Eur Radiol (2014) 24:1487–1496 DOI 10.1007/s00330-014-3190-1

GASTROINTESTINAL

Perforation rate in CT colonography: a systematic review of the literature and meta-analysis Davide Bellini & Marco Rengo & Carlo Nicola De Cecco & Franco Iafrate & Cesare Hassan & Andrea Laghi

Received: 17 January 2014 / Revised: 5 April 2014 / Accepted: 15 April 2014 / Published online: 10 May 2014 # European Society of Radiology 2014

Abstract Purpose The primary aim was to assess the perforation rate of CTC; the secondary aim was to identify potential clinical/ technical predictors of this complication. Methods Methods for analysis were based on PRISMA (preferred reporting items for systematic reviews and metaanalyses). From the selected studies, the rate of CTC perforation and patient/technical characteristics potentially associated with this event were extracted. Forest plots showing individual and pooled estimates of the perforation rate were obtained for all analyses. I2 was used to evaluate heterogeneity between studies. Results Eleven articles out of the 187 initially identified were selected for the analysis (103,399 patients). There were 29,048 (28 %) asymptomatic individuals and 30,773 (30 %) symptomatic patients; this characteristic was not reported in the remaining subjects (42 %). Colon distension was obtained manually in 69,222 (67 %) and using an automated carbon dioxide insufflator in 26,479 (26 %) patients; in the remaining 7 % of patients, this information was missing. Twenty-eight colonic perforations were reported, with the CTC perforation rate estimated to be 0.04 % (95 % CI. 0.00-0.10), 19-fold higher in symptomatic than in screening subjects (OR: 19.2, D. Bellini (*) : M. Rengo : C. N. De Cecco : A. Laghi Department of Radiological Sciences, Oncology and Pathology, “Sapienza” University of Rome, ICOT Hospital, Via Franco Faggiana 34, 04100 Latina, Italy e-mail: [email protected] F. Iafrate Department of Radiological Sciences, Oncology and Pathology, “Sapienza” University of Rome, Policlinico Umberto I Hospital, Rome, Italy C. Hassan Gastroenterology and Digestive Endoscopy Unit, Nuovo Regina Margherita Hospital, Rome, Italy

CI 3.3-108 and P=0.001). The surgical rate was 0.008 %. No CTC-related deaths were reported. Conclusions The perforation rate in CTC is very low, particularly considering asymptomatic individuals. Key Points • This is the first meta-analysis on this topic, based on 100,000 patients. • The CTC-related colorectal perforation rate is 0.04 %, 0.02 % in asymptomatic subjects. • The CTC-induced surgery rate is 0.008 % (1:12,500). • The perforation rate in CTC is low, particularly in averagerisk, asymptomatic individuals. Keywords Computed tomographic colonography . Intestinal perforation . Mass screening . Insufflation . General surgery

Abbreviations and acronyms CTC Computed tomographic colonography CRC Colorectal cancer CC Conventional colonoscopy ES Effect size OR Odds ratio PR Perforation rate DCBE Double-contrast barium enema

Introduction Computed tomographic colonography (CTC) is a minimally invasive and accurate imaging technique, able to detect already developed colorectal cancer (CRC) and adenomatous polyps in both symptomatic and asymptomatic patients [1–5]. According to recent guideline recommendations, CTC,

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performed every 5 years, is now recognised as an acceptable alternative screening option by both radiological and gastrointestinal societies [6–8]. CTC has been shown to be highly accurate [9] for the detection of CRC and clinically relevant polyps [10], and is also comparable to conventional colonoscopy (CC). Moreover, CTC is generally preferred by patients, especially because of its lighter bowel preparation, faster noninvasive implementation and very uncommon related adverse events [11–15]. Despite being generally regarded as safer than CC [16], CTC has been shown to be associated with potentially serious adverse events, mainly represented by large bowel perforation [17, 18]. Until now, few research articles have aimed to estimate the rate of bowel perforation and few other additional case reports have been published [18–27]. Cumulative data from multicentre series documented a perforation rate for CTC in a range from 0.009 % [20] to 0.05 % [21]. However, when considering the relative rarity of the event, any individual study was underpowered to provide a reliable estimate of the real rate of CTC perforation. The primary aim of this systematic review and meta-analysis was to assess the perforation rate of CTC. The secondary aim was to identify potential clinical/technical predictors of this complication.

