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
ii
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
2
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.
3
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
4
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
5
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
6
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.
suzannew
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.
8
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.
9
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?
16
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
17
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).
18
y.
20
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.
21
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%
29
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
31
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
32
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).
33
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.
38
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.
40
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
41
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.
42
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
43
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.
44
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.
45
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
49
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.
50
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.
51
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
52
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
53
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
54
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.
55
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.
56
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).
57
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