Microsoft Word - CT colonography Report - final version for Comms 270508v3.docISBN 1- 84404-891- 8 First published September 2007
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Computed Tomography (CT) colonography
3.3.1 HTAs and systematic reviews: assessment method......................15
3.3.2 HTAs and systematic reviews: assessment results .......................16
3.3.3 Guidelines: assessment method....................................................28
4.1.1 Is there evidence to demonstrate whether CT colonography will improve health outcomes compared with ‘conventional’ colonoscopy or DCBE in those diagnosed with clinically significant polyp(s)?........................................................................................30
4.1.2 What is the accuracy (in terms of sensitivity and specificity) of CT colonography for detecting polyps compared with conventional colonoscopy or DCBE? .................................................................30
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4.1.3 What are the reported complication rates for CT colonography compared with ‘conventional’ colonoscopy or DCBE?...................53
4.1.4 What is the level of patient acceptance of CT colonography compared with ‘conventional’ colonoscopy or DCBE?...................55
4.1.5 What impact does the ability of CT colonography to visualise structures outwith the bowel have on health outcomes? ...............58
4.2 Cost effectiveness ................................................................................59
4.2.1 Is CT colonography cost effective compared with ‘conventional’ colonoscopy or DCBE in the detection of large bowel pathology? 59
5 Discussion ...................................................................................................61
6 Conclusions .................................................................................................65
1 Executive summary
Colorectal cancer is the third most common cancer in Scotland, resulting in over 1,500 deaths and costing the country in the region of £30 million each year. The disease develops when particular types of polyps which develop in the colon and rectum, increasing in prevalence in older age, transform to become malignant. Detection and removal of these polyps reduces the risk of cancer developing or progressing.
A colorectal cancer screening initiative has recently been rolled out across Scotland. It is based upon the faecal occult blood test (FOBT), a cheap and practical option for population screening. However, subsequent investigation of screen detected FOBT-positive and symptomatic individuals requires a more sophisticated detection technique. Colonoscopy, in which an endoscope is used to directly examine the colon, is commonly used. This also permits biopsy of abnormalities and removal of any polyps detected. Another approach is to use imaging techniques, of which double contrast barium enema (DCBE), where the colon is filled with barium, insufflated with air, and x-rays taken, has been the accepted method. A newer alternative imaging technique of potential interest for wider use in Scotland is computed tomography (CT) colonography. First described in 1994, this method uses CT technology and computer processing algorithms to generate images of the colon non-invasively. The cross-sectional images may be further processed to reconstruct a three-dimensional simulation of conventional endoscopic examination, and for this reason, the technique is sometimes referred to as virtual colonoscopy.
A proposal to undertake a Health Technology Assessment (HTA) on CT colonography was submitted to NHS Quality Improvement Scotland (NHS QIS) by the Scottish Executive Health Department Diagnostics Collaborative. Due to the existing evidence base, and an ongoing large UK randomised controlled trial, carrying out such an HTA was not considered to be appropriate at this time. However, given the interest in this topic it was decided to carry out a clinical and cost effectiveness review based upon existing secondary literature (HTAs, systematic reviews, evidence-based guidelines and consensus statements) instead. This considered CT colonography as a diagnostic tool compared with colonoscopy or DCBE. The findings of the review are made available in this HTA scoping report.
A systematic literature search to identify all secondary evidence was conducted in January 2007. Fourteen international HTAs and systematic reviews were selected for inclusion, as well as one guideline, and two consensus statements. The studies were quality assessed against validated checklists, and data extraction performed independently by two reviewers.
The secondary literature did not identify any studies which considered morbidity and mortality as outcomes. The relative performances of the tests were therefore considered in terms of other outcomes, namely accuracy, adverse events, patient
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acceptance, incidental findings and cost effectiveness, which together contribute to the overall effectiveness of the test.
Regarding accuracy, it was found that the sensitivities currently achievable with CT colonography are variable and further research on the technique and its standardisation is required. Consensus on diagnostic thresholds is also needed.
While CT colonography removes many of the risks of invasive colonoscopy, there have been rare occurrences of bowel perforation. Radiation exposure is also incurred, although this is at a level similar to that of DCBE.
CT colonography avoids the need for sedation which colonoscopy requires, and therefore allows quicker return to normal activities. However, if a suspicious mass is discovered, a subsequent colonoscopy is necessary. There is some evidence that patients are more accepting of CT colonography than colonoscopy, and stronger evidence that CT colonoscopy is more acceptable to patients than DCBE. Nevertheless, all the different diagnostic methods are unpleasant and embarrassing to the patient. CT colonography in contrast to colonoscopy allows the identification of abnormalities outside the colon, but there is insufficient evidence to determine the impact of this aspect of the technique on overall effectiveness.
While a number of economic evaluations of CT colonography have been undertaken, no information on the cost effectiveness of CT colonography in a Scottish setting was available from the literature considered.
The review concluded that despite the fairly extensive body of literature on this topic, there is as yet insufficient evidence to inform recommendations on the routine use of CT colonography as a diagnostic tool in Scotland. The technique does appear to be useful as an alternative approach in particular patient groups in certain circumstances, however consideration would need to be given as to how such use would operate in practice. The manner in which services need to be organised to deliver CT colonography, in comparison to colonoscopy or DCBE is likely to be at least as significant, if not more so, as diagnostic performance, for planners making choices between the techniques.
Evidence gathering needs to continue in a structured manner, and include long- term studies assessing the impact of CT colonography on colorectal cancer morbidity and mortality, investigation of the accuracies which can be achieved using the technique, and further assessment of patient preferences, adverse events and incidental findings. NHS QIS has no further plans to undertake work in this area but awaits the results of a large randomised controlled trial (RCT) currently in progress with interest. This is due to report in 2009 and will contribute UK clinical and cost effectiveness data to the evidence base. Survey work relating to the use of CT colonography in Scotland, and an economic evaluation based upon Scottish costs and practice could be usefully undertaken.
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2.1 Colorectal cancer
Colorectal polyps arise from uncontrolled division of cells in the colon or rectum and the incidence increases with age (Vandaele et al., 2006). Most of these polyps are harmless, but about 10% are adenomas, which have the potential to become cancerous. The majority of these adenomas will remain benign, but a small fraction, of the order of 1%, will undergo a stepwise transformation to become malignant. The larger the adenoma, the greater the risk of this change. The shape of the adenoma also predicts the likelihood of malignancy developing. Some 30% of individuals over 50 years of age have more than one adenoma (Levin, 2005). Transformation does not happen suddenly, but takes place gradually over a period of 5–10 years (Pearlman et al., 2007). When an adenoma becomes cancerous, it begins to invade the surrounding tissue and can also spread to other sites in the body. Patients are usually asymptomatic until the disease has reached an advanced stage (Scottish Executive Health Department, 2001; Pearlman et al., 2007).
In 2003, there were 3,366 new cases of colorectal cancer diagnosed in Scotland (www.isdscotland.org). The incidence has been rising over the last 50 years and it is now the third most common cancer in Scotland for both men and women (Scottish Executive Health Department, 2001). It is most prevalent in people in their 60s and 70s. In 2005, there were 1,550 deaths from the disease. Based on UK data (UK Flexible Sigmoidoscopy Trial Investigators, 2002) and assuming comparable costs across the UK, the economic burden of colorectal cancer in Scotland is likely to be in the region of £30 million per annum.
Detection of polyps at an early stage and their subsequent removal reduces the risk of cancer developing or progressing (Winawer et al., 1993). There are two approaches to detection. The first uses an endoscope to directly examine the colon and comprises two main techniques, flexible sigmoidoscopy and colonoscopy. Flexible sigmoidoscopy which uses a shorter endoscope than colonoscopy can only examine part of the colon and its use is therefore declining. SIGN guidelines recommend the use of colonoscopy, which also permits biopsy and polypectomy (polyp removal) for diagnosing colorectal cancer (Scottish Intercollegiate Guidelines Network, 2003). The second approach is based upon imaging of the colon. Traditionally double contrast barium enema (DCBE) was used. This technique involves filling the colon with barium, insufflating the colon with air, and taking x-rays. This is considered by SIGN to represent a safe, sensitive alternative to colonoscopy. A newer alternative approach is computed tomography (CT) colonography.
2.2 CT colonography
CT colonography, first described in 1994, uses CT technology and computer processing algorithms to generate images of the colon non-invasively. These
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images can be processed to simulate those obtained during the conventional endoscopic examination, colonoscopy. For this reason, the technique is also known as virtual colonoscopy (ECRI, 2005). Magnetic resonance imaging (MRI) colonography can also generate simulated 3D images of the colonic lumen, and be referred to as virtual colonoscopy, so for clarity, this report will not use the term virtual colonoscopy.