Materials and methods Methods for analysis and inclusion criteria were based on PRISMA (preferred reporting items for systematic reviews and meta-analyses) recommendations for systematic reviews and meta-analyses [28]. Literature search The MEDLINE, Cochrane Library, Sumsearch2 and Web of Science databases (from inception to August 2013) were searched independently by two observers for studies that reported perforation rates in CTC. The following keywords were used for the search: virtual colon* (thus including colonoscopy, colonography), computed tomographic colon* (thus including colonoscopy, colonography) and CT colon* (thus including colonoscopy, colonography), combined with perforation, intestinal perforation and bowel perforation. Our selection criteria were broad in order to include as many studies as possible. The search was performed without any language restriction, with the presence of the search terms in the title or abstract of the article, but it was limited to human subjects. Comments, letters, review articles, case reports and unpublished data were excluded by the search. Additional exclusion criteria included studies with fewer than 500 patients. Potentially eligible papers were initially screened by two reviewers (A.L., an abdominal radiologist with more than 15 years of experience with CTC, and D.B., a radiology

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resident with 4 years of CTC experience) on the basis of title, abstract and keywords; full articles were retrieved for further assessment if given information suggested that the study might include perforations in CTC and the references of the collected articles were crosschecked for further relevant studies. Evaluation of eligibility and selection of articles was performed independently by the two radiologists; different opinions in study selection were resolved by consensus. Data extraction Relevant data of selected studies were independently extracted by the radiologists using a data extraction form. Differences in data collection were resolved by consensus with a third reviewer (M.R., an abdominal radiologist with more than 10 years of experience in CTC) referring back to the original article. From each primary study, the following sample characteristics were extracted: (1) year of publication; (2) country where the study was performed; (3) whether it was a single or a multicentre study; (4) if multicentre, number of centres involved; (5) number of patients; (6) number of patients who underwent CTC for screening; (7) number of patients who underwent CTC because symptomatic; (8) technique for colon distension, whether manual with room air or automatic with carbon dioxide; (9) number of perforated patients; (10) temporal distribution of perforations; (11) modality for data collection (self-reported or questionnaire); (12) centre where the experience was recorded. Additionally, for each one of the perforated patients, (1) the clinical indication for CTC, (2) age, (3) whether CC was performed and how long before CTC, (4) whether colon diseases were present (colon cancer, acute diverticular disease, active inflammatory bowel disease, colonic hernia, bowel obstruction), (5) institutional experience, (6) site of perforation, (7) distribution of gas, (8) symptoms associated with perforation, if any, and (9) type of treatment (conservative versus surgery). Multiple attempts were made to contact authors if data presentation was incomplete or if it was necessary to resolve an apparent conflict or inconsistency in the article. To assess the methodological quality of the included primary studies and to detect potential bias, we used items from the Quality Assessment of Diagnostic Accuracy Studies, or QUADAS, tool that were relevant for our analysis [29]. Moreover, we recorded whether patients had undergone CC before CTC. Summary measures The primary end point of this systematic review and metaanalysis was to assess the perforation rate in CTC. Secondary end points were: (1) assessment of CTC perforation risk in symptomatic patients versus asymptomatic screening individuals and (2) the possible association between the modality of

