- Email: [email protected]
Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients With Colorectal Cancer
Accepted Manuscript Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients with Colorectal Cancer Zaida Adrián-de-Ganzo, MD, Onofre Alarcón-Fernández, MD, Laura Ramos, MD, Antonio Gimeno-García, MD, PhD, Inmaculada Alonso-Abreu, MD, Marta Carrillo, MD, PhD, Enrique Quintero, MD, PhD. PII: DOI: Reference:
S1542-3565(15)00908-8 10.1016/j.cgh.2015.06.032 YJCGH 54356
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 9 June 2015 Please cite this article as: Adrián-de-Ganzo Z, Alarcón-Fernández O, Ramos L, Gimeno-García A, Alonso-Abreu I, Carrillo M, Quintero E, Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients with Colorectal Cancer, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/j.cgh.2015.06.032. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients with Colorectal Cancer ACCEPTED MANUSCRIPT
Zaida Adrián-de-Ganzo MD, Onofre Alarcón-Fernández MD, Laura Ramos MD, Antonio Gimeno-García MD, PhD, Inmaculada Alonso-Abreu MD, Marta Carrillo MD, PhD, and Enrique Quintero MD, PhD. de
Gastroenterología, Hospital
Universitario
de
Canarias.
Instituto
RI PT
Servicio
Universitario de Tecnologías Biomédicas (ITB) & Centro de Investigación Biomédica de Canarias (CIBICAN). Departamento de Medicina Interna. Universidad de La
SC
Laguna. Tenerife. España Grant support.
M AN U
This study was supported by a grant from the European Capsule Endoscopy Group (ECEG), by a grant from Caja Canarias Banca Cívica and by funds of the Department of Internal Medicine of La Laguna University. Abbreviations.
CCR: colorectal cancer
TE D
CCE: colon capsule endoscopy
CI: confidence intervals
AC C
OR: odds ratios
EP
FDR: first-degree relatives
Disclosures: None of the authors have any potential conflict of interest to disclose.
Author Contributions
Enrique Quintero was responsible for the conception and design of the trial. Zaida Adrián-de-Ganzo and Enrique Quintero took responsibility for the integrity of the data,
1
ACCEPTED MANUSCRIPT performed the analysis and interpretation of the results and were involved in the drafting of the article. Zaida Adrián-de-Ganzo, Onofre Alarcón, Antonio Z Gimeno-García, Laura Ramos, Inmaculada Alonso-Abreu and Marta Carrillo were involved in the acquisition of data. All the authors performed a critical revision of the article for
RI PT
important intellectual content and gave their final approval of the manuscript submitted.
Acknowledgements.
SC
The authors gratefully acknowledge Dr. Victor Abraira and Dr. Alfonso Muriel (Unidad de Bioestadística, Hospital Ramón y Cajal, Madrid) for assistance on the statistical
Correspondence: Enrique Quintero M.D. Department of Gastroenterology.
M AN U
analysis and critical reading of the manuscript.
TE D
Hospital Universitario de Canarias. Ctra. Ofra S/N La Cuesta,
38320 La Laguna, Tenerife, Spain.
EP
Email: [email protected]
AC C
Word count: 3,993 words
2
ACCEPTED MANUSCRIPT
ABSTRACT Background & Aims: The efficacy of screening colonoscopy in first-degree relatives (FDRs) of patients with colorectal cancer (CRC) is limited by suboptimal uptake. We compared
RI PT
screening uptake of colon capsule endoscopy (CCE) vs colonoscopy in this population.
Methods: We performed a prospective study of 329 asymptomatic FDRs of patients with CRC who were randomly assigned to groups examined by CCE (PillCam, 2nd generation;
SC
n=165) or colonoscopy (n=164) at a tertiary hospital in Spain, from July 2012 through December 2013. Crossover was permitted for patients who did not wish to undergo the
M AN U
assigned procedure. Subjects assigned to CCE who had a significant lesion (polyp ≥10 mm, >2 polyps of any size, or CRC) were invited to undergo colonoscopy. Results: One-hundred twenty subjects in the CCE group and 113 in the colonoscopy group were eligible for inclusion. In the intention-to-screen analysis, uptake was similar between
TE D
groups (55.8% CCE vs 52.2% colonoscopy; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.51−1.44; P=.57); 57.4% of subjects crossed-over from the CCE group and 30.2% crossed-over from the colonoscopy group (OR, 3.11; 95% CI, 1.51−6.41; P=.002).