As with endoscope examination, CT colonography relies on the bowel being as clear as possible of faecal matter, such that polyps and growths can be clearly distinguished. The same bowel preparation as for endoscopy is therefore required. This normally entails the patient following a restricted diet and using laxatives for 1–2 days prior to the examination. Stool markers may also be administered to help differentiate retained stool from suspect lesions. Such preparation can disrupt work and other planned activities of the patient. At examination, a catheter is placed in the rectum and the colon is insufflated either with room air or carbon dioxide (CO2) to the maximum pressure that the patient can tolerate. Spasmolytic agents are sometimes used to improve bowel distension, and intravenous contrast agents to aid detection, but these can produce adverse effects in some patients. CT scans are carried out, usually in the prone and supine positions, while the patient holds their breath. Depending on whether a single or multidetector row scanner is used, either several overlapping scans, or one overall scan in each position will be obtained. Unlike endoscopy, the patient does not normally require sedation during the examination, so may resume normal activities immediately afterwards.
It has been suggested, that as a less invasive technique than colonoscopy, CT colonography may be more acceptable to patients. As the whole abdominal, pelvic and lower lung area is viewed during a scan, it also offers the potential to detect lesions in other organs (Xiong et al., 2005). The procedure does however result in the exposure of the patient to radiation and if lesions are detected by CT colonography which are considered to require removal, the patient must then have a colonoscopy to biopsy or remove the suspect polyps.
CT colonography can be used as a method of screening for colorectal polyps, for diagnostic purposes in those with colorectal symptoms or suspicious findings on a prior screening test, and for surveillance of already detected polyps or individuals who have cancer.
CT colonography practice in the UK was surveyed in 2004 (Burling et al., 2004). Questionnaires were sent to 216 hospital departments identified as providing an adult gastrointestinal radiological service. Of the 138 who replied, 50 (36%) provided CT colonography in day-to-day clinical practice. Half of these departments carried out one scan per week, with six performing one or more per day. The majority of scans were undertaken following incomplete colonoscopy or failed barium enema. The lack of conclusive evidence on CT colonography has limited its uptake, but the major barrier to more widespread use is considered to
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be CT scanner capacity. Similar considerations limit uptake of MRI colonography (Scottish Intercollegiate Guidelines Network, 2003).
2.3 CT colonography within NHSScotland
Specifying a standard patient pathway for bowel screening and subsequent diagnosis and treatment of colorectal cancer within NHSScotland is not straightforward as practice varies depending on local circumstances and according to clinical judgement.
While CT colonography may find some application in screening high-risk individuals, it is unlikely at present, particularly given limited CT scanner capacity, to be used for population screening in Scotland. This contrasts with the United States (USA) where the technology is promoted as a screening tool (Burling et al., 2004). The bowel screening initiative currently being rolled out across Scotland (Scottish Executive Health Department, 2006) is based on the FOBT, a more practical and safe option for mass screening than CT colonography. Instead, CT colonography is more likely to be used in the diagnosis of patients with positive results on the FOBT and symptomatic individuals. Such diagnostic testing is mainly performed using DCBE or colonoscopy (Scottish Intercollegiate Guidelines Network, 2003), with the latter considered to be the reference standard.
A simple pathway for diagnosis is given below, however it should be noted that this is provided only to illustrate potential options available and not to represent any particular pathway currently used in Scotland.
Figure 1 Diagnostic alternatives for suspected colorectal polyps
Positive FOB test or symptoms suggestive of colorectal cancer
CT colonography
Suspected detection of clinically significant polyp
Colonoscopy
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In Figure 1, following a positive FOB screening test or given symptoms leading to a suspicion of colorectal cancer, patients may be examined either by colonoscopy, CT colonography, or DCBE. If a clinically significant polyp is found during CT colonography or DCBE, a subsequent colonoscopy is required for its removal. As indicated by the dashed line, if an initial colonoscopy examination is incomplete, CT colonography or DCBE may then be undertaken instead.
The key clinical question of interest for NHSScotland regarding CT colonography is therefore whether its use as a diagnostic test, followed by colonosocopy if required, is more clinically and cost effective than DCBE followed by colonoscopy if required, or colonoscopy alone, in the pathway between FOB test or colorectal symptoms and removal of identified polyps.
2.4 Purpose of report
A proposal to undertake an HTA on CT colonography was submitted to NHS QIS by the Scottish Executive Health Department Diagnostics Collaborative. Given the existing evidence base and an ongoing large UK randomised controlled trial (http://www.controlled-trials.com/ISRCTN95152621), carrying out such an HTA was not considered to be appropriate at this time. Given the interest in this topic however it was decided instead to carry out a clinical and cost-effectiveness review based upon existing secondary literature (HTAs, systematic reviews, evidence-based guidelines and consensus statements). This considered CT colonography as a diagnostic tool, compared with colonoscopy or DCBE. The findings of the review are made available in this HTA scoping report. A key aspect of NHS QIS HTA scoping reports is to share with NHSScotland the synthesised literature that has been identified by a high-level literature search to provide a foundation for decision making and further research.
2.5 Structure of report
The following section of the report (section 3) reviews the methodology used in identifying and selecting studies, and assessing their quality. Section 4 reviews firstly the clinical-effectiveness evidence and secondly the cost-effectiveness evidence from the included studies. The results are discussed in section 5, and finally conclusions in terms of implications for NHSScotland and for future research are presented in Section 6. Appendices provide details of the sources searched, the search strategy adopted and ongoing research.
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3.1 Literature search
A systematic literature search was undertaken in January 2007 to identify all HTAs, Cochrane reviews, other systematic reviews, evidence-based guidelines and consensus statements available in databases or websites, which met the following criteria:
• population – adult patients (≥18 years) with positive results from colorectal cancer screening test, or colorectal symptoms suggestive of colorectal cancer
• intervention – CT colonography (all methodologies)
• comparator – colonoscopy or DCBE
• outcomes – accuracy of test (sensitivity, specificity) for detecting polyps, morbidity and mortality, adverse events, acceptability to patients, incremental cost.
No date or language restrictions were applied. A list of the databases and websites searched and the key terms used is available in Appendix 1.
3.2 Selected studies
Eighteen potentially relevant HTAs and systematic reviews were identified by the literature search. Of these, 14 were included and these are described in Table 1. The reasons for excluding the other four studies are listed at the end of this section. The included studies comprised five HTAs (three from the USA, one each from Canada and France), eight systematic reviews of which four included meta-analyses, and one rapid literature review. All studies were published between 2000–2007. English summaries were available for the French HTA and a Swedish systematic review. Translations of the full documents were not obtained.
The majority of the HTAs and reviews identified were primarily concerned with the use of CT colonography for screening rather than diagnosis. This probably reflects the fact that many of the reports originate from North America where CT colonography is promoted for screening. Despite this aim, the primary studies identified in the reviews mainly included symptomatic patients, therefore the evidence presented is appropriate for consideration of CT colonography for diagnostic purposes. All reviews compared the performance of CT colonography to colonoscopy. Some also compared the technique with DCBE, but this was never the exclusive comparator.
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The search also identified one guideline specific to CT colonography, published by the American College of Radiology (ACR), and two consensus statements, one based upon international expert opinion, and another following on from this, from the European perspective. Details of these studies are given in Table 2. A position statement from the American Gastroenterological Association (AGA) was also retrieved, but excluded.
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3.3.1 HTAs and systematic reviews: assessment method
The methodological quality of the included HTAs and systematic reviews was assessed using the 10 item Oxman checklist (Oxman, 1994). In some instances it was necessary to consider supporting documentation, for example, a methods guide published on an organisational website, to fully assess a study. All assessments made were quality assured by a second reviewer, and any disagreements resolved by consensus. Scores assigned differed for only four out of the 12 studies, were all within one point and did not affect the interpretation and conclusions. The criteria on this checklist are as follows:
3.3.1.1 Study identification and selection
Q1. Were the search methods used to find evidence on the primary question stated?
Q2. Was the search for evidence reasonably comprehensive?
Q3. Were the criteria used for deciding which studies to include in the review reported?
Q4. Was bias in the selection of articles avoided?
3.3.1.2 Critical appraisal
Q5. Were the criteria used for assessing the validity of the studies that were reviewed reported?
Q6. Was the validity of all the studies referred to in the text assessed using appropriate criteria?
3.3.1.3 Study synthesis
Q7. Were the methods used to combine the findings of the relevant studies reported?
Q8. Were the findings of the relevant studies combined appropriately relative to the primary question the review addresses?
3.3.1.4 Conclusion
Q9. Were the conclusions made by the author supported by the data and/or analysis reported in the review?
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The checklist also included the assigning of a quality score based on an overall assessment of the study. A score of 7 denotes a study with minimal bias and a score of 1 indicates major biases.
