Endoscopy 2012; 44(S 03): SE15-SE30
DOI: 10.1055/s-0032-1308898
Guidelines
© Georg Thieme Verlag KG Stuttgart · New York

# European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition – Introduction

› Author Affiliations
Further Information

### Corresponding author

I. Lansdorp-Vogelaar
Department of Public Health
Erasmus MC
University Medical Centre
Room AE-32
P.O. Box 2040
3000 CA Rotterdam
The Netherlands
Email: [email protected]

### Publication History

Publication Date:
25 September 2012 (online)

Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The first chapter deals with the evidence for the effectiveness of CRC screening; key operational parameters such as age-range, interval between two negative screening examinations, and some combinations of tests; and cost-effectiveness. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of the screening process, including multi-disciplinary diagnosis and management of the disease.

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### Background

According to the most recent estimates by the International Agency for Research on Cancer [33] colorectal cancer (CRC) is the most common cancer in Europe with 432 000 new cases in men and women reported annually. It is the second most common cause of cancer deaths in Europe with 212 000 deaths reported in 2008. Worldwide CRC ranks third in incidence and fourth in mortality with an estimated 1.2 million cases and 0.6 million deaths annually. The European Union (EU) recommends population-based screening for breast, cervical and colorectal cancer using evidence-based tests with quality assurance of the entire screening process including diagnosis and management of patients with screen-detected lesions [21]. The EU policy takes into account the principles of cancer screening developed by the World Health Organization [137] and the extensive experience in the EU in piloting and implementing population-based cancer screening programmes [131]. Screening is an important tool in cancer control in countries with a significant burden of CRC, provided the screening services are high quality [132]. The presently reported multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts and published by the EU [109].

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### Methods

The methods used are described in detail elsewhere in this supplement [74]. Briefly a multidisciplinary group of authors and editors experienced in programme implementation and quality assurance in colorectal cancer screening and in guideline development collaborated with a literature group consisting of epidemiologists with special expertise in the field of CRC and in performing systematic literature reviews. The literature group systematically retrieved, evaluated and synthesized relevant publications according to defined clinical questions (modified Patient-Intervention-Comparison-Outcome-Study method). Bibliographic searches for most clinical questions were limited to the years 2000 to 2008 and were performed on Medline, and in many cases also on Embase and The Cochrane Library. Additional searches were conducted without date restrictions or starting before 2000 if the authors or editors who were experts in the field knew that there were relevant articles published before 2000. Articles of adequate quality recommended by authors because of their clinical relevance were also included.

Only scientific publications in English, Italian, French and Spanish were included. Priority was given to recently published, systematic reviews or clinical guidelines. If systematic reviews of high methodological quality were retrieved, the search for primary studies was limited to those published after the last search date of the most recently published systematic review, i.e. if the systematic review had searched primary studies until February 2006, primary studies published after February 2006 were sought. If no systematic reviews were found, a search for primary studies published since 2000 was performed.

In selected cases references not identified by the above process were included in the evidence base, i.e. when authors of the chapters found relevant articles published after 2008 during the period when chapter manuscripts were drafted and revised prior to publication. The criteria for relevance were: articles concerning new and emerging technologies where the research grows rapidly, high-quality and updated systematic reviews, and large trials giving high contribution to the robustness of the results or allowing upgrading of the level of evidence.

The methodological quality of the retrieved publications was assessed using the criteria obtained from published and validated check lists. Evidence tables were prepared for the selected studies. The evidence tables, clinical questions and bibliographic literature searches are documented elsewhere [73].

In the full guidelines document [109] over 250 recommendations were formulated according to the level of the evidence and the strength of the recommendation using the following grading scales.

#### Level of evidence:

I multiple randomised controlled trials (RCTs) of reasonable sample size, or systematic reviews (SRs) of RCTs

II one RCT of reasonable sample size, or 3 or less RCTs with small sample size

III prospective or retrospective cohort studies or SRs of cohort studies; diagnostic cross sectional accuracy studies

IV retrospective case-control studies or SRs of case-control studies, time-series analyses

V case series; before/after studies without control group, cross sectional surveys

VI expert opinion

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#### Strength of recommendation:

A intervention strongly recommended for all patients or targeted individuals

B intervention recommended

C intervention to be considered but with uncertainty about its impact

D intervention not recommended

E intervention strongly not recommended

Some statements of advisory character considered to be good practice but not sufficiently important to warrant formal grading were included in the text.