EP
Unwillingness to repeat bowel preparation in the case of a positive result was the main reason that subjects assigned to the CCE group crossed over; fear of colonoscopy was the reason that
AC C
most patients in this group crossed over. A significant lesion was detected in 14 subjects (11.7%) in the CCE group and 13 subjects (11.5%) in the colonoscopy group (OR, 1.02; 95% CI, 0.45−2.26; P=.96).
Conclusion: In a prospective study, similar numbers of FDRs of patients with CRC assigned to undergo CCE or colonoscopy agreed to participate, but most preferred to undergo colonoscopy. CCE was as effective as colonoscopy in detecting significant lesions; it could be a valid rescue strategy for subjects who reject screening colonoscopy.
3
ACCEPTED MANUSCRIPT
ClinicalTrials.gov number NCT01557101.
RI PT
KEY WORDS: participation; colon cancer; colon capsule-2; detection; tumor
INTRODUCTION.
Family history is a major risk-factor for developing CRC.1 Risk increases two to five-fold in FDR of patients with CRC if the index-case is younger than 60 years or when 2, 3
Based on this premise, clinical practice guidelines
SC
there are two or more FDR affected.
M AN U
empirically recommend colonoscopy every five years, starting at the age of 40 or ten years less than the index-case at first diagnosis, as the first-line screening strategy in this setting.4-6
Colonoscopy is the gold standard procedure for detecting CRC and advanced adenomas. The advantage of colonoscopy over other screening tests is that polypectomy can
TE D
be performed, thus breaking the adenoma-carcinoma sequence and reducing subsequent development of CRC. However, it is far from being an ideal screening technique: it fails to identify as many as 12% of advanced adenomas and 5% of CRC, 7,
8
it is an invasive or
EP
procedure that carries an increased risk for complications, especially bleeding
perforation following caecal polypectomy,9 and screening uptake is suboptimal with
AC C
participation rates below 40% in the familial risk population. 10-12 For these reasons, alternative-screening strategies are currently under investigation. Colon capsule endoscopy (CCE) is a minimally invasive tool with similar accuracy
for detecting advanced neoplasia as optical colonoscopy.13-16 Currently, CCE is used in clinical practice as an alternative diagnostic tool in patients with non- occlusive, incomplete optical colonoscopy.17 Recently, it has been suggested that CCE may be cost-effective as compared to colonoscopy if it is able to increase CRC screening uptake by 20%. 18 In a pilot
4
ACCEPTED MANUSCRIPT
study in which all individuals were invited to undergo CCE followed by colonoscopy, the authors reported a four-fold higher screening uptake for CCE than for colonoscopy, with both techniques showing the same diagnostic yields for detecting adenomas. However,
RI PT
there are no prospective, randomized, controlled studies comparing CRC screening uptake between colonoscopy and CCE.
To test the hypothesis that CCE may improve CRC screening uptake in the familial-
SC
risk population, we designed a pragmatic, prospective, randomized open trial to compare
M AN U
screening uptake of colonoscopy versus CCE in screening naïve FDR of patients with CRC.
METHODS. Subjects
The study was conducted in a tertiary hospital serving approximately 375.000
TE D
inhabitants between July 2012 and December 2013. Consecutive patients with nonsyndromic CRC diagnosed during the previous two years were interviewed at the high-risk CRC clinic of our hospital. The trial registered as ClinicalTrials.gov number NCT01557101
EP
complied with the CONSORT extension for pragmatic trials.19 Inclusion criteria were: asymptomatic FDR ≥40 years of age or ten years less
AC C
than the youngest relative with CRC. Exclusion criteria were: previous CRC screening; history of colorectal neoplasia or inflammatory bowel disease; hereditary CRC; gastrointestinal surgery; pregnancy; allergy or other severe comorbidity (mean life expectancy of <5 years) or major limitation of physical activity (performance status ≥2); and contraindication for bisacodyl, polyethylen glycol or phosphates.