3.3.2 HTAs and systematic reviews: assessment results
The results obtained are given in Table 3. Three studies met all the nine criteria (ECRI, 2005; ECRI, 2006; Halligan et al., 2005). A further study (Mulhall et al., 2005) met eight criteria, and partially met the assessment of the comprehensiveness of the literature search. For two studies (Swedish Council of Technology Assessment in Health Care, 2004; Agence Nationale d'Accreditation et d'Evaluation en Sante, 2001) it was not possible to judge quality from the limited data available in English.
3.3.2.1 Study identification and selection
All reports met criterion 1 on stating the search methods used to find evidence. Criterion 2 was fulfilled in six reports (Kruskal, 2007; ECRI, 2005; ECRI, 2006; Halligan et al., 2005; Xiong et al., 2005; National Institute for Clinical Excellence, 2004) as the search for evidence was reasonably comprehensive. The other reports were considered to only partially meet this criterion. Mulhall et al. (2005) applied language restrictions and also did not report hand searching, scanning reference lists or contacting authors. The Institute for Clinical Systems Improvement (ICSI) (2004) report did search bibliographies and consult work group members, but only searched the Medline database. Likewise the Technology Evaluation Center report (2004) only searched the Medline database. Sosna et al. (2003) applied language restrictions, did not hand search, use reference lists or contact authors, and only searched Medline. The Medical Advisory Secretariat report followed a similar approach, although also searched Embase. The Health Advisory Committee, searched a small range of databases, applied no language restrictions, but did not use extended search methods. Resulting variations in the included studies in each review are presented in Table 4.
Eight reviews (ECRI, 2005; ECRI, 2006; Halligan et al., 2005; Mulhall et al., 2005; NICE, 2004; Technology Evaluation Center 2004; Sosna et al., 2003; Medical Advisory Secretariat 2003) reported the criteria used for deciding which studies to include in the review (criterion 3). Kruskal (2007), ICSI (2004) and the Health Technology Advisory Committee (2002) did not provide this information. Xiong et al. (2005) provided minimal details. Regarding the avoidance of bias in selecting articles, five reviews (ECRI, 2005; ECRI, 2006; Halligan et al., 2005; Xiong et al., 2005; Mulhall, 2005) were felt to adequately meet this criterion, by following explicit selection criteria and having two reviewers making selection. Of the others, Kruskal (2007), ICSI (2004) and the Health Technology Advisory Committee (2002) did not provide any information on how selection was carried out (criterion 4). NICE (2004), the Medical Advisory Secretariat (2003) and the Technology Evaluation Center (2004) partially met this criterion by using explicit
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selection criteria, but did not provide any details of whether double selection was used or not.
3.3.2.2 Critical appraisal
Only five studies (ECRI, 2005; ECRI, 2006; Halligan et al., 2005; Xiong et al., 2005; Mulhall et al., 2005) reported the criteria they used for assessing the validity of the studies that were reviewed (criterion 5). The other reviews provided no information on the criteria they were using. The same five studies were also the only ones to quality assess the studies referred to in the text (Criterion 6).
3.3.2.3 Study synthesis
Most reviews provided some indication of how studies were being combined to reach a conclusion (criterion 7), although only six (ECRI, 2005; ECRI, 2006; Halligan et al., 2005; Mulhall et al., 2005; Sosna et al., 2003; Medical Advisory Secretariat, 2003) were considered to do so adequately. More detail is required in the Kruskal (2007), Xiong et al. (2005), and the Technology Evaluation Center (2004) reports. NICE (2004), ICSI (2004) and the Health Technology Advisory Committee (2002) give no adequate explanations of the manner in which data is being combined, although it should be noted that the purpose of the NICE report was to provide a rapid review of the evidence, not a systematic review. With regards to criterion 8, it was generally felt that studies were combined appropriately, although this was difficult to assess where criterion 7 had not been met, and no explanations had been given as to why qualitative synthesis was being used rather than meta-analysis. Where meta-analysis had been undertaken, heterogeneity was addressed.
3.3.2.4 Conclusion
For all studies but one, it was considered that the conclusions made by the authors were supported by the data and analysis reported in the review (criterion 9). It was not clear how exactly the conclusions in the Health Technology Advisory Committee (2002) report derived from the presentation of the findings.
3.3.2.5 Overall quality scores
Quality scores assigned ranged from 2–7, with the highest scores being achieved by studies undertaking meta-analysis (ECRI, 2005; Halligan et al., 2005; Mulhall et al., 2005; Sosna et al., 2003).
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y.
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Table 4 indicates the primary studies included in each HTA/systematic review. Only the first author of each primary study and the year are given. Further details of the primary studies can be found in the corresponding reviews.
It can be seen that whilst there is a relationship between the review date and the date of the included studies, there is also considerable variation in included studies. While the range and number of included studies depends on the different inclusion criteria applied in the reviews, it is likely also to reflect the comprehensiveness of the literature search undertaken, and hence attempt to overcome bias. Mulhall et al. (2005) includes 29 studies, the largest number of all the reviews considered. Pickhardt (2003) is the individual study which features most often in the secondary literature. Other primary studies which have been included most frequently are Johnson (2003), Pineau (2003), Gluecker (2002), Macari (2002), Hara (2001), Yee (2001), Fletcher (2000), Macari (2000), Fenlon (1999) and Rex (1999). Apart from the UptoDate review (Kruskal, 2007), there is little sign of later reviews building upon the findings of previous reviews, as would be evidenced by a descending diagonal distribution of crosses across Table 4.
The majority of the primary studies were carried out in symptomatic or high-risk patients. This is at odds with most of the reviews which were interested in average risk screening populations, however symptomatic and high-risk patients are the groups in which CT colonography is likely to be used in Scotland. Pickhardt et al. (2003) is the only study which considered asymptomatic average- risk screening patients. Although this is a different population group to that of interest in Scotland, with a different spectrum of disease and hence implications for the predictive power of the test, the application of the technique is the same as its use in the diagnosis of FOBT screen positive or symptomatic patients. In addition, the study is of interest as it is the largest study on CT colonography to date and is very well conducted (ECRI, 2005). The Pickhardt study (n=1,233), Cotton study (2004) (n=600) and Rockey study (2005) (n=614) were large multi- centre studies. The other studies were all single centre and mainly involved a much smaller number of subjects.
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3.3.3 Guidelines: assessment method
Aspects of the quality of the ACR guideline were assessed using the Appraisal of Guidelines Research & Evaluation (AGREE) checklist (http://www.agreecollaboration.org/). This assesses guidelines according to six domains, with scores expressed as a percentage of the maximum possible score for each domain. The domains are independent so should not be combined into an aggregate measure, however an overall assessment can be made of whether the guidelines should be recommended for use in practice or not. Guidelines scoring above 60% on most domains are usually highly recommended, those scoring between 30–60% are recommended with provisos or alterations, and those below 30% are not recommended.
3.3.4 Guidelines: assessment results
The scores obtained are in Table 5. The ACR guideline scored highly in terms of scope and purpose but did not score particularly well on a number of the other domains. It did not seek the views of patients, or carry out a pilot among target users. There is no information provided on whether systematic methods were used to search for evidence, what criteria were used for selecting evidence and how recommendations were formulated. No consideration was given to organisational barriers in implementing the recommendations of the guidelines or to likely cost implications. Conflicts of interest of the guideline developers are not reported. Such shortcomings are not unusual among guidelines developed by professional bodies for their members (Minhas, 2007).
The AGREE instrument does not assess the clinical content of guidelines or the quality of the evidence used. Assessment of the clinical content would require input from a clinical expert. Some confidence in this aspect of the quality of the guideline can be obtained however from the similarities between the guideline recommendations and the findings of the included HTAs/systematic reviews.
Table 5 Quality assessment of included studies: guidelines
Scope and purpose
83% 56% 54% 75% 50% 63%
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3.3.5 Consensus statements
There were no checklists identified to assess the consensus statements. The limited methodological information provided in the reports of both consensus statements made it difficult to judge their quality. Both consensus statements surveyed only a small number of subjects who were selected based upon fairly narrow criteria. While they may have been the experts in the field, this does not allow for the consideration of diverse viewpoints from the wider community and a variety of specialities. It is not clear how the existing evidence base was used in arriving at a consensus, and also what the strength of feeling was for and against the statements produced.
Table 6 Excluded studies
Study Reason for exclusion
Colon examination with CT Colonography. Danish Centre for Evaluation and Health Technology Assessment (DACEHTA) (2005).
Primary study.
Pre-assessment brief – full systematic review not undertaken.
Virtual colonoscopy (computed tomography colonography). Hayes (2003).
Report not available.
Virtual colonoscopy. MSAC, Australia (2001). Horizon scanning report – all trials considered are incomplete.