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### Results

Several guiding principles and 17 graded recommendations are provided in Chapter 1.

#### Guiding principles

1. The aim of screening as a tool for cancer control is to lower the burden of cancer in the population by discovering latent disease in its early stages and treating it more effectively than if diagnosed later when symptoms have appeared.

2. As such, screening is a commendable method to reduce the burden of disease. However, population screening targets a predominantly healthy population, and should therefore only be conducted after a careful consideration of both harms and benefits.

3. In 1968 the World Health Organisation (WHO) defined the first set of principles for population screening [137]. These principles are still valid today. Together with the substantial experience in implementation of population-based screening programmes in the EU, they have been taken into account in the Council Recommendation on Cancer Screening of 2 December 2003 [21].

4. The Council Recommendation spells out fundamental principles of best practice in early detection of cancer and invites EU Member States to take common action to implement cancer screening programmes with an organised, population-based approach and with appropriate quality assurance at all levels, taking into account European quality assurance guidelines for cancer screening, where they exist.

5. The Council Recommendation calls for introduction of new cancer screening tests in routine healthcare only after they have been evaluated for efficacy in randomised controlled trials (RCTs) and after other relevant aspects such as cost-effectiveness in the different healthcare systems have been taken into account. Only the FOBT for men and women aged 50 – 74 years has been recommended for CRC screening by the EU to date.

6. Any screening policy for colorectal cancer should also take into account the available evidence and the numerous other principles and standards of best practice laid down in the Council Recommendation.

7. The overwhelming majority of colorectal cancer screening examinations performed in the EU use the primary screening test recommended by the Council of the European Union; the Faecal Occult Blood Test (FOBT). The purpose of the European Guidelines for Quality Assurance in Colorectal Cancer Screening is not to provide recommendations on which other modalities might now be suitable for CRC screening in the EU. Instead, the new European Guidelines provide guiding principles and evidence-based recommendations on the quality assurance which should be followed when implementing CRC screening using the various modalities currently adopted in publically mandated programmes in the EU Member States.

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#### Guaiac FOBT

1.1  There is good evidence that invitation to screening with FOBT using the guaiac test reduces mortality from colorectal cancer (CRC) by approximately 15 % in average-risk populations of appropriate age (I).Sect 1.2.1.1

1.2  RCTs have only investigated annual and biennial screening with guaiac FOBT (gFOBT) (II). To ensure effectiveness of gFOBT screening, the screening interval in a national screening programme should not exceed two years (II – B).Sect 1.2.1.2

1.3  Circumstantial evidence suggests that mortality reduction from gFOBT is similar in different age ranges between 45 and 80 years (IV). The age range for a national screening programme should at least include 60 to 64 years in which CRC incidence and mortality are high and life-expectancy is still considerable. From there the age range could be expanded to include younger and older individuals, taking into account the balance between risk and benefit and the available resources (VI – B).Sect 1.2.1.3

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#### Immunochemical FOBT

1.4  There is reasonable evidence from an RCT (II) that iFOBT screening reduces rectal cancer mortality, and from case control studies (IV) that it reduces overall CRC mortality. Sect 1.2.2.1 Additional evidence indicates that iFOBT is superior to gFOBT with respect to detection rate and positive predictive value for adenomas and cancer (see also Ch. 4 [41], Rec. 4.2) (III).Sect 1.2.2.1; 4.2.5; 4.3; 4.4.2

1.5  Given the lack of additional evidence, the interval for iFOBT screening can best be set at that of gFOBT, and should not exceed three years (VI – C).Sect 1.2.2.2

1.6   In the absence of additional evidence, the age range for a screening programme with iFOBT can be based on the limited evidence for the optimal age range in gFOBT trials (see Rec. 1.3) (VI – C).Sect 1.2.2.3; 1.2.1.3

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#### Sigmoidoscopy

1.7  There is reasonable evidence from one large RCT that flexible sigmoidoscopy (FS) screening reduces CRC incidence and mortality if performed in an organised screening programme with careful monitoring of the quality and systematic evaluation of the outcomes, adverse effects and costs (II).Sect 1.3.1.1