Information and Randomization
5
ACCEPTED MANUSCRIPT
To analyze screening uptake under real-life practice conditions we used the Zelen design.20 Briefly, participants in the two arms of the study are randomized before giving informed consent and have the opportunity to refuse their allotted strategy, and ¨crossover” to
RI PT
the alternative strategy is permitted (Figure 1). This design ensures the inclusion of all eligible subjects whereas the conventional randomization design (informed consent signed before randomization) includes only subjects consenting to participate. The Zelen design helps to
SC
reduce selection bias by preventing belief in the effectiveness of the intervention by physicians or participants and improves recruitment rates by reducing drop-out rates from the
M AN U
reference group.21
At the initial interview with the index-case, a gastroenterologist provided detailed verbal and written information about the study. After obtaining signed informed consent to accept familial participation, a one-generation family history of cancer was taken to identify
TE D
all FDR that met no exclusion criteria. Then, randomization (1:1) of eligible FDR was performed using a computer generated random sequence with sealed envelopes to one of the two study groups: Group 1: screening by CCE and colonoscopy in the event of a significant
EP
lesion (polyp ≥10 mm in diameter, >2 polyps of any size, or CRC); and Group 2: screening with optical colonoscopy. Sealed envelopes were prepared for eligible FDR in the family and
AC C
given to the index-case for their delivery. The envelopes contained a leaflet with detailed information about the trial, the strategy allocated, the informed consent document to participate in the study and a contact telephone number to arrange an appointment at the High Risk CRC Clinic. The possibility of changing group was not mentioned in the information leaflet, to minimize as much as possible crossover in both arms. In that event, a structured questionnaire was used to determine the reason for crossover between the assigned strategies (Table 1).
6
ACCEPTED MANUSCRIPT
Subjects assigned to CCE received information about the procedure (bowel preparation, duration and possible adverse events) and were told that they would be scheduled to undergo colonoscopy in the event of positive result. By contrast, subjects
RI PT
assigned to colonoscopy received detailed information about the technique (bowel cleansing, sedation, advantages of polypectomy in the event of polyp detection, and possible complications). Specific informed consent for the agreed strategy (CCE or conventional
SC
colonoscopy) was sought before the procedure. Both screening procedures were free of charge. The Clinical Research Ethics Committee of our center approved the study protocol
M AN U
and all authors had access to the study data and reviewed and approved the final manuscript
Colon capsule endoscopy.
CCE was performed with second-generation PillCam™ CCE system (PillCam® colon
TE D
capsule, Given Imaging Inc, Yoqneam, Israel) previously described. 13 Colon cleanliness for CCE was scheduled in one-day, low-volume preparation, as previously described, to facilitate adherence to screening. 22, 23 Colon cleanliness was graded for the following colonic
EP
segments: right colon, transverse colon, left colon and rectum, and classified using a validated 4-point scale as previously described:13 (1) excellent (no material or liquid material covering
AC C
<10% of the mucosal surface in each location), good (liquid material or mucus covering >10% of the mucosal surface), fair (solid material impossible to suction, covering <10% of the mucosal surface) or poor (solid material covering >10% of the mucosal surface). In the current study a colon preparation rated as “excellent” or “good” was considered as “adequate” whereas colon cleansing rated as “fair” and “poor” was classified as “inadequate”. CCE readings were performed by one independent blinded observer (AG or OA), as previously described.23 Polyp size was estimated by using the polyp size estimation
7
ACCEPTED MANUSCRIPT
tool included in the RAPID software (Given Imaging Ltd, Yoqneam, Israel, version 7.0). CCE findings were collected and a global lesion evaluation for each patient was recorded as: negative examination (no polyps or CCR), polyps, CRC or miscellaneous (diverticula,
RI PT
angiomas, inflammation or hemorrhoids). CCE examination was considered to be valid when the capsule was excreted (or hemorrhoidal plexus was observed), had adequate colonic cleansing or a significant lesion was detected. Subjects with an incomplete CCE
SC
exploration due to poor bowel cleansing were scheduled for optical colonoscopy. Colonoscopy
M AN U
Colonoscopies were carried out by experienced endoscopists as previously described.24 The endoscopic report contained the parameters for quality assessment (caecal intubation, quality of cleanliness for each colorectal segment, number of polyps identified, removed and recovered for histological examination and immediate complications).
TE D
Colonoscopy was considered complete if the cecum was reached and bowel cleansing was good or excellent.24 Colon cleansing was defined as inadequate when less than 90% of colorectal mucosa could be properly evaluated due to the presence of faeces. Patients with
colonoscopy.