Position of the American Gastroenterological Association (AGA) Institute on Computer Tomographic Colonography (2006).
No useful data.
4.1 Clinical effectiveness
The review of the clinical effectiveness of CT colonography considers its impact on health outcomes, the accuracy of the technique, its safety, its acceptability to patients, and the impact of incidental findings.
4.1.1 Is there evidence to demonstrate whether CT colonography will improve health outcomes compared with ‘conventional’ colonoscopy or DCBE in those diagnosed with clinically significant polyp(s)?
This is the question ultimately of interest when considering the clinical effectiveness of CT colonography. However none of the systematic reviews or HTAs identified by the literature search found any primary studies examining the effect of CT colonography versus colonoscopy or DCBE on the key health outcomes of colorectal cancer morbidity and mortality. In the absence of longitudinal or modelling studies examining these outcomes measures of test performance, which are discussed in the following section of this report, provide surrogate outcome measures, bearing in mind the implications of length and lead time biases.
There is no direct evidence for the efficacy of colonoscopy itself in improving colorectal cancer-related morbidity and mortality, although indirect evidence relating to sigmoidoscopy (ECRI, 2005) does support its efficacy as a screening tool. If close equivalence of CT colonography to colonoscopy in detecting polyps is demonstrated, further research would still be required to determine whether CT colonography could be assumed to have a comparable effect on morbidity and mortality (Kruskal, 2007). Also, in NHSScotland, the interest in using CT colonography is likely to be in diagnosis rather than screening, with the requirement for other technologies in the pathway from initial screen to polyp removal.
4.1.2 What is the accuracy (in terms of sensitivity and specificity) of CT colonography for detecting polyps compared with conventional colonoscopy or DCBE?
To assess whether CT colonography can be used as a diagnostic tool its accuracy in detecting polyps must be measured. There is no gold standard available. Colonoscopy is not 100% accurate (Rex et al., 1997), but it is commonly used as a reference standard. To improve the accuracy of colonoscopy as a reference standard segmental unblinding, in which CT colonography results are revealed to the examiner after each bowel segment scanned by colonoscopy, and the colonoscopy redone if the results for that segment do not agree, is sometimes employed (Pineau et al., 2001). This provides a truer measure of the performance of CT colonography. A major
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source of uncertainty in assessing accuracy is whether false-positive results on CT colonography are due to no lesion being seen at colonoscopy, or size or anatomic mismatching.
It is also of interest to consider the performance of CT colonography against DCBE, which has application in current diagnostic practice. The estimates of test performance will vary depending on which reference standard is used.
Results can be presented per-patient, in which the presence of one or more polyps is detected in a patient, or per-polyp, which considers each individual polyp detected. Given that the detection of even one polyp in a patient would be sufficient to trigger further investigation, the per-patient analysis is of greater clinical relevance. Specificities are only available for the per-patient data, as the denominator for the per-polyp analysis is unknown. Due to considerable variability in the detection of polyps of different size and their relative clinical significance, results are generally presented stratified by polyp size. Most studies classify polyps into three categories: ≥ 10 mm (large), 6–9 mm (medium), ≤5 mm (small), although some studies adopt different thresholds.
Performance of CT colonography is affected by factors relating to the patient group being studied, aspects of the technique used and the experience of the examiner. The performance of colonoscopy and DCBE will likewise be affected by similar factors.
Regarding patient characteristics, while sensitivity and specificity theoretically do not alter in response to the prevalence of a condition in the population under study, the results may be affected by whether the test is used in a screening or diagnostic capacity. If the baseline risk of study participants is apparent to investigators, there is a potential for clinical review bias. Patients will have polyps of a variety of types and shapes. Some of these, particularly flat polyps (Medical Advisory Secretariat, 2003; Fidler et al., 2004), are more difficult to detect using CT colonography. In some patient examinations there can be misinterpretation of stools or folds as polyps and vice versa, and also breath-hold artefacts.
In terms of the technique used, there can be variations in the prescanning procedure, the scanning and image acquisition itself, and image processing. Aspects of prescanning include the particular bowel cleansing preparation carried out, the use of room air or CO2 for bowel distension, and whether intravenous contrasts or spasmolytic medications are used. In scanning and image acquisition, factors that can vary include the use of spiral versus sequential CT, multi-slice or single-slice scans, the particular pitch setting and slice thickness, and the use of prone and/or supine positions. Whether CT colonography is used to detect all types of polyp, or adenomas only, may also affect test performance. Image processing can involve the use of either 2D or 3D views, or both.
A marked learning curve has been noted for those performing CT colonography exams and training is considered of key importance (National Institute for Clinical
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Excellence, 2004). Some studies have shown that double reading of results significantly improves sensitivity (Institute for Clinical Systems Improvement, 2004). Whilst consensus readings may improve accuracy, such an approach may not be typical of CT image reading practice.
In addition to the above considerations, the technology employed is continually developing with consequent changes in the measures of performance obtained. For example, faecal tagging has been used (Pickhardt et al., 2003) and novel image displays systems which shorten interpretation time are being developed (Vandaele et al., 2006). Similarly the technology of the reference standard colonoscopy is evolving with new imaging techniques developing, such as magnification colonoscopy and chromendoscopy (Kruskal, 2007). DCBE is a more mature technology and as such, is less subject to development.
4.1.2.1 Summary of evidence
Twelve identified HTAs and systematic reviews, judged to be of varying quality, presented data relating to the sensitivity and specificity of CT colonography. Each HTA and systematic review was based upon a different set of primary studies according to the particular inclusion/exclusion criteria applied in the review and the date and scope of literature search undertaken. The identified guideline and the two consensus statements were also examined to determine if they provided additional evidence for this question and where they did it is reported in the relevant subsections below.
4.1.2.2 Assessment of evidence – test performance
Given the considerable variability in the populations, procedures and experience levels of examiners within the primary studies included, most systematic reviews and HTAs did not conduct a meta-analysis of test performance. Three studies, assessed to be of good to high quality, did however present pooled estimates of sensitivity and specificity (Mulhall et al., 2005; Halligan et al., 2005; Sosna et al., 2003), although all noted significant heterogeneity. A further robust study (ECRI, 2005) also carried out a meta-analysis, but considered it impossible to present pooled estimates of the sensitivity and specificity. Results for this study are therefore presented under the narrative synthesis section. Further details of the studies performing meta-analyses are given in Table 7. The results obtained in each of the meta-analyses undertaken are given in Table 8 for the per-polyp analysis, and graphically in Figure 2 for the per-patient analysis. Corresponding data values for Figure 2 are presented in Appendix 2 (included studies in each meta-analysis are given in Table 4).
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Table 8 Pooled sensitivity values for the per-polyp analysis
Figure 2 Pooled sensitivity and specificity values (%) for the per-patient analysis
Polyp size
≥10 mm ≥6 mm 6-9 mm ≤5 mm
Halligan et al. (2005) 77 (70, 83) 70 (63, 76) Not reported Not reported
Sosna et al. (2003) 81 (76, 85) Not reported 62 (58, 67) 43 (39, 47)
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Sensitivity
4.1.2.3 Discussion of meta-analysis results
Figure 2 presents the sensitivities (x-axis) and specificities (y-axis) for each polyp size considered in the per-patient analysis for each of the three meta-analyses. It can be seen from this figure, that in the per-patient analysis for large polyps, sensitivities ranged from 85% (95% CI 79%, 91%) for Mulhall et al. to 93% (95% CI 73%, 98%) for Halligan et al. with considerable overlap of the wide confidence intervals. For medium-sized polyps, Mulhall et al. again obtained the lowest value of 70% (95% CI 55%,84%) whereas Halligan et al. found 86% (95% CI 75%, 93%), again with overlap of the confidence intervals. Halligan et al. did not attempt to pool the data for small polyps due to the large degree of heterogeneity. Mulhall et al. obtained a low sensitivity of 48% (95% CI 25%, 70%) but with very large confidence interval, and the sensitivity for the Sosna et al. study was 65% (95% CI 57, 73%).
As can be seen in Figure 2, there is much greater consistency and narrower confidence intervals in the per-patient analysis specificities. For large polyps, both Mulhall et al. and Halligan et al. calculated an overall specificity of 97% and Sosna et al. reported a specificity of 95%. For medium-sized polyps, the values were slightly less consistent, with Halligan et al. estimating a specificity of 86% with fairly wide confidence intervals and Mulhall et al. a specificity of 93%.
The authors’ conclusions for each meta-analysis are given in Table 9. All authors were in agreement that sensitivities and specificities were higher for larger polyps, and that the technique was less effective for detecting small polyps. Greater consistency in specificities than sensitivities were noted by all studies. However the studies differed slightly in their assessment of the accuracy of the technique for use in screening. Sosna et al. concluded that CT colonography is an accurate tool for detecting large polyps and Halligan et al. that the average sensitivities and specificities for large and medium polyps are high. Mulhall et al. also noted high specificities, but wide variations in sensitivities. Mulhall et al. considered that further study of the technique is required before it can be recommended for general use in screening, and Halligan et al. noted the need for further research in asymptomatic subjects.