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colon distension (manual air insufflation versus automatic insufflation of carbon dioxide) and risk of CTC perforation. Statistical methods For each analysis, the effect size (ES), reported as the Z value, and percentage of heterogeneity between studies, computing I2 values, were calculated. Between-study heterogeneity was analysed using the following equation: I2 =[(Q−df)/Q]× 100%, where Q was the chi-squared statistic and df was the degree of freedom. Values of I2 equal to 25 %, 50 % and 75 % were assumed to represent low, moderate and high heterogeneity respectively. This describes the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (chance). First, meta-analyses were performed by computing the event rate in one group (patients who underwent CTC, patients who underwent CTC for screening and patients who underwent CTC because symptomatic) using a random effects model. The perforation rate and 95 % confidence intervals (CIs) were calculated. Second, meta-analyses were performed by computing the odds ratio Fig. 1 Flowchart of metaanalysis (PRISMA flow diagram)

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(OR) using a random effects model. Odds ratios and 95 % confidence intervals (CIs) for PR in CTC were calculated between groups (screening versus symptomatic population and carbon dioxide versus manually distended population). Statistical significance was assigned at P<0.05. All analyses were performed with comprehensive meta-analyses (version 2.2.064, 27 July 2011).

Results Study selection The process for selecting studies (identification, screening, eligibility and inclusion in the meta-analysis) is reported in a flow diagram in Fig. 1. In summary, 187 articles were identified through database searching, and, after duplicates had been removed, 65 articles were considered for the screening process. In 35 articles neither the title nor abstract indicated that the study met the inclusion criteria and 30 articles were selected for full-text extraction. After cross-referencing the

2006 2010 2006 2007 2013 2012 2008 2012 2013 2013

Burling D Atalla MA Sosna J Kim DH Iafrate F Stoop E Johnson C Zalis M Halligan S Atkin W

NA 0 3,120 10,748 982 NA 618 NA NA

Atalla MA Sosna J Kim DH Iafrate F Stoop E Johnson C Zalis M Halligan S Atkin W

NA: Not available

8,857 2,154

Pickhardt PJ Burling D

n

NA 0 100 27 100 NA 100 NA NA

40 13

%

2 7 0 7 0 0 0 1 0

2 9

No of perf.

US, Italy, Belgium, Ireland, The Netherlands UK Australia Israel US Italy The Netherlands US US UK UK

County

Automated CO2 distension

2006

Pickhardt PJ

First author

Publication year

First author

Table 1 Relevant data from included studies

50 10 11 1 13 1 15 4 21 21

16

1 6 0 NA 0 0 0 1 0

2 9

17,067 3,458 11,870 3,120 40,121 982 2,531 618 1,206 503

21,923

1 1 0 NA 0 0 0 0 0

0 0

0 NA 10,090 3,120 NA 982 2,531 618 0 0

11,707

0 0 0 0 0 0 0 NA 0

0 2

2 7 0 7 0 0 0 NA 0

2 6

No. of perf. in CO2

0 NA 85 100 NA 100 100 100 0 0

53 100 NA 15 0 NA 0 0 0 100 100

47

0.0578 0.0590 0.0000 0.0174 0.0000 0.0000 0.0000 0.0829 0.0000

% % % % %

% % %

0.0091 % 0.0527 %

%

Perforation rate

17,067 NA 1,781 0 NA 0 0 0 1,206 503

10,216

%

n

n

%

Patients in symptomatic group

Patients in screening group

No. of perf. In manual

Total no. of patients

No. of perf. in screening group

No. of centres involved

No. of perf. in symptomatic group

M M M S M M M M M M

M

Single (S) or multicentre (M)

87 NA 100 0 73 0 NA 0 NA NA

60

%

Perforation rate Perforation rate, adverse events Number of perforations Perforation rate Number of perforations Adverse events Diagnostic yield Accuracy of CTC Accuracy of CTC Accuracy of CTC Accuracy of CTC

Outcomes

14,913 NA 11,870 0 29,373 0 NA 0 NA NA

13,066

n

Manual distension

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Table 2 QUADAS tool for the studies included The QUADAS tool

1

2 3

4

5

6

7

8

9

10

11

12

13

14

Was the spectrum of patients representative of the patients who will receive the test in practice? Were selection criteria clearly described? Is the reference standard likely to correctly classify the target condition? Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? Did the whole sample or a random selection of the sample, receive verification using a reference standard of diagnosis? Did patients receive the same reference standard regardless of the index test result? Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)? Was the execution of the index test described in sufficient detail to permit replication of the test? Was the execution of the reference standard described in sufficient detail to permit its replication Were the index test results interpreted without knowledge of the results of the reference standard? Were the reference standard results interpreted without knowledge of the results of the index test? Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? Were uninterpretable/ intermediate test results reported? Were withdrawals from the study explained?