1.8  The available evidence suggests that the optimal interval for FS screening should not be less than 10 years and may even be extended to 20 years (see Rec. 1.11) (IV – C).Sect 1.3.1.2; 1.3.2.2

1.9  There is limited evidence suggesting that the best age range for FS screening should be between 55 and 64 years (III – C). After age 74, average-risk FS screening should be discontinued, given the increasing co-morbidity in this age range (V – D).Sect 1.3.1.3

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#### Colonoscopy

1.10 Limited evidence exists on the efficacy of colonoscopy screening in reducing CRC incidence and mortality (III). However, recent studies suggest that colonoscopy screening might not be as effective in the right colon as in other segments of the colorectum (IV).Sect 1.3.2.1

1.11 Limited available evidence suggests that the optimal interval for colonoscopy screening should not be less than 10 years and may even extend up to 20 years (III – C).Sect 1.3.2.2

1.12 Indirect evidence suggests that the prevalence of neoplastic lesions in the population below 50 years of age is too low to justify colonoscopic screening, while in the elderly population (75 years and above) lack of benefit could be a major issue. The optimal age for a single colonoscopy appears to be around 55 years (IV – C). Average risk colonoscopy screening should not be performed before age 50 and should be discontinued after age 74 (V – D).Sect 1.3.2.3

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#### Combination of FOBT and sigmoidoscopy

1.13 The impact on CRC incidence and mortality of combining sigmoidoscopy screening with annual or biennial FOBT has not yet been evaluated in trials. There is currently no evidence for extra benefit from adding a once-only FOBT to sigmoidoscopy screening (II).Sect 1.4

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#### New screening technologies under evaluation

1.14 There currently is no evidence on the effect of new screening tests under evaluation on CRC incidence and mortality (VI). New screening technologies such as CT colonography, stool DNA testing and capsule endoscopy should therefore not be used for screening the average-risk population (VI – D).Sect 1.5

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#### 1.2.2.1 Evidence for efficacy

To date, there has been one RCT evaluating the efficacy of iFOBT screening. In this study, 94 423 individuals were offered a once-only iFOBT screen. After 8 years, the investigators found a statistically significant 32 % reduction in rectal cancer mortality, but no reduction in colonic or overall CRC mortality [144]. There are two caveats concerning this study: Firstly, follow-up of positive iFOBT was performed by flexible sigmoidoscopy, which may explain the lack of effectiveness in the entire colon. Furthermore, randomisation was based on townships and not on individuals.

In addition, three Japanese case-control studies evaluated the efficacy of iFOBT [80] [104] [105]. All three studies found a significant reduction in CRC mortality from iFOBT screening, ranging from 23 % to 81 %, depending on the study and years since last iFOBT.

Clinical societies have argued that it might be appropriate to implement a new CRC screening test without an RCT on CRC mortality, if there is convincing evidence that the new test has: (1) at least comparable performance (e. g. sensitivity and specificity) in detecting cancers and adenomas; (2) is equally acceptable to patients and (3) has comparable or lower complication rates and costs [138]. This evidence is available for iFOBT: there have been 13 population-based screening studies comparing performance characteristics of gFOBT and iFOBT [2] [3] [16] [24] [39] [46] [50] [60] [102] [117] [128] [140] [142]. Although the studies used different tests and slightly different protocols, the results of all studies consistently showed that iFOBT has significantly higher sensitivity for advanced adenomas and cancer than the gFOBT (Hemoccult II). For some cut-off levels for referral, iFOBT was also more specific (see also Ch. 4 [41], Sect. 4.2.5 and 4.3.2).

There is reasonable evidence from an RCT (II) that iFOBT screening reduces rectal cancer mortality, and from case control studies (IV) that it reduces overall CRC mortality. There is additional evidence showing that iFOBT is superior to gFOBT with respect to detection rate and positive predictive value (III).Rec 1.4

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#### 1.2.2.2 Evidence for the interval

The three case–control studies evaluating the efficacy of iFOBT showed that a reduction in risk of CRC death was only statistically significant for those subjects screened within three years prior to the diagnosis. No reduction in risk was observed after three years.

