman & Korsten 2007; Walleser et al. 2007; Whitlock et al. 2008). All metaanalyses and primary studies (Reuterskiold et al. 2006; Arnesen et al. 2007; Chaparro Sanchez et al. 2007) reported that sensitivity was low for small polyps and increased with polyp size. The incidence of adverse events was very low in all studies which assessed this outcome. Three studies also reported patient preferences and found that participants prefer CT colonography over colonoscopy, (Jensch et al. 2008; Roberts-Thomson et al. 2008). None of the retrieved studies considered the possible damage associated with radiation. All studies concluded that CT is not ready for routine use in clinical practice.

Before CTC can be recommended for average-risk screening, it must be demonstrated to be highly and consistently sensitive in a variety of settings and questions about the optimal technological characteristics of the technique must be settled. These questions include the appropriate threshold size for referral of findings, costs of the procedure in relation to its effectiveness and the potential risks from the radiation exposure  

Stool DNA 

With stool DNA testing, faeces are investigated for the presence of disrupted or methylated DNA. There have been no studies evaluating the CRC incidence or mortality reduction from stool DNA testing. Systematic reviews of performance characteristics of stool DNA tests (Bluecross Blueshield Association Special Report: 2006; Whitlock et al. 2008; Loganayagam 2008) included two prospective studies assessing diagnostic performance in an average-risk population (Imperiale et al. 2004; Ahlquist et al. 2005). Both studies found that stool DNA testing was more sensitive than Hemoccult II for advanced neoplasia, without loss of specificity. However, sensitivity of stool DNA was still only 50% and 20% in the respective studies

A new version of the stool DNA test has been developed that incorporates only two markers. The use of only two markers will make the test easier to perform, reduce the cost, and facilitate distribution to local laboratories. In a case–control study of this test, Itzkowitz found a high sensitivity of 83% but the specificity was significantly worse than the older version at 82%

An important issue which must be addressed before widespread implementation of stool DNA testing becomes possible involves costs. Two studies have shown that at current costs of approximately US$ 350, stool DNA screening is not a cost-effective option for CRC screening (Zauber et al. 2007; Parekh, Fendrick & Ladabaum 2008). According to one study, costs should be 6–10 times lower before stool DNA screening could compete with other available screening tests 

Stool DNA with version 1 testing has superior sensitivity over Hemoccult II, at similar levels of specificity (III). Version 2 seems to have even better sensitivity, at the expense of worse specificity (IV). The diagnostic accuracy of stool DNA needs to be confirmed by large multicentre prospective trials in the average-risk population, and costs need to be reduced before stool DNA testing can be recommended for CRC screening  

Capsule endoscopy 

With capsule endoscopy, a camera with the size and shape of a pill is swallowed to visualise the gastrointestinal tract. No studies have reported on CRC incidence and mortality reduction from capsule endoscopy. Two reviews have evaluated its test performance characteristics compared to colonoscopy and/or CT colonography (Fireman & Kopelman 2007; Tran 2007). Since the reviews, four more studies on the diagnostic accuracy of capsule endoscopy have been published (Eliakim et al. 2009; Gay et al. 2009; Sieg, Friedrich & Sieg 2009; Van Gossum et al. 2009). Sensitivity in the studies included in the review varied from 56–76%, and specificity from 64–69% (Fireman & Kopelman 2007; Tran 2007). The newer studies showed somewhat better estimates than the earlier studies, with sensitivity ranging from 72–78% and specificity from 53–78% (Eliakim et al. 2009; Gay et al. 2009; Sieg, Friedrich & Sieg 2009; Van Gossum et al. 2009). However, these test characteristics are still inferior compared to colonoscopy.

Capsule endoscopy bears promise as an alternative to colonoscopy, because the examination can be realised without intubation, insufflation, pain, sedation or radiation; no serious adverse effects have been reported. However, accuracy data show inferior performance compared to colonoscopy (III). Better diagnostic performance results from large multicentre prospective trials in the average-risk population are required before capsule endoscopy can be recommended for screening