Carbon dioxide insufflation

Gas insufflation is mandatory to ensure good visualisation during colonoscopy. Currently, air is commonly used for this purpose (Janssens et al. 2009). However, significant amounts of air can be retained in the GI tract (Bretthauer et al. 2003) causing pain and discomfort for the patient. Pain associated with colonoscopy has been identified as a major barrier to participation in CRC screening

Randomised trials have shown that carbon dioxide insufflation significantly reduces abdominal pain and discomfort in patients undergoing colonoscopy and flexible sigmoidoscopy (Bretthauer et al. 2002a; Bretthauer et al. 2002b; Sumanac et al. 2002; Church & Delaney 2003; Wong et al. 2008)

Side effects of C02 insufflation were not detected in unsedated patients in two randomised studies identified in the present literature search and involving 350 patients (Bretthauer et al. 2002b; Bretthauer et al. 2005). Slightly elevated end-tidal C02 levels were detected in sedated patients in the latter study, but only 52 sedated patients were included in the study and patients with chronic obstructive pulmonary disease, as well as patients with known C02 retention, were excluded.

Since carbon dioxide is an inert gas that cannot form a combustible mixture with hydrogen and methane, C02 insufflation will avoid the very rare risk of explosion during sigmoidoscopy or colonoscopy

Following incomplete colonoscopy, an alternative examination is frequently required. Provided adequate facilities are available, same-day CT or MRI colonography, or, in appropriate cases, doublecontrast barium enema would be desirable. However, same-day radiologic examination following colonoscopy frequently yields suboptimal quality when air insufflation is used for colonoscopy, due to retained air in the colon. If CO2 insufflation has been used, same-day radiologic imaging is generally feasible with appropriate quality. This avoids the necessity of scheduling the additional radiologic examinations on another day and further colon cleansing (Phaosawasdi et al. 1986; Rodney, Randolph & Peterson 1988)

In light of the above evidence and considerations: 

 Carbon dioxide insufflation is recommended for colonic endoscopic procedures (I - A).Rec 5.31

 Carbon dioxide insufflation should be avoided in patients with COPD, known C02 retention or otherwise reduced pulmonary function (VI - A).

Support services

Only rarely will a person undergoing a primary screening procedure require admission to hospital for further care. Thus it is not necessary to have medical support facilities close at hand. However, services performing endoscopy in more remote settings must have robust guidelines and processes in place to enable patients to be resuscitated effectively and be transferred rapidly and safely to a hospital where surgical services are available. On this basis it is recommended that any screening service, regardless of setting, should make an assessment of risks and develop the ability to respond to emergencies

While there are no absolutes, a case can be made for delivering high-volume screening endoscopy outside traditional hospital settings to improve the patient experience and to reduce healthcare and societal costs. In contrast, risk assessments will indicate that colonoscopy following a positive FOBT or a positive FS is a more complex procedure that is associated with higher risks and should, therefore, be performed in acute hospital settings. 

Audit and quality improvement  

This section proposes that endoscopy services monitor key outcomes to ensure that a high-quality and safe service is being provided and to identify areas in need of improvement. Two terms are used for such outcomes: auditable outcomes and quality indicators. An auditable outcome refers to an outcome that should be measured, but for which there is not an evidence base to recommend a standard, such as the comfort of the procedure. A quality indicator is an outcome for which there is a sufficient evidence base to recommend a standard, such as caecal intubation rate.

It is expected that some auditable outcomes will become quality indicators as the evidence base improves, and that the standards of quality indicators will rise as standards improve. 

On the basis of this, it is recommended that all screening programmes should have processes in place for monitoring, auditing, reviewing and acting upon key auditable outcomes and quality indicators in the following areas 

• Quality; 
•  Safety; and 
•  Patient feedback  

QUALITY ASSURANCE IN ENDOSCOPY

The colonoscopist needs to judge whether he/she is competent to remove a lesion and whether it is safe to remove the lesion in this setting. On the basis of good practice it is recommended that if there is doubt, the lesion must be appropriately documented and the patient referred elsewhere to have the lesion removed

Thus, when considering where endoscopic screening services are to be located, the commissioner should be aware of how often a patient may need to be referred elsewhere. If it is expected that referral somewhere else will be a frequent occurrence (perhaps >1% of patients) then it is better to consider locating the service elsewhere, i.e. where the competence of the available endoscopists would permit less referral. 