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Author conclusions
Halligan et al. (2005) CT colonography has high average sensitivity and specificity for large and medium colorectal polyps and excellent sensitivity for cancer in symptomatic patients. More work is needed in asymptomatic subjects.
Mulhall et al. (2005) CT colonography is highly specific especially for large polyps, however the reported sensitivities vary widely even for large polyps. CT colonography needs further refinement before it can be recommended for general use in screening for colorectal cancer.
Sosna et al. (2003) CT colonography is an accurate tool for detecting clinically important colorectal polyps. The specificity and sensitivity are especially good for detecting large polyps.
The variations in results and differing conclusions can be examined by considering the studies included in each meta-analysis and also the methodology followed. The meta-analysis by Mulhall et al. included the largest number of patients, and the most up-to-date literature. However, several studies that were included in the Halligan et al. review were not retrieved by Mulhall et al. as their search was limited to English language. In addition, the study by Cotton et al. (2004) which has been criticised over various aspects of its methodology, including the lack of experience of some of the examiners (ECRI, 2005), was included. The meta-analysis by Sosna et al. was undertaken prior to the publication of the largest primary study to date by Pickhardt et al. (2003).
The studies adopted different approaches to pooling primary studies and dealing with the heterogeneity among them. Sosna et al. considered heterogeneity using the exact contingency test which considers sensitivity and specificity separately thus ignoring a possible threshold effect. Both Halligan et al. and Mulhall et al. carried out meta-analysis of paired per-patient sensitivities and specificities, by generating summary receiver operator curves which allow for variation in threshold between studies. These latter two studies are consequently more robust in their analyses. It should be noted that the methodology in this area has developed considerably in recent years and the methods used are all inferior to those recommended as best practice for meta-analysis of diagnostic studies (Dr J Cook, Health Services Research Unit, University of Aberdeen, personal communication, 5 March 2007).
Halligan et al. and Mulhall et al. both tried to investigate sources of heterogeneity among studies. Halligan et al. attempted to assess the effect of using a modified
39
reference standard (segmental unblinding of colonoscopy) and of individual versus consensus agreement, but there were too few studies available to allow analysis. Mulhall et al. carried out subgroup analysis by year of publication, imaging technique, collimation width, reconstruction interval, type of scanner, use of contrast agent and patient characteristics. They found that thinner slices for collimation and the use of multidetector scanners resulted in higher sensitivities. Concomitant 2D and 3D imaging produced higher sensitivities than confirmatory 3D, and fly-through imaging appeared to offer the highest sensitivities, although this finding was based upon a small number of studies. No effect was observed for the other variables. However the authors noted that this does not mean that these are not sources of heterogeneity; only that it is not possible to show heterogeneity given the current data set. All three meta-analyses considered here adopted a fairly inclusive approach in that the precise techniques used in conducting CT colonography in the included studies varied, but all techniques were in line with the generally accepted most current requirements for technically competent CT colonography.
4.1.2.4 Studies performing narrative synthesis
Eight other HTAs and systematic reviews did not attempt to statistically pool the data, but instead undertook narrative synthesis. These were judged to be of varying quality, and their findings interpreted and used accordingly. The studies included in each of these documents can be seen in Table 6. The conclusions drawn regarding test characteristics are summarised in Table 10. This table also indicates whether the reviews included the three largest trials undertaken (Pickhardt, 2003; Cotton, 2004; Rockey, 2005) and summarises any sensitivity and specificity data presented in table format within the report. Details of the Pickhardt et al. (2003) and Cotton et al. (2004) studies are presented in Appendix 4. Equivalent information for the Rockey et al. (2005) study is given in Table 11.
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Notes Author conclusions
Kruskal (2007) Reports Pickhardt, Cotton and Rockey studies.
Sensitivity has been variable in different reports raising questions about the generalisability of findings from studies; effectiveness as a screening tool has not yet been demonstrated.
ECRI (2005); ECRI (2006) Includes Rockey and Pickhardt studies; actively excludes Cotton.
Sensitivity:
Specificity:
≥10 mm 73.8–100%.
CT colonography is able to detect most large colorectal polyps and masses but is less sensitive for detecting smaller polyps. Authors could find no explanation for the fact that CT colonography was found to be more effective in some studies than others.
National Institute for Clinical Excellence (2004)
Includes Sosna meta-analysis, and Pickhardt study.
Noted that the main efficacy concern is the risk of missing flat or small lesions.
Institute for Clinical Systems Improvement (2004)
Includes Sosna meta-analysis, Cotton and Pickhardt studies.
In a screening population with the present data acquisition and interpretation protocols, it is not clear how colonography compares with colonoscopy in terms of sensitivity and specificity due to limited available data.
Swedish Council of Technology Assessment in Health Care (2004)
Includes Pickhardt and Cotton studies.
Sensitivity:
≥10 mm range 35–100%.
Scientific evidence on diagnostic reliability of colonography is not conclusive. The differences in results from different studies can be due to differences in equipment, procedures and experience. Studies should
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concentrate on expected effects and costs under ordinary conditions before applying the method more generally in the health service.
Technology Evaluation Center (2004)
Sensitivity:
Specificity:
Overall sensitivities were variable between studies. At smaller threshold sizes of detection, CT colonography was both less sensitive and less specific. Variable performance of colonography may be associated with interpreter experience of other technical factors.
The current evidence does not allow conclusions as to the comparative efficacy of colonography and colonoscopy.
Medical Advisory Secretariat (2003)
Sensitivity:
≥10 mm range 80–100% for multi-slice scanning and 57– 100% for single-slice scanning
6–9 mm range 33–86% for multi-slice scanning and 0– 80% for single-slice scanning
≤5 mm range 3–70% for multi- slice and 18–68% for single- slice scanning.
Performance of CT colonography depends on the size of the lesions, also technical factors such as scanning techniques, method of bowel preparation, and the radiologist’s experience.
Based on current evidence, colonography cannot be proposed for population-based colorectal cancer screening.
Health Technology Advisory Committee (2002)
Sensitivity:
Specificity:
≥10 mm range 82–98%.
Further research needed before CT colonography can be recommended as a screening tool. Sensitivity and specificity need to improve to be comparable with colonoscopy.
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Sensitivity:
5–9 mm range 38.5–82%
<5 mm range 0–59%.
Specificity:
≥10 mm range 62–98%.
Wide variations among studies in sensitivity and specificity which can probably be explained by differences in the hardware and software used, and in the experience of the operators examining the images.
It can be seen from Table 10 that the included studies reported sensitivities for polyps greater than 10 mm, ranging widely from 35–100%. The authors of the ECRI report attempted to analyse the factors responsible for the differences but were unable to provide an explanation. Most of the other reviews suggest explanations for these variations including the particular techniques adopted, patient populations and experience of examiners, as discussed in Section 4.1.2, but do not perform actual analyses. It is interesting that despite the reviews being conducted over a six-year period, and the later reviews including the large trials that were unavailable to the earlier ones, there is very little difference in the conclusions drawn. Despite some studies being less robust than others, there is considerable consistency in their findings. All the studies conclude that sensitivities vary greatly and four specifically conclude there is insufficient evidence to recommend CT colonography as a screening tool.
The values quoted for the sensitivity and specificity of CT colonography are based upon a reference standard of colonoscopy with a 100% sensitivity and specificity. As discussed in the introduction to this question, the sensitivity and specificity of colonoscopy is not 100%, which leads to the question of how CT colonography actually compares with colonoscopy. Given that there is no perfect reference standard to use short of pathological examination of a resected surgical specimen, there is no way of making this direct comparison. A comparison of sorts is offered by the trials (Pineau 2001, Pickhardt 2003, Cotton 2004, Rockey 2005) which use segmental unblinding of the colon, in which the results of CT colonography are revealed after each colon segment is examined by colonoscopy, and the colonoscopy redone if the results for that segment do not agree.
This provides revised estimates of CT colonography sensitivities and specificities, and also colonoscopy test-retest results in a selected sample of patients, in relation to a new reference standard of CT colonography plus
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colonoscopy and a second colonoscopy where there are discrepant results. Given that colonoscopy will always have to follow a clinically significant positive CT colonography, this comparison is probably only of theoretical interest, although it also gives some indication of the independent prognostic value of CT colonography and suggests perhaps an additional benefit of doing CT colonography followed by colonoscopy, rather than progressing straight to colonoscopy .