Pickhardt Burling PJ D UNCLEAR YES

Atalla MA YES

Sosna Kim Iafrate F Halligan Atkin Johnson Zalis Stoop J DH S W C M E YES YES UNCLEAR YES YES YES YES YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES YES

NO

NO

NO

NO

NO

NO

NO

NO

NO

NO

NO

UNCLEAR NO

YES

YES

UNCLEAR YES

YES

YES

YES YES

NO

UNCLEAR UNCLEAR YES

YES

NO

YES

YES

YES

YES YES

NA

NA

NA

NA

NA

NA

NA

NA

YES

YES NA

NA

NA

NA

NA

NA

NA

NA

NA

YES

YES NA

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES YES

NO

NO

NO

NO

NO

NO

YES

YES

NO

YES YES

YES

UNCLEAR YES

YES

NO

YES YES

UNCLEAR YES

UNCLEAR YES

NO

NA: non assessable

references, five extra studies were included (large trials with more than 500 patients and with no duplication of data), thus

reaching a total number of 35. After revision, 24 studies were excluded for the following reasons: two because they were

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editorials, eight because they were reviews, five because they had a different aim and nine because they were case reports. Finally, 11 articles [19–21, 30–37] fulfilled the eligibility criteria and were selected for quantitative synthesis (evaluation of perforation rate in CTC). Four studies offered the data for the evaluation of ORs between groups [20, 21, 30, 32]. Three studies were eligible for the evaluation of the OR between symptomatic and screening groups [20, 21, 32] and two for computing the OR between carbon dioxide and room air groups [20, 30]. One study is a review article that also reports new data from the Working Group of Virtual Colonoscopy [20]; only original data from this article had been collected and included for the analysis. Characteristics of included studies Table 1 reports a data summary of the 11 eligible studies. One study was performed in a single centre in the USA [31] and one in The Netherlands [37]; nine studies were multicentre and performed respectively in Italy [32], Australia [19], the UK [21, 34, 36], the US [33, 35] and Israel [30], and across several countries (the US, Italy, Belgium, Ireland and The Netherlands) [20]. The total number of centres involved was 121. Table 2 reports the quality assessment of studies included in the current meta-analysis. Patient cohort A total of 103,399 patients were enrolled in the selected studies (Table 1). The number of patients enrolled per study ranged from 503 to 40,121, with a median of 9,400. Only two studies including 33,793 patients (34.6 %) clearly reported whether patients were asymptomatic or symptomatic. Four

Fig. 2 Forest plot of studies included in the meta-analysis shows individual and pooled estimates for perforation rate in CT colonography. For each study, lower limit, upper limit and the effect size (Z-value) are also reported, whereas in the last row global effect size and overall perforation rate are described

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studies examined a population of only asymptomatic patients [31, 33, 35, 37]; three studies examined a population of only symptomatic patients [21, 34, 36], whilst in two studies [19, 32] these data were not available. In detail, a total of 29,048 (28 %) patients underwent CTC for screening, 30,773 (30 %) being symptomatic; this characteristic is not reported in the remaining subjects (42 %). In 69,222 (67 %) patients colon distension was performed manually and in 26,479 (26 %) using an automated insufflator of carbon dioxide; in the remaining 7 % of patients this information is missing.