EP
incomplete colonoscopy because of poor bowel preparation were re-scheduled to
AC C
Adenomas ≥10 mm in diameter, with tubulovillous architecture, high-grade
dysplasia or intramucosal carcinoma were classified as advanced adenomas. Invasive cancer was considered when malignant cells were observed beyond the muscularis mucosa. Tumor staging was performed according to the classification system of the American Joint Committee on Cancer 25 and patients were classified according to the most advanced lesion. Data collection Demographic characteristics of participants, kinship, degree of bowel cleanliness for
8
ACCEPTED MANUSCRIPT
each procedure, colonoscopy and CCE completion, colonoscopy or CCE findings, reason for failure and reason for crossover between the assigned groups was recorded. The level of patient satisfaction and potential procedure-related adverse effects were assessed using a
RI PT
questionnaire administered by telephone interview two weeks later (Supplementary Table 1). Sample Size
We hypothesized that uptake of CCE screening should be at least 20% higher
SC
than that of colonoscopy, on the basis that this is the minimal estimated difference that would make CCE cost-effective.18 Assuming a participation rate of 38% for colonoscopy12 and of
M AN U
58% for CCE screening, with an alpha risk of 0.05 and a beta risk of 0.20 in a two -sided test, 108 subjects in each arm of the study were needed to find a statistically significant difference.
TE D
Statistical Analysis.
The primary objective of this study was to compare screening uptake of CCE versus optical colonoscopy in FDR of patients with CRC. Screening uptake was defined as
EP
number of invited subjects screened by CCE or colonoscopy as a proportion of eligible subjects. The principal analysis consisted of an intention-to-screen comparison of the uptake
AC C
proportions between both study arms (subjects were analyzed according to their randomly assigned strategy, irrespective of whether they actually received it or not). The detection rate of neoplastic lesions (number of subjects with true positive results divided by the number of subjects who actually underwent testing) was based on as-screened analyses (subjects that underwent screening by colonoscopy or CCE, independently to their randomly assigned strategy). Statistical comparisons for secondary endpoints (efficacy of each procedure to
9
ACCEPTED MANUSCRIPT
explore the entire colon, and acceptance of each strategy) were performed according to asscreened analysis. Comparisons between groups were carried out by logistic-regression analysis and reported as odds ratios (OR) with 95% confidence intervals (CI). Continuous
RI PT
variables were expressed as means and standard deviation. Categorical variables were expressed as frequencies and percentages. Chi-square test was used to compare categorical variables. Differences with a P value <0.05 were considered statistically significant. Data
M AN U
SC
were analyzed using SPSS version 15.0 (SPSS Inc., Chicago, IL).
RESULTS.
Three hundred twenty nine FDR of 84 index-cases were prospectively randomized to undergo either CCE (n=165) or colonoscopy (n=164). Of these, 45 (27.7%) and 51 subjects (31.1%) were excluded from the CCE and colonoscopy groups, respectively
TE D
(Figure 2). Finally, the eligible population comprised 233 FDR (121 female, median age 55 years, range 31 to 78 years) who were assigned to CCE (n=120) or colonoscopy (n=113). As shown in Table 2, there were no statistically significant differences between the
EP
two groups in age, gender, body mass index (BMI), smoking or alcohol abuse and
AC C
demographic characteristics of the index-case.
Screening uptake and crossover rates. Among the 120 eligible FDR that were assigned to undergo CCE, 52 (43.3%)
declined to be screened and 68 (56.6%) agreed to participate in the study. Overall, 29 (24.2%) accepted the assigned strategy and 28 (23.3%) finally underwent CCE, whereas 39 (32.5%) that declined CCE were offered colonoscopy and actually did so. Among the 113 eligible FDR that were invited to undergo colonoscopy, 50 (44.2%) declined and 63
10
ACCEPTED MANUSCRIPT
(55.8%) agreed to participate. Of these, 44 (38.9%) accepted the assigned strategy and 42 (37.1%) finally underwent colonoscopy, whereas 19 (16.8%) that declined colonoscopy were offered CCE and 17 (15.0%) actually did so (Figure 2). Consequently, the crossover rate
group (30.2%) (OR 3.11; 95% CI, 1.51-6.41; P=0.002).
RI PT
between groups was significantly higher in the CCE group (57.4%) than in the colonoscopy
According to the intention-to-screen analysis, screening uptake was similar in the
SC
CCE group (n=67, 55.8%) compared to the colonoscopy group (n=59, 52.2%) (OR 0.86; 95% CI, 0.51-1.44; P=0.57). Overall, of the 233 eligible subjects, 45 (19.3%) underwent
M AN U
CCE whereas 81 (34.7%) completed colonoscopy.
The reasons for declining to be screened by CCE was “to avoid a second bowel preparation in the event of a positive result” in 35/39 (89.7%) subjects, "feeling more confident about colonoscopy" in three (7.7%) subjects and "the index case or another first-
TE D
degree relative reported having had an unpleasant experience" in one (2.6%) subject. Among FDR assigned to colonoscopy, the reason for rejecting that option was “fear of colonoscopy”
EP
in 19/19 (100%) of cases.