4.1.2.5 Double contrast barium enema (DCBE) as comparator
The Medical Services Advisory Committee (2001) notes that CT colonography provides information on lesion density, colon wall thickness, and extra colonic structures, which DCBE cannot. CT colonography has been almost exclusively compared with colonoscopy, although there are a few studies included in the HTAs and systematic reviews that use DCBE as a comparator. Also DCBE is limited to planar views and images are affected by radiodense shadows. In the absence of any synthesis of data from studies in the included reviews, the results of individual studies examining colonography in comparison with DCBE are discussed briefly. Three studies were identified in the systematic reviews (Rockey et al., 2005; Johnson et al., 2004; Hara et al., 1997). The Hara et al. study was not considered further as it could only be retrieved in abstract form, and the technology for CT colonography has progressed considerably since 1997.
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Table 11 Details of studies comparing the accuracy of CT colonography versus DCBE
Aim Type of study Population Intervention Reference
test
Rockey et al. (2005)
Compare the accuracy of DCBE, CT colonography and colonoscopy for the detection of large colon polyps and cancers – test of non-inferiority between CT colonography and colonosocopy for detections of lesions ≥10 mm and test of superiority between CT colonography and DCBE for significant lesions.
Prospective cohort.
Patients with a high likelihood of colon abnormalities (n=614 completed all three tests).
1. DCBE according to standard guidelines (DCBE).
2. CT colonography: prone and supine positions; air or CO2 insufflation; multislice scanner; 2D analysis with 3D problem solving (CTC).
3.Colonoscopy according to standard procedures (COL).
Reconciliation of all three tests to develop consensus view of the colon.
Johnson et al. (2004)
To compare the relative sensitivities and specificity of CT colonography with DCBE.
Prospective cohort study.
Asymptomatic subjects at higher than average risk of colorectal cancer scheduled to have a barium enema X-ray (n=837 completed both tests).
CT colonography (read by 2 radiologists).
Barium enema x-ray (read by single radiologist).
Colonoscopy.
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1
48
As can be seen from Table 12, Rockey et al. found that for lesions greater than 10 mm, there was no evidence of the sensitivity of CT colonography being significantly superior to that of DCBE. However, for lesions of 6–9 mm and ≤5 mm, CT colonography was significantly more sensitive than DCBE. The specificity for CT colonography was significantly greater than that of DCBE for all polyp sizes. In contrast, Johnson et al. found that the sensitivity of double-read CT colonography was significantly greater than of single-read DCBE for all polyp sizes, but the specificities of DCBE were significantly higher than CT colonography for all polyp sizes. It is difficult to compare the results of these studies given the different reference standards employed and the double reading process used in the Johnson et al. study. Several aspects of the studies point to that, by Rockey et al., as being more robust, and hence the results carrying more weight. Firstly, Rockey et al. made use of a combined reference standard. Secondly, there was possible verification bias in the Johnson et al. study as a result of suspected positive DCBE all being followed by confirmatory colonoscopy but not all the positive CT colonography tests being followed by colonoscopy. Thirdly, the use of two readers in the Johnson et al. study does not reflect clinical practice.
A comparison of the accuracy of DCBE with colonoscopy is beyond the scope of this study, however such a comparison would provide validation of results obtained for the comparison of CT colonography versus colonoscopy and CT colonoscopy versus DCBE. Several points relating to this comparison were noted in the literature. Firstly, it is reported that preliminary data from the national polyp study, in which more than 3,000 patients underwent both DCBE and colonoscopy, showed that barium enema could only detect 44% of colorectal neoplasms, 1 cm or greater (Ahlquist & Johnson, 1999). The SBU report (Swedish Council of Technology Assessment in Health Care, 2004) noted that the diagnostic reliability of CT colonography compared with colonoscopy appears to be at least equal to the diagnostic reliability of DCBE compared with colonoscopy.
4.1.2.6 What are the implications of ‘missing’ a patient with one or more polyps, based upon the likelihood of a polyp already being, or becoming, cancerous?
Given that the sensitivities and specificities of CT colonography are lower for smaller polyps, its utility in diagnosis depends upon the threshold polyp size considered clinically significant, and the growth rate of polyps. Debate over what size of polyp is clinically significant and merits removal is ongoing (Church, 2004). The prevailing view from the literature appears to be that polyps greater than 10 mm should be removed, and that those less than 5 mm can be left, however the position for polyps falling between these values is not clear (Pickhardt et al., 2003). If a 6 mm cut-off was adopted, Mulhall et al. determined that CT colonography would preclude the need for colonoscopy in 86% and 68% of patients with a 1% or 2% false negative rate respectively. Forty-six percent (11/24) of respondents in the Barish (2005) consensus study believed that
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polypectomy should not be routinely recommended for polyps ≤10 mm detected by CT colonography. The remainder believed that the threshold should lie between 5–9 mm. The European consensus statement (Taylor et al., 2007) proposes that polyps < 5 mm should not be reported. According to the American College of Radiology (2005) guidelines, all polyps ≥10 mm should be identified and reported. Reporting of polyps ≤5 mm is not recommended. The position regarding 6–9 mm polyps depends on the certainty of the finding and the clinical context.
Analysis of epidemiological studies examining the growth and progression rate of different types and sizes of polyps, in conjunction with expert opinion, is required to fully examine the implications of failing to identify a patient with one or more polyps. However, this is outside the scope of the current study.
4.1.2.7 Does the effectiveness of CT colonography as a technique for detecting polyps differ between patient subgroups?
In some patients, completion of colonoscopy is impossible due to redundancy or convolution of the colon, pain or spasm, fixed bowel loops, diverticula and colonic obstruction/stenosis (ECRI, 2005). The report from the Medical Advisory Secretariat in Ontario (2003) noted that colonoscopy fails to reach the caecum in 5–10% of average risk patients. CT colonography can be used to investigate the unseen regions. The Ontario report considered three very small studies which looked at the use of CT colonography after incomplete colonoscopy and concluded that CT colonography has a valuable role for patients with obstructions. ECRI (2005) considered 13 more recent studies which reported totals for both incomplete colonoscopy and CT colonography. They found that the proportions for both modalities were similar, but noted that the clinical impact differed because incomplete colonoscopy is likely to leave more of the colon unexamined than incomplete CT colonography. Two of the studies included in the Ontario report considered the relative performances of CT colonography and barium enema in detecting unseen areas of the colon after incomplete colonoscopy. One study showed that colonography detected more lesions, and the other showed equivalence between the techniques. Both studies were too small for the results to be considered other than exploratory. Regarding the choice of technique following incomplete colonoscopy, the report by the Minnesota Department of Health (Health Technology Advisory Committee, 2002) notes that the colon is often distended with air after an incomplete colonoscopy, which means that little additional insufflation is needed for CT colonography if carried out immediately afterwards. In contrast, effective DCBE is impeded.
Elderly patients, patients on anticoagulation therapy or for whom sedation is contraindicated might also be considered as subgroups in which CT colonography would be advantageous, as it avoids the need for an invasive procedure (Health Technology Advisory Committee, 2002). However, while acknowledging the practicality of CT colonography in these groups, the identified literature does not report supporting evidence.
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4.1.2.8 How do different bowel preparation methods influence the accuracy of the results obtained by CT colonography?
The Ontario HTA (Medical Advisory Secretariat, 2003) noted that the authors of most included studies considered adequate bowel preparation to be of major importance in the accurate interpretation of CT colonographic images. Consensus on the use of spasmolytic agents in CT colonography is lacking. Some believe that their use prevents collapse of segments of the bowel and improves imaging, whereas others believe that it may result in unwanted reflux of air into the small bowel (Institute for Clinical Systems Improvement, 2004). The majority of respondents in the Barish et al. (2005) study were against the use of spasmolytics, whereas Taylor et al. (2007) suggested that they are routinely used. The ACR guidelines (American College of Radiology, 2005) are not prescriptive. For insufflating the bowel, CO2 is used by some centres rather than room air, as it is felt to be better tolerated by the patient (Kruskal, 2007). The consensus statements and ACR guideline suggested that either could be used. Intravenous contrast has been shown to improve diagnostic accuracy, and is considered useful in certain patients by specialist advisors to NICE (National Institute for Clinical Excellence, 2004) but it is not used in most centres. It can cause adverse reactions in patients, and also increase costs (Medical Advisory Secretariat, 2003). Of the respondents to the Barish et al. study, the majority (81%), believed that the use of intravenous contrast material is not necessary. Taking the opposite viewpoint, Taylor et al. considered that it should be used for symptomatic patients and the ACR guideline stated that it should be used where not contraindicated.