This circumstantial evidence suggests that the screening interval with iFOBT should not exceed three years (III). Due to lack of additional evidence, the interval for iFOBT screening can best be set at that for gFOBT, but should not exceed three years (VI – C).Rec 1.5

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#### 1.2.2.3 Evidence for the age range

No evidence is available on the best age range for iFOBT screening. Given the similarities between the tests, the age range for a screening programme using iFOBT can best be based on the limited evidence for the optimal age range from gFOBT trials (see Rec. 1.3, Sect. 1.2.1.3) (VI – C).Rec 1.6

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#### 1.2.2.4 Evidence on risks vs. benefit and cost-effectiveness

As with gFOBT, there are no serious adverse health effects directly attributable to iFOBT screening. Complications in an iFOBT screening programme occur from diagnostic colonoscopies after positive test results. Approximately 2 – 3 % of individuals offered iFOBT screening in the Italian SCORE 2 and 3 trials [110] [112] and in the NORCCAP trial [38] had a positive iFOBT without adenomas or CRC detected at subsequent diagnostic colonoscopy. In the NORCCAP study, six perforations were reported after colonoscopy [38]. However, all of these complications occurred in therapeutic colonoscopies following polypectomy. There were no perforations in purely diagnostic colonoscopies without adenomas or cancer detected. In addition, there were four major bleeds and one burnt serosa syndrome. The total complication rate with colonoscopy was 4 per 1000 colonoscopies [38].

In a well-organised high-quality iFOBT screening programme, the risks of adverse effects are limited (III).

There were no studies specifically addressing the cost-effectiveness of iFOBT, but three studies that compared the cost-effectiveness of iFOBT to that of gFOBT [11] [64] [83]. Two studies concluded that iFOBT screening was at least as effective as gFOBT screening, but less costly [64] [83]. In the third analysis, the use of iFOBT for 20 years of biennial screening cost € 59 more than gFOBT per target individual, and led to a mean increase in individual life expectancy of 0.0198 years, which corresponds to an incremental cost-effectiveness ratio of US$4100 (€ 2980) per years of life saved. In conclusion, iFOBT seems to be a cost-effective alternative to gFOBT, either dominating gFOBT or providing incremental benefit at costs per life-year gained well below the commonly used threshold of US$ 50 000 per life-year gained (III).Rec 1.15; 1.16

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### 1.3 Evidence for effectiveness of endoscopy screening

With endoscopy screening, a flexible tube is inserted into the anus to inspect the colorectum. With this procedure, the physician can detect abnormalities and remove them in one procedure. The two main endoscopy procedures are flexible sigmoidoscopy and colonoscopy. With sigmoidoscopy only approximately one-half of the colorectum can be inspected, whereas colonoscopy generally visualises the complete colorectum.

#### 1.3.1.1 Evidence for efficacy

For sigmoidoscopy screening, evidence on the efficacy is available from three RCTs: the Telemark and NORCCAP studies in Norway and the large UK study in which 57 237 individuals were randomised to the screening group for once-only sigmoidoscopy alone ([ Table 1.3 ]). The UK study was the only study to find a significant 31 % reduction in CRC mortality from sigmoidoscopy in an intention-to-treat analysis [8]. However, the Norwegian trials had considerably smaller sample sizes (13 823 individuals in the screening group in the NORCCAP study, and only 400 in the Telemark study); the NORCCAP study also had a shorter follow-up. Therefore these studies may have been underpowered [47] [123]. In per-protocol analyses, the NORCCAP study did find a significant reduction in CRC mortality. Both the Telemark and UK study found a significant reduction in CRC incidence. The disturbing finding in the very small Telemark study that sigmoidoscopy screening might increase overall mortality in the screening group was not corroborated by either the NORCCAP or UK study. The UK trial used a two-step invitation process in which only people who actively expressed their interest in being randomised were enrolled. Although CRC incidence in the trial control group was similar to what is expected in the general population, the results cannot be directly extrapolated to the general population. Future results from 2 other large RCTs in Italy and the US will be used to assess the findings of these trials [91] [111].

Table 1.3

### CRC Incidence and mortality reduction from three randomised controlled trials on sigmoidoscopy screening.

Outcome

Telemark, Norway

NORCCAP, Norway

UK FS trial, UK

Intention-to-treat analysis

CRC incidence

80 % reduction[1]

No difference

23 % reduction[1]

CRC mortality

50 % reduction

27 % reduction

31 % reduction[1]

Overall mortality

57 % increase[1]

No difference

No difference

Per-protocol analysis

CRC incidence

33 % reduction[1]

CRC mortality

59 % reduction[1]

43 % reduction[1]

1 significant; – not reported.