Perforation rate The pooled perforation rate in CTC, computed using the random effect mode, was 0.04 % (95 % CI 0.00-0.10; I2 = 29.1 %) (Fig. 2). In detail, it was 0.02 % (95 % CI 0.000.10 %; I2 =0 %) in the asymptomatic group and 0.08 % (95 % CI 0.00-0.30; I2 =77.4 %) in the symptomatic group (Fig. 3). The pooled perforation rate was 0.034 % (95 % CI 0.00-0.10; I2 =32.1 %) in the group of patients with manual colon distension and 0.032 % in the group of patients in which an automatic carbon dioxide insufflator was used (95 % CI 0.000.10; I2 =20.8 %) (Fig. 4). Quantitative analysis between screening and symptomatic groups showed a pooled OR of 19.2 (CI 3.3-108 and P= 0.001) in favour of the symptomatic group (Fig. 5). The test of heterogeneity did not show differences in effect among the studies (Q-value=0.89, df=1, I2 estimated 0 %). Quantitative analysis between manual air and automatic carbon dioxide distension did not show a meaningful association, resulting in a pooled OR of 0.745 (CI 0.13-4.07 and P= 0.7) in favour of carbon dioxide (Fig. 6). The heterogeneity test did not show significant differences in effect among the studies (Q-value=3.02, df=2, I2 estimated 33.9 %).

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Fig. 3 Forest plot showing perforation rate in CTC according to subgroup analysis: screening individuals versus symptomatic patients. For each group, overall perforation rate, lower limit, upper limit and the effect size (Z-value) are also reported

Characteristics of perforated patients

Discussion

No deaths were reported among the 28 colonic perforations collected in the selected studies. As shown in Table 3, about 40.7 % of perforations (n=11) occurred in the sigmoid colon, 22.2 % (n=6) in the rectum and 14.8 % (n=4) in the caecum. The distribution of gas after perforation was intra-peritoneal in 9 (33 %) patients, retro-peritoneal in 7 (26 %) and intra- and extra-peritoneal in 4 (14 %). Twelve (44 %) perforated patients were completely asymptomatic and eight (29 %) presented with abdominal pain. Surgical treatment was required in 9 (32 %) of 28 perforated patients, whereas 19 patients (68 %) were treated conservatively. The surgical rate, considering all patients who underwent CTC, was 0.008 %.

The rate of CTC-related colorectal perforation, according to our meta-analysis, is 0.04 % (1:2,500), being as low as 0.02 % (1:5,000) in asymptomatic subjects, resulting in a CTCinduced surgery rate of 0.008 % (1:12,500). The results of our study are relevant for several reasons. First, our estimate was based on a population of over 100,000 patients. When considering the rarity of CTC-related perforation events, a large sample size was required, supporting the adoption of a meta-analytical approach. This is the first metaanalysis on this topic of note. Second, CTC has now been incorporated within CRC screening programmes in Europe for patients with a positive faecal test unable to undertake/

Fig. 4 Forest plot showing perforation rate in CTC according to subgroup analysis: manual air versus carbon dioxide distension. For each group, overall perforation rate, lower limit, upper limit and the effect size (Z-value) are also reported

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Fig. 5 Forest plots showing cumulative and per-study odds ratios with 95 % CI when comparing screening individuals versus symptomatic patients

complete colonoscopy [38]. Thus, our estimate is informative for the safety aspects of screening programmes. Third, the CTC-related perforation rate is only slightly inferior to that reported for cumulatively diagnostic/therapeutic colonoscopy, being 0.09 % according to a recent systematic review [16]. This is in apparent disagreement with a clear advantage on safety issue of this minimally invasive procedure. However, the low sensitivity of CC for detection of extraluminal gas as a sign of perforation—especially if patients are asymptomatic— compared with CTC, may have a relatively underestimated perforation rate at CC. It should also be noted that compared to CC, most CTC-related perforations can be treated conservatively [39, 40]. The risk of CTC perforation-related surgery in our analysis was only 0.008 % (1:12,500 patients); therefore, it can be estimated that only one in every three CTC perforations will require surgery. This is very different from CC, where most diagnostic perforations need extensive surgical treatment [41]. Thus, CTC is likely to be much safer than CC. Fourth, our meta-analysis allowed a clinical stratification of the CTC perforation risk, identifying asymptomatic subjects as a very low-risk group. In detail, a 19-fold difference in favour of asymptomatic patients was observed. This is Fig. 6 Forest plots showing cumulative and per-study odds ratios with 95 % CI when comparing manual air versus carbon dioxide distension