The UpToDate report (Kruskal, 2007) discusses several studies in which patients have not undergone a standard bowel preparation, but instead have been asked to ingest a contrast agent with several meals prior to the CT colonography examination. The contrast agent leads to ‘faecal tagging’, and allows the contrast-enhanced faeces to be differentiated from the surrounding tissue. The method is enhanced by the use of digital subtraction techniques. Research in this area is ongoing, and the benefits gained from the reduced bowel preparation must be weighed against safety considerations, and the contrast agent precluding immediate subsequent colonoscopy for polypectomy (polyp removal). The Barish et al. consensus statement found that 62% of respondents did not believe that faecal tagging is necessary. Partly based upon the Pickhardt et al. (2003) study results, Taylor et al. recorded more support for the use of oral tagging agents, although it was considered that symptomatic patients should still be offered a full bowel preparation. The view expressed in the ACR guideline is that there is insufficient evidence for the use of oral contrast for labelling stools, and that minimal or no preparation approaches have not been validated in clinical trials.
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4.1.2.9 What is the influence of CT scanning protocol and scanner detection technology on image quality and motion artefacts?
Spiral (helical) CT scanning has advantages over sequential CT scanning because, with the exception of very large patients, it uses one breath hold to scan the whole colon, eliminating imaging gaps. The scan time for multi-slice scanners is faster (average 24 seconds per scan) than that for single-slice scanners (average 35 seconds per scan) (Institute for Clinical Systems Improvement, 2004). This results in less motion artefact, and is particularly useful for individuals who have problems holding their breath. Multi-slice systems can scan using 1 mm thick slices compared with the 3–5 mm thickness of the single- slice detector. Production of increased numbers of very low slice images will however increase the radiation dose received by the patient and place increased demands on storage capacity. The former issue is being addressed by newer systems which use lower radiation doses, although evidence of effectiveness of the lower dose systems needs further assessment, preferably through large- scale randomised trials (ECRI, 2005). Most of the included studies did not consider evidence on the comparative performance of different types of scanner. The meta-analysis conducted by Mulhall et al. (2005) showed the sensitivity of detectors using multiple scanners to be higher than those with single detectors, and there to be an almost 5% decrease in sensitivity with every 1 mm increase in collimation width. The Ontario HTA (Medical Advisory Secretariat, 2003) compared 16 studies performed with a multi-slice scanner with studies performed with a single-slice machine. They concluded that superior sensitivity was achieved using narrower slice widths, however only two of the studies considered had undertaken within-study comparisons. The Barish et al. and Taylor et al. consensus statements and the ACR guidelines all considered that a slice thickness of ≤3 mm is optimal.
Patients may be scanned in both the prone and supine positions. The Ontario HTA report (Medical Advisory Secretariat, 2003) found that studies in which scanning was performed in both positions showed higher sensitivities. The use of both positions redistributes colonic fluid and gases thus reducing measurement artefacts. Both consensus statements and the ACR guidelines suggested that patients are scanned in prone and supine positions.
4.1.2.10 How do different image processing technologies impact upon the accuracy of CT colonography for detecting polyps?
The use of 2D and 3D images is complementary, with 2D images allowing accurate assessment of the colonic wall and detection of lesions behind folds, and 3D images confirming lesions and helping to distinguish folds from polyps. There are three main algorithms used to generate 3D images: surface rendering, maximum intensity projection and volume rendering. The third of these is the newest approach and by making use of all the available data creates a more accurate image (Medical Advisory Secretariat, 2003). The meta-analysis by Mulhall et al. (2005) found that use of 3D endoluminal “fly-through” technology
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offered higher sensitivity than using 2D, either followed by confirmatory 3D analysis, or concomitant 3D analysis. However this finding was based upon only two studies. The consensus statements and the ACR guidelines indicated that a combination of 2D and 3D images should be used for analysis. The ECRI Windows report (ECRI, 2005) noted that there is great interest in applying computer aided detection (CAD) techniques to CT colonography but at the time of publication no such systems had reached the clinical trial stage. Respondents to the European consensus statement (Taylor et al., 2007) expressed the view that CAD is likely to improve reader performance, but the appropriate protocols were not yet in place.
4.1.2.11 What impact does the experience of the examiner have on the accuracy of interpretation of the images?
It is widely acknowledged in the literature that the accuracy of radiologists in interpreting images improves with experience (Technology Evaluation Center, 2004; Health Technology Advisory Committee, 2002; Institute for Clinical Systems Improvement, 2004; National Institute for Clinical Excellence, 2004; Swedish Council of Technology Assessment in Health Care, 2004). However, no synthesis of evidence is presented in the reviews which demonstrates this relationship. Mulhall et al. (2005) were unable, given the data available, to evaluate the role of radiological expertise as a source of heterogeneity in the meta-analysis undertaken.
In the absence of clear-cut evidence and given variations in skills and aptitudes of those interpreting images, the ACR guidelines recommend that supervising and interpreting physicians should have reviewed at least 50 cases. This should be either as part of formal hands-on training, or with a supervisor acting as a double reader, or by correlating findings in patients undergoing CT colonography and colonoscopy. The European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus statement (Taylor et al., 2007) concurs with the specified minimum of 50 cases, and expands upon this to state that testing should be carried out to ensure that an adequate level of competency has been achieved. The test dataset should include at least 20 cases with a prevalence of abnormalities of between 21–50%.
4.1.2.12 Conclusions on the accuracy of CT colonograpy for detecting polyps
The results of the meta-analyses and the narrative synthesis of the accuracy of CT colonography point to the same general conclusion. While specificities are fairly consistent, there is considerable uncertainty over the optimal sensitivity achievable using the technique. Variations in the equipment, procedure and experience of the examiner affect sensitivities. Given the variability between studies, the results from the recent large-scale multi-centre trials might provide the most accurate representation of the performance of the technique. The Cotton et al. study has considerable flaws however and does not therefore lend
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itself to generalisation; the Pickhardt et al. study was well conducted but concerns a screening rather than diagnostic population.
In all the studies considered, the sensitivity of CT colonography was higher for large polyps than smaller ones. What size of polyp is clinically significant however is still being debated. The consensus appears to be that the threshold lies somewhere between 5–9 mm but agreement upon this is required to determine the usefulness of CT colonography as a diagnostic method.
Colonoscopy is used as reference standard in most trials, and direct comparisons of CT colonography and colonoscopy are thus not possible. Several trials have however used segmental unblinding which does allow an assessment of the accuracy of each technique in relation to the combined reference standard of both methods. In relation to DCBE, the results of one trial suggest that CT colonography is more sensitive in detecting small and medium-sized polyps than DCBE, and more specific for all types of polyp.
The small amount of evidence on the use of CT colonography in particular patient groups showed a valuable role for CT colonography where bowel obstructions prevent complete examination of the colon by colonoscopy. Furthermore incomplete CT colonography examinations generally manage to assess more of the colon than incomplete colonoscopies. CT colonography is believed to offer benefits over colonoscopy for elderly patients, those on anticoagulation therapy or where sedation is contraindicated, however no evidence is presented within the reviews in relation to this.
There is consensus over some aspects of bowel preparation, but not others. It is possible that various options offer similar levels of performance. The use of faecal tagging is still under development. Most included studies did not consider comparative performance of different scanners, although there is evidence for scanning in both the prone and supine positions and for the superior performance of multi-slice detectors with narrower collimation widths. Slices of ≤3 mm are generally considered optimal. Based upon a small number of studies, there is evidence for the superior efficacy of 3D fly-through imaging technology, but the general view is that at present 2D and 3D imaging modalities are complementary. CAD for CT colonography is still under development. Based upon consensus agreement, it is suggested that image interpreters should have reviewed at least 50 cases before being considered proficient.
4.1.3 What are the reported complication rates for CT colonography compared with ‘conventional’ colonoscopy or DCBE?
The systematic reviews and HTAs, and other literature identified by the search were scanned to identify whether they provided evidence on adverse events relating to CT colonography, colonoscopy or DCBE. Five studies (ECRI, 2005; Kruskal, 2007; National Institute for Clinical Excellence, 2004; Institute for Clinical Systems Improvement, 2004; Medical Advisory Secretariat, 2003) all reviewed
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literature in relation to this question. A number of the other reports did not formally review literature on this topic, but provided some discussion of the issue.
With colonoscopy there is a risk of perforation to the bowel. It is noted in the introduction to the ECRI Windows report (ECRI, 2005) that two very large case series studies demonstrated that perforation of the colon occurred in one out of every 1,300 colonoscopy procedures (0.077%), and about 5% of these perforations are fatal. The US Preventative Services Task Force found perforation rates for colonoscopy ranged from 0.029–0.61% (Technology Evaluation Center, 2004).