In addition, three case-control studies of good methodological quality have been published. In these studies, sigmoidoscopy was compared with no screening [78] [81] [113] while adjusting for the main confounding factors (family history of CRC, FAP, polyposis, ulcerative colitis and number of periodic health examinations). All three studies found a significant reduction in CRC mortality and two of them also in CRC incidence. Finally, a prospective cohort study including 24 744 asymptomatic men aged 40 – 75 years at average risk of CRC, showed a significant 42 % reduction in overall CRC incidence and 56 % in distal cancer incidence from screening endoscopy after 8 years of follow-up. The study did not find a significant difference in proximal cancer incidence or overall CRC mortality [57].

In conclusion, there is reasonable evidence that flexible sigmoidoscopy screening reduces CRC incidence and mortality, if performed in an organised screening programme with careful monitoring of the quality and systematic evaluation of the outcomes, adverse effects and costs (II).Rec 1.7

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#### 1.3.1.2 Evidence for the interval

There are no studies directly assessing the optimal interval for sigmoidoscopy screening. Two studies have evaluated the detection rate of adenomas and cancer three and five years, respectively, after a negative sigmoidoscopy [90] [106]. Both studies found a significantly lower detection rate at the second screening than at initial screening. The rates were 65 – 75 % lower three years after a negative examination, [106] and 50 % lower 5 years after a negative examination [90]. Nevertheless, the authors of the two studies arrived at different conclusions: Platell suggested that rescreening the average-risk population with flexible sigmoidoscopy at intervals longer than 5 years could be considered, whereas Schoen concluded that although the overall percentage of detected abnormalities is modest, the data raise concern about the impact of a screen interval longer than 3 years after a negative examination. The UK flexible sigmoidoscopy screening study showed that there was little attenuation of the protective effect of sigmoidoscopy after 11 years of follow-up [8], suggesting that the interval for rescreening should not be less than 10 years. This is in line with the evidence for colonoscopy screening (see Sect. 1.3.2.2).

In conclusion, the optimal interval for sigmoidoscopy screening was only assessed in two indirect studies that only considered intervals of three and five years. The UK flexible sigmoidoscopy study and evidence for colonoscopy screening seems to indicate that the optimal interval for endoscopy screening should not be less than 10 years and may even be extended to 20 years (see Sect. 1.3.2.2)

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#### 1.3.1.3 Evidence for the age range

Evidence on the age-specific prevalence of colorectal adenomas suggests that the best age range for flexible sigmoidoscopy screening is between 55 and 64 [112]. A significant reduction in incidence and mortality of CRC has recently been shown in this age range in a large RCT using flexible sigmoidoscopy performed once in a lifetime as the primary screening test [8].

There has been one cross-sectional study comparing safety, tolerability, completion, and endoscopic findings of sigmoidoscopy between individuals 50 – 74 years old and individuals 75 years and older [82]. The study demonstrated that elderly subjects ≥ 75 years old have an increased rate of endoscopist-reported difficulties and a higher rate of incomplete examinations compared to subjects aged 50 – 74 years. Complication rate and detection rate of adenomas and advanced adenomas were similar in both cohorts, while an increased detection of carcinomas in the elderly was observed.

In conclusion, there is limited evidence suggesting that the best age range for flexible sigmoidoscopy screening should be between 55 and 64 years (III – C). One study suggests that for screening in the elderly population (75 years and older) tolerability is an issue (V). Average-risk sigmoidoscopy screening should be discontinued after age 74, given the increasing co-morbidity in this age range (V – D).Rec 1.9

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#### 1.3.1.4 Evidence on risks vs. benefit and cost-effectiveness

Four population-based screening trials reported on complication rates with flexible sigmoidoscopy ([ Table 1.4 ]). Severe complication rates from sigmoidoscopy varied from 0 % to 0.03 %. Minor complications occurred in 0.2 – 0.6 % of sigmoidoscopies. Severe complication rates with follow-up colonoscopy were about 10 times as high as with sigmoidoscopy (0.3 – 0.5 %). Minor complications occurred in 1.6 – 3.9 % of follow-up colonoscopies.