Efficacy for detecting colorectal neoplasia.
AC C
Table 3 shows the efficacy of the two strategies to detect colorectal neoplasia according to the intention-to-screen and as-screened analyses. No statistical differences between the two groups were observed regarding the detection rate of significant lesions.
Completion of CCE and colonoscopy. Overall, the mean average CCE recording time was 373±265 minutes and the mean capsule recording time in the colon was 215±231 minutes. CCE was excreted in
11
ACCEPTED MANUSCRIPT
33/45 subjects (73.3%) within 10 hours. In 12 subjects (26.7%) the capsule was not excreted or did not reach the rectum. Of these, CCE was considered valid in four subjects who had an advanced adenoma (n=2) or three non-advanced adenomas (n=2), and
RI PT
an optical colonoscopy was indicated and completed. The overall cleansing rate was inadequate in 9/45 additional subjects (20%), but the procedure was considered valid in two cases with positive findings (one had advanced adenoma and one had three non- advanced
SC
adenomas) and an optical colonoscopy was completed. Therefore, in 30 subjects (66.6%) CCE was considered complete, whereas in 15 subjects (33.4%) in whom the capsule did not
M AN U
reach the rectum or had inadequate cleansing it was considered inadequate and a colonoscopy was scheduled. In the colonoscopy group, the overall cleansing rate was adequate and colonoscopy was complete in 66/81 subjects (81.5%). The remaining 15
TE D
subjects (18.5%) with inadequate bowel preparation were re-scheduled for colonoscopy.
Satisfaction level and adverse events.
No major complications were registered during capsule ingestion or transit period,
EP
nor during colonoscopy. Only one patient (2.2%) in the CCE group and three (3.7%) in the colonoscopy group had discrete abdominal discomfort during the procedure. Nine out of
AC C
11 (81.8%) subjects undergoing CCE and colonoscopy were satisfied with the technique and considered that CCE was less unpleasant than colonoscopy. No subjects reported any longterm secondary effects related with CCE or colonoscopy.
DISCUSSION.
12
ACCEPTED MANUSCRIPT
In the current study we aimed to determine whether CCE would improve screening uptake of optical colonoscopy in FDR of patients with CRC. Contrary to expectations, the study failed to support this hypothesis and screening uptake was similar between CCE
RI PT
and colonoscopy in FDR of patients with CRC. The higher crossover rate from the CCE group to the colonoscopy group suggests better acceptance of screening colonoscopy. This finding runs counter to those of two recent pilot studies on screening modalities which
SC
suggested that CCE is about four-fold better accepted than optical colonoscopy26 or computed tomographic colonoscopy.27 However, these studies had important methodological
M AN U
flaws for the assessment of screening uptake. They were designed as single-arm studies rather than randomized trials, which makes it difficult to assess the adherence to each strategy separately, and sample size was small.
One of the main findings of our study was that the crossover rate in individuals
TE D
assigned to CCE was three-fold higher than in those assigned to colonoscopy, which definitively contributed to low CCE adherence rate. The main reason for low CCE uptake in this study is probably the fact that subjects knew they would have to undergo a second bowel
EP
preparation and colonoscopy on another day in the event of a positive CCE finding. In fact, “to avoid a second bowel preparation in the event of a positive result” was the most
AC C
frequent answer (89%) given by individuals assigned to CCE who decided to take the alternative test. Although we assumed a higher screening uptake in the CCE group, it is possible that a more complex family history (i.e. having more than one FDR with CRC) led to CCE rejection because of higher risk perception. This group of patients might therefore have been more predisposed to undergo conventional colonoscopy. In our opinion, logistical difficulties impede same-day CCE and optical colonoscopy in the screening setting. The main problem is prolonged duration of the procedure which 13
ACCEPTED MANUSCRIPT
requires two hours for bowel preparation, about nine hours for transit time, no less than 3 hours for data downloading to the RAPID workstation and about 90 minutes for reading and reporting the results. In total, the whole process takes no less than 15 hours which makes it
RI PT
very difficult to program optical colonoscopy on the same day in patients with a positive CCE result. We are aware that this may have influenced CCE uptake. Another factor that could have contributed to low adherence to CCE was the “good experience” of the index-case
SC
with colonoscopy, as we systematically use intravenous sedation in all colonoscopies. However, this is also expected to occur in real clinical practice and should be considered as a
M AN U
factor that could reduce the overall adherence to CCE screening.