ECRI identified 11 studies, comprising 3,157 patients, which reported adverse event rates for both CT colonography and colonoscopy. Only one perforation of the colon during colonoscopy was reported, giving a perforation proportion of 0.03%, which is consistent with the literature discussed above. There were no significant adverse effects noted from CT colonography. The use of CT colonography instead of colonoscopy removes much of the risk of the invasive procedure, although UptoDate (Kruskal, 2007) notes two case reports of colonic perforation due to air insufflation. Both of these were in patients with other bowel disease. The consensus statement from ESGAR (Taylor et al., 2007) suggests that there is increasing awareness of a risk of perforation during CT colonography. This risk may be related to the use of larger bore inflated balloon catheters, which are no longer recommended.
Besides the risk of perforation, there are further possible adverse events from colonoscopy. A large study, also discussed in the introduction to the ECRI report, found that the most frequent major complication of colonoscopy was gastrointestinal bleeding, for which 0.2% patients required hospitalisation. The most frequent minor complications were vasovagal attacks (5.9%) and transient oxygen desaturation (4.4%).
None of the included studies in the reviews considered reported significant adverse events from CT colonography, however the risk of exposure to radiation is discussed. The ECRI Windows report (ECRI, 2005) suggested that there is a small risk of long-term harm from radiation. This risk is increased if multiple images are obtained, and is likely to be greater for women than men (Medical Advisory Secretariat, 2003). The radiation dose experienced by those undergoing CT colonography is however similar or less than that of DCBE, and considerably less than that from abdominal or pelvic CT scans (Kruskal, 2007). There is no quantification of the radiation risk within the secondary literature. A recent primary study suggests a lifetime cancer risk association with radiation exposure from paired CT colonography scans to be approximately 0.14% for a 50 year old. There have been preliminary studies of low dose CT colonography reported, but no large scale trials yet (ECRI, 2005). The Institute for Clinical Systems Improvement (2004) noted that studies suggest that even lower doses than used currently could be employed. Further research is required.
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For both tests, there is a risk of reaction to the bowel preparation agents, and as with all such tests, the effect on patient anxiety engendered by false-positive results, false reassurance from false-negative results and disappointment and anger caused by false results.
While removal of polyps by colonoscopy can be, and is ideally, carried out immediately after a CT colonography examination, there are issues with the safety of performing this procedure after DCBE (Medical Advisory Secretariat, 2003). Undertaking DCBE straight after an incomplete colonoscopy also carries risks (Medical Advisory Secretariat, 2003).
A study by Burling et al. (2006), not included in the secondary literature but identified in the course of other reading on this topic, provides details of a recent UK-wide survey on adverse events from CT colonography. The results are broadly consistent with those reported here.
At 50 centres, 17,067 CT colonographic examinations (mean number per centre, 359; range 10–3000) were performed. No deaths were reported. Thirteen patients (1 in 1,313 patients, 0.08%) had had a potentially serious adverse event related to the procedure. There were nine perforations: four (44%) were asymptomatic and five (56%) were symptomatic, and perforation had an attributable cause, with a symptomatic perforation rate of 0.03% (1 in 3,413 patients). One patient required laparotomy. An inflated rectal balloon was used to perform 9,378 examinations. There was no significant difference between the proportion of perforations associated with rectal balloon inflation (n=6) and the proportion of those that were not (n=2) (p=0.3).
4.1.4 What is the level of patient acceptance of CT colonography compared with ‘conventional’ colonoscopy or DCBE?
It has been suggested that CT colonography might be more acceptable to patients than either DCBE or colonoscopy. Although this would have more impact on increasing uptake where CT colonography is offered as a screening test, greater acceptability as a diagnostic test is also an outcome worthy of consideration. It improves the patient experience at a time when they may already be experiencing considerable distress and anxiety about both cancer and the diagnostic and treatment interventions needed.
Six reports reviewed literature on patient acceptance of CT colonography, mostly in relation to colonoscopy (Kruskal, 2007; National Institute for Clinical Excellence, 2004; Institute for Clinical Systems Improvement, 2004; Medical Advisory Secretariat, 2003; Agence Nationale d'Accreditation et d'Evaluation en Sante, 2001; ECRI, 2005). There is considerable overlap between the primary studies covered by each review. Most, as a result of the heterogeneity of the primary studies, simply described the results rather than attempting any kind of synthesis. Several of the other reviews also considered the patient acceptance of CT colonography within their introductions and discussions.
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4.1.4.1 CT colonography versus colonoscopy
The authors of the ECRI report (2005) set out to compare the actual uptake of CT colonography screening compared with colonoscopy screening in similar populations. They found no trials where uptake was the outcome measured, therefore they examined what they considered to be indirect measures of uptake, namely patient acceptance and preferences. They considered however that using these measures tends to produce inconsistent findings, because these aspects constitute only one factor of a number that contribute to the overall decision making process in complying with screening. The ECRI report also noted that the studies undertaken in this area usually only capture patients who have already consented to receive a bowel examination. They do not provide any information on those who have currently rejected screening.
To ensure as much consistency as possible, the authors of the ECRI report only considered studies in which the majority of patients had both colonoscopy and CT colonography as evidence. Of nine included studies (it was not listed within the report which studies were used), most found that patients preferred CT colonography compared with colonoscopy. However, one study found the opposite, and another study that patients’ preferences had reversed when they were surveyed again 5 weeks later.
UpToDate (Kruskal, 2007) reported five studies (Svensson 2002; Angtuaco 2001; Akerkar 2001; Thomeer 2003, Gluecker 2003) which addressed patient acceptability of CT colonography compared with colonoscopy. Most found little difference between the techniques. Patients are sedated during colonoscopy so potentially experience less anxiety and distress than during CT colonography, however they can return to normal activities more quickly after CT colonography.
The NICE Interventional Procedures Programme guideline (National Institute for Clinical Excellence, 2004) discusses two large studies which considered acceptability. The first of these was the trial by Pickhardt et al. (2003) which concerned asymptomatic patients. Fifty-four percent of a sample of 1,005 patients found CT colonography to be more uncomfortable than colonoscopy. This was probably because patients were sedated for colonoscopy and not for colonography. Despite this, 68% of patients found CT colonography to be more acceptable compared with 24% for colonoscopy (p<0.001). Removal of diminutive polyps did introduce bias into this study, however this would have been expected to influence results in favour of colonoscopy. A second study (Gluecker et al. 2003), which is one of the largest to have looked specifically at patient preferences, found that 1.3% of 696 patients experienced ‘extreme or severe’ discomfort during CT colonography compared with 3.6% for colonoscopy (p=0.63) during which they were sedated. In the same study, 72% of patients found CT colonography to be more acceptable than colonoscopy, compared with 5% who preferred colonoscopy (p<0.001).
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A further large trial (Cotton et al. 2004), described in the ICSI report (Institute for Clinical Systems Improvement, 2004), showed little difference between the methods in terms of patient acceptance. Forty-six percent of 518 patients expressed a preference for CT colonography, 41% for colonoscopy and 13% had no preference.
4.1.4.2 CT colonography versus DCBE
Three studies identified within the reviews (Taylor et al., 2005; Gluecker et al., 2003; Bosworth et al., 2006) considered the acceptability to patients of CT colonoscopy compared with DCBE. Taylor et al. (ECRI, 2005) found that patients considered DCBE to be more painful and uncomfortable than CT colonography, and significantly fewer said that they would be willing to undergo another DCBE than would CT colonography. Similar results were reported by Gluecker et al. (National Institute for Clinical Excellence, 2004), who found that 0.7% of a sample of 617 patients had ‘severe or extreme’ discomfort during colonography compared with 29.3% for DCBE (p<0.001). Ninety-seven percent (518/534) of patients preferred CT colonography to DCBE, compared to 0.4% (2/534) who preferred DCBE (p<0.001). Lastly, UpToDate (Kruskal, 2007) notes the study by Bosworth et al. of 614 patients, which showed that patients were less satisfied with DCBE than CT colonography.
4.1.4.3 Conclusions on patient acceptance of CT colonography
The main reasons for considering patient acceptance of CT colonography in comparison with other techniques is in relation to increasing uptake of diagnostic testing and improving the patient experience. No studies were identified by the reviews which directly compare the impact of different techniques on uptake. As a result, the reviews have looked at studies measuring indirect measures of uptake such as acceptance itself, or patient preferences. Only certain aspects of the overall uptake decision are being captured in each study and therefore the studies are varied in their findings. In addition all the studies conducted have been of subjects already consenting to bowel examinations. No data have been collected on those who are currently not participating in examinations. Patient experiences have been assessed directly.
The overall evidence from the reviews is weak given the heterogeneity of the studies and the shortcomings identified above. The ECRI study which carried out the most robust analysis showed a preference for CT colonography over colonoscopy, as did some of the other larger studies included in other reviews. However, other studies showed little difference or found a preference for colonoscopy. The evidence is sparse for CT colonography versus DCBE, but appears more consistent, with all studies showing a preference for CT colonography.
Bowel preparation and embarrassment due