Table 1.4

### Major and minor complication rates in population-based sigmoidoscopy screening.

SCORE [111]

SCORE 2 [110]

UK FS trial [125]

NORCCAP [38]

Sigmoidoscopy

Severe complications

0.02 %

0.02 %

0.03 %

0 %

Minor complications

0.6 %

0.5 %

0.2 %

0.2 %

FU colonoscopy

Severe complications

0.3 %

0.3 %

0.5 %

0.4 %

Minor complications

3.9 %

3.9 %

0.4 %

1.6 %

In a well-organised high-quality flexible sigmoidoscopy screening programme the risk of severe complications is about 0 – 0.03 % for sigmoidoscopies and 0.3 – 0.5 % for follow-up colonoscopies (III).

Six studies in the USPSTF review estimated the cost-effectiveness of sigmoidoscopy screening, [89]. One study showed that with favourable conditions sigmoidoscopy screening could be cost-saving. In the other studies the cost-effectiveness ratio varied from US$12 477 to US$ 39 359 per life-year gained. More recent cost-effectiveness analyses found similar ratios (US$7407 – US$ 23 830) [87] [118] [129]. A recent study based in England also estimated that sigmoidoscopy screening could be cost-saving [122].

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### 1.4 Evidence for effectiveness of FOBT and sigmoidoscopy combined[7]

No trials have assessed the impact of combining sigmoidoscopy screening with annual or biennial FOBT on CRC incidence or mortality. One trial comparing a combination of flexible sigmoidoscopy and once-only FOBT with sigmoidoscopy alone did not find a lower post-screening CRC incidence in the group with the combination strategy than in the group with sigmoidoscopy alone [47].

A few studies reported diagnostic yield with a combination of once-only sigmoidoscopy and once-only FOBT, compared to FOBT and/or sigmoidoscopy alone [38] [65] [95] [96] [110]. The yield of the combination of once-only sigmoidoscopy with once-only FOBT was significantly higher than that of once-only FOBT alone, but not higher than that of once-only sigmoidoscopy alone.

When a once-only combination of sigmoidoscopy with FOBT was compared with biennial FOBT alone, the cumulative detection rates for cancer and advanced adenoma became similar among the two strategies after 5 rounds of biennial FOBT screening [95]. When the detection rate was calculated among the invited (as opposed to examinees) diagnostic yield was higher in the biennial FOBT programme because of the higher compliance with FOBT. These conclusions should be considered cautiously, however, because they are based on an indirect comparison of two trials and because sigmoidoscopy may prevent advanced adenomas and CRC. A comparison of cumulative detection rates of advanced adenomas and CRC may therefore be biased in favour of biennial FOBT screening.

Two studies evaluated the effect of offering combined once-in-a-lifetime testing on screening compliance [38] [110]. While one study showed a significantly lower compliance with the combination of sigmoidoscopy and FOBT compared to FOBT alone [110] the other did not find a difference between the combination, and sigmoidoscopy alone [38].

The impact on CRC incidence and mortality of combining sigmoidoscopy screening with annual or biennial FOBT has not yet been evaluated in trials. There is currently no evidence for extra benefit from adding a once-only FOBT to sigmoidoscopy screening (II).Rec 1.13

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### 1.5 New screening technologies under evaluation[8]

Besides the established FOBT and endoscopy tests, several new technologies are currently under development for CRC screening. The most important ones are CT colonography (CTC), stool DNA and capsule endoscopy screening. There currently is no evidence on the effect of these and other new screening tests under evaluation on CRC incidence and mortality (see Sections 1.5.1 – 3). New screening technologies are therefore not recommended for screening the average-risk population (VI – D).Rec 1.14

#### 1.5.1 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 [40] [77] [92] [101] [119] [133] [135]. All meta-analyses and primary studies [6] [17] [98] 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, [55] [100]. 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 (VI – A).

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#### 1.5.2 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 [12] [69] [135] included two prospective studies assessing diagnostic performance in an average-risk population [1] [51]. 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 [1] [51].

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 % [53].

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 [83] [143]. According to one study, costs should be 6 – 10 times lower before stool DNA screening could compete with other available screening tests [143].

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 (VI – D).