To help in the planning of location of endoscopic services for screening, the following five levels of competency are proposed. 

Level 0: The operator does not remove any lesions, referring on all patients with any detected lesions. The operator will be able to biopsy lesions, and pathological material may inform the decision to refer. Basic level of competency for diagnostic FS but not recommended for screening FS. 

 Level 1: Removing lesions <10 mm in diameter at FS. Rationale: larger lesions will indicate a need for colonoscopy and can be removed when the colonoscopy is performed. Tissue is required from smaller lesions to decide whether colonoscopy is necessary. Thus any person performing FS screening should have this level of competency. 

 Level 2: Removing polypoid and sessile lesions <25 mm providing there is good access. All colonoscopists should have this level of competency. 

 Level 3: Removing smaller flat lesions (<20 mm) that are suitable for endoscopic therapy, larger sessile and polypoid lesions, and smaller lesions with more difficult access. Some flat lesions <20 mm with poor access might be unsuitable for this level. Any person doing colonoscopy for positive FOBT in a screening programme should have this level of competency. 

 Level 4: Removing large flat lesions or other challenging polypoid lesions that might also be treated with surgery. This is the type of lesion that would not be removed at the first colonoscopy because of time constraints, if applicable, or because the surgical option needs to be discussed with the patient. If the patient chooses to have endoscopic therapy, then he/she should be referred to a level 4 competent endoscopist. This level of competency would be expected of only a small number of regionally based colonoscopists. 

In the context of colorectal screening and diagnosis in Europe, units only providing Level 0 competencies are not recommended, because unnecessary endoscopic procedures would be required to remove small lesions which could have been removed during the initial FS. Furthermore, unnecessary colonoscopies may be encouraged in the absence of histopathological evaluation of small lesions left in place during the initial FS. 

Sequential testing

Two consecutive diagnostic accuracy studies conducted in Scotland as part of the UK pilot screening study investigated whether testing individuals with positive gFOBT tests using an iFOBT could be more effective in selecting those who should receive colonoscopy (Fraser et al. 2006; Fraser et al. 2007) In both studies the two-tier approach gave very high sensitivities of 95–96% with a negative carrying a less than 1% chance of invasive cancer. The odds ratio for iFOBT positive subjects of having cancer was 7.75 (95% CI 1.84–31.4). 

A Chinese study (Li et al. 2006) of 324 subjects who had colonoscopy (mean age 53.5±15.3) showed that an iFOBT following a positive gFOBT had a better specificity for colon cancer detection than gFOBT (94.2% vs. 75.5%), and with similar sensitivity (93.8% and 95.9% vs. 95.9%, p>0.05). 

In a multicentre comparison using different FOBT tests on 554 patients referred for colonoscopy (mean age 59.8±11.7), a combination test with a highly sensitive gFOBT (Hemoccult SENSA) and an iFOBT (FlexSure-FS or Hemeselect-HS, Beckman Coulter Inc. Fullerton, CA, USA) showed slightly reduced sensitivity but significantly fewer false-positive tests than any single test (Greenberg et al. 2000). The specificity of SENSA/FS (95.7%, p=0.03) and SENSA/HS (95.2%, p=0.07) for the detection of colorectal cancer were each greater than that of any individual test. 

Participation rate and choice of test 

Factors that influence participation rate (uptake) are addressed in Chapter 2 (Sect. 2.4, 2.5.1.1 and 2.5.1.2). Whilst many studies have reported the effect on compliance of different test devices and sampling permutations, some of these are contradictory and many reflect local circumstances. Whilst the analytical methodology, gFOBT vs. iFOBT, will not directly influence compliance, the influence of test methodology on the method of sampling, the number of samples required, a requirement for dietary restriction and the improved clinical outcome will all have a bearing on uptake. The magnitude of the influence will depend on local circumstances. Well-conducted randomised trials have clearly demonstrated that better compliance can be achieved using current iFOBTs than with gFOBTs, but the major influencing factor(s) remain a matter of speculation. In his recent paper Grazzini makes the important observation that, in a biennial screening programme looking for a slow growing adenoma, greater compliance over the long term might be more important than a higher detection rate on a single screen (Grazzini et al. 2009).

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. 

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%).