relevant since CTC has been officially endorsed in the US as an opportunistic screening option for average-risk patients [8]. Moreover, when considering characteristics of perforated patients, even if not clearly reported in all included studies, it is possible to identify some potential preconditions that can be related to perforations. Four (14 %) out of 28 perforated patients underwent CC with biopsy before CTC; four patients had a known hernia, one had active ulcerative colitis, one patient was distended using 8 l of carbon dioxide, and in one case the perforation occurred after inflation of the rectal stump. If excluding those cases because of either malpractice or wrong indication to CTC, the perforation rate would be definitively lower (0.02 %) (21/103,399). Fifth, we chose not to restrict our inclusion criteria to stateof-the-art CTC techniques so that our estimates could be appropriately generalised to daily practice. This decision resulted in a wide variety of different technical combinations, including single- and multi-detector CT systems, variable use of faecal tagging and intravenous contrast material, standard supine and prone imaging versus single-position examinations and the use or the avoidance of rectal balloon catheters. Despite this considerable variability in CTC techniques, very

9 32.3 % 5 9 18.5 % 33.3 %

7 25.9 %

4 8 12 14.8 % 29.6 % 44.4 %

8 29.6 %

8 19 29.6 % 67.8 %

little heterogeneity in perforation rates was noted. In particular, no statistically significant difference in perforation risk between air and carbon dioxide was detected by our analysis. Sixth, no CTC-related patient deaths have been reported in the included analysis and, as far as we know, in the medical literature. This is not the case for CC, which has an associated mortality rate around 0.0009 % (1:111,000 patients) [16], and for DCBE, which has been reported to have a related mortality close to 0.07 % (1:1,428 patients), most likely because of barium-related peritonitis [16]. Some inherent limitations exist in the study design and should be considered when interpreting the results. First of all, several studies reviewed and meta-analysed were retrospective, with a resultant inherent bias. Results of this research should promote the initiation of prospective trials collecting data on perforation on CTC. Second, the number of studies included in our meta-analysis is relatively small, only 11, but fairly in line with the average number of eligible studies for all medical areas [42]. Despite this, the sample size is extremely large (over 100,000 patients), particularly if compared with medians and quartiles of studies in the field of diagnostic imaging. In conclusion, our systematic review and meta-analysis demonstrate that the perforation rate in CTC is low, particularly if considering asymptomatic individuals. The surgery rate is even lower, demonstrating that in most cases perforations can be treated conservatively. Acknowledgements The scientific guarantor of this publication is Andrea Laghi. The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. The authors state that this work has not received any funding. One of the authors has significant statistical expertise. Institutional Review Board approval was not required because this is a meta-analysis. Written informed consent was not required for this study because this is a meta-analysis. Methodology: Systematic review with meta-analysis.

References

1 3.7 %

NA: Not available

28 Total no. %

6 11 22.2 % 40.7 %

1 3.7 %

4 14.8 %

0 1 1 4 3 0 2 8 1 3 4 1 0 0 0 7 0 1 2 5 1 0 0 0 0 4 1 0 7 0 0 0 0 7 0 1 0 1 0 0 3 0 0 3 1 0 3 0 2 5 1 0 1 0 2 1 1 0 0 1 0 1 0 0 0 0 2 9 2 7 7 1

0 2 0 2 2 0

0 1 0 5 5 0

0 1 0 0 0 0

0 3 1 0 0 0

1495

Atalla MA Burling D Pickhardt PJ Sosna J Iafrate F Halligan S

Conservative Surgery Asymptomatic Abdominal NA pain Intra Retro Retro peritoneal peritoneal AND Intra

Total no. of Site of Perforation perforations Rectum Sigmoid Descending Transverse Ascending/ NA colon colon colon caecum

Table 3 Characteristics of perforated patients

NA

Symptoms Distribution of Gas

Treatment

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