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#### 1.5.3 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 [34] [124]. Since the reviews, four more studies on the diagnostic accuracy of capsule endoscopy have been published [27] [35] [115] [127]. Sensitivity in the studies included in the review varied from 56 – 76 %, and specificity from 64 – 69 % [34] [124]. The newer studies showed somewhat better estimates than the earlier studies, with sensitivity ranging from 72 – 78 % and specificity from 53 – 78 % [27] [35] [115] [127]. 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 (VI – A).Rec 1.14

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### Conclusions

In a multidisciplinary process, wide consensus has been achieved on a comprehensive package of evidence-based recommendations for quality assurance in colorectal cancer screening. Following these recommendations has the potential to enhance the control of colorectal cancer in Europe and elsewhere through improvement in the quality and effectiveness of the screening process that extends from systematic invitation to management of screen-detected cases.

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### Disclaimer

The views expressed in this document are those of the authors. Neither the European Commission nor any person acting on its behalf can be held responsible for any use that may be made of the information in this document.

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Competing interests: No competing interests reported.

### Acknowledgements

The comments and suggestions received from consultation of the European Cancer Network are gratefully acknowledged.

The production of the Guidelines was supported by the European Union through the EU Public Health Programme, (grant agreement no. 2005317: Development of European Guidelines for Quality Assurance of Colorectal Cancer Screening). Partner institutions: Oxford University Cancer Screening Research Unit, Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom; Unit of Cancer Epidemiology, Centre for Cancer Epidemiology and Prevention (CPO) and S. Giovanni University Hospital, Turin, Italy; Public Association for Healthy People, Budapest, Hungary; European Cancer Patient Coalition (ECPC), Utrecht, Netherlands ; Quality Assurance Group, Section of Early Detection and Prevention, International Agency for Research on Cancer, Lyon, France.

Financial support was also received through the Public Affairs Committee of the United European Gastroenterology Federation, and from a cooperative agreement between the American Cancer Society and the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention.

1 Sect (superscript) after each recommendation in the list refers the reader to the section/s of the Guidelines dealing with the respective recommendation.*
Rec (superscript) throughout the chapter refers to the number of the recommendation dealt with in the preceding text.*
* The first digit of the section numbers and recommendation numbers refers to the respective chapter in the guidelines. For Chapters 2 to 10 see: [7] [9] [41] [70] [76] [93] [120] [121] [126] respectively.

2 Other evidence-based screening tests currently recommended by the Council of the European Union: pap smear screening (cervical cytology) for cervical cancer precursors starting not before the age of 20 and not later than the age of 30 years in accordance with European guidelines for quality assurance in cervical cancer screening (Council Recommendation 1(b)); mammography screening for breast cancer in women aged 50 to 69 years in accordance with European guidelines for quality assurance in breast cancer screening and diagnosis (Council Recommendation 1(b)).

3 gFOBT is an evidence-based screening test for CRC recommended by the EU. The applicable item in the Council Recommendation of 2 December 2003 is 1(a) (see Sect. 1.14 and [21]).

4 iFOBT is an evidence-based screening test for CRC that fulfils the requirements of the Council Recommendation of 2 December 2003. The applicable items in the Recommendation are 1(a) in combination with 6(e) (see Sect. 1.14 and [21]).

5 Flexible sigmoidoscopy is not a screening test for CRC recommended by the EU. The applicable items in the Council Recommendation of 2 December 2003 are 6(a) to 6(d) (see Sect. 1.14 and [21]).

6 Colonoscopy is not a screening test for CRC recommended by the EU. The applicable items in the Council Recommendation of 2 December 2003 are 6(a) to 6(d) (see Sect. 1.14 and [21]).

7 Combination of FOBT and sigmoidoscopy is not a screening approach for CRC recommended by the EU. The applicable items in the Council Recommendation of 2 December 2003 are 6(a) to 6(d) (see Sect. 1.14 and [21]).

8 New technologies under evaluation are not recommended for CRC screening by the EU. The applicable items in the Council Recommendation of 2 December 2003 are 6(a) to 6(d) (see Sect. 1.14 and [21]).

### Corresponding author

I. Lansdorp-Vogelaar
Department of Public Health
Erasmus MC
University Medical Centre
Room AE-32
P.O. Box 2040
3000 CA Rotterdam
The Netherlands
Email: [email protected]