Apart from individual perceptions on the procedure, CCE has two additional drawbacks for use as a screening procedure. Firstly, between 20-35% of cases (in our study 33%) have an incomplete examination due to inadequate bowel preparation, not
17,
23,
26
16,
TE D
allowing the capsule to reach the hemorrhoid plexus or because of technical problems. 13,
Therefore, a significant proportion of examinations need rescheduling to
colonoscopy. Secondly, at least in Spain, CCE is about two-fold more expensive than
EP
colonoscopy. Although we did not analyze costs in the current study, CCE is very unlikely to be cost -effective nowadays for CRC screening; a recent study has shown that screening
AC C
uptake should be at least 20% higher than that of colonoscopy to be cost-effective,17 which was not the case in our study. Taking into account these circumstances, it seems reasonable for now not to recommend CCE as a first-line screening option in FDR of patients with CRC. Our study has several strengths. It is the first randomized controlled trial comparing the uptake of CCE with colonoscopy for CRC screening and it was designed as a pragmatic study, allowing crossover between groups. In addition, randomization was performed before informed consent was signed, to minimize selection bias.
14
ACCEPTED MANUSCRIPT
We are also aware of the study limitations. First, apart from individual perceptions on the screening techniques, we did not evaluate other potential causes for non-adherence (i.e. socio-economic status or index-case influence on the final decision of their respective
RI PT
relatives). Second, we cannot provide accurate information on the reasons for declining screening in subjects who did not attend the appointment at our high-risk CRC clinic because Spanish law does not allow recording data of individuals without their signed
SC
informed consent. Third, the low performance of CCE in terms of completeness and cleansing level observed in our study could be influenced by the low-volume preparation
M AN U
used. However, it has been reported that cleansing quality was similar between low-volume and high-volume preparations28 and the proportion of poor cleansing in our study was similar to that of other studies.16,
17, 23, 26
In addition, the evidence supporting the benefit of high-
volume preparation regimens recommended by a recent guideline is low (Evidence level 4;
TE D
Grade of recommendation D).29
The efficacy of CCE with respect to the final diagnosis of a significant lesion deserves comment. Although our study was not powered to assess diagnostic yield, the
EP
intention-to-screen and as-screened analysis showed that CCE was as effective as colonoscopy for detecting significant lesions. This result is in line with two recent
AC C
multicenter studies that compared the diagnostic capacity of CCE and colonoscopy for detecting colorectal neoplasia. 14, 16 In conclusion, our study showed that screening uptake of CCE was about the same as
that of colonoscopy in FDR of patients with CRC. Interestingly, the crossover rate was markedly higher in subjects invited to CCE than in those invited to colonoscopy, suggesting better acceptance of colonoscopy. For these reasons, colonoscopy should still be considered the first-choice screening strategy in the familial risk population, leaving
15
ACCEPTED MANUSCRIPT
CCE as a rescue technique for those individuals unwilling to undergo colonoscopy.
REFERENCES Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer
RI PT
1.
for individuals with a family history: a meta-analysis. European journal of cancer 2006;42:216-27.
Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance:
SC
2.
clinical guidelines and rationale-Update based on new evidence. Gastroenterology
3.
M AN U
2003;124:544-60.
Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001;96:2992-3003.
4.
Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance
TE D
after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2012;143:844-57. 5.
Davila RE, Rajan E, Baron TH, et al. ASGE guideline: colorectal cancer screening and
6.
EP
surveillance. Gastrointestinal endoscopy 2006;63:546-57. Castells A, Marzo-Castillejo M, Mascort JJ, et al. [Clinical practice guideline.
AC C
Prevention of colorectal cancer. 2009 update. Asociacion Espanola de Gastroenterologia]. Gastroenterologia y hepatologia 2009;32:717 e1-58. 7.
Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112:24-8.
8.
Pickhardt PJ, Nugent PA, Mysliwiec PA, et al. Location of adenomas missed by optical colonoscopy. Ann Intern Med 2004;141:352-9.
9.
Rutter MD, Nickerson C, Rees CJ, et al. Risk factors for adverse events related to
16
ACCEPTED MANUSCRIPT
polypectomy in the English Bowel Cancer Screening Programme. Endoscopy 2014;46:90-7. 10.
Ait Ouakrim D, Lockett T, Boussioutas A, et al. Screening participation for people at
RI PT
increased risk of colorectal cancer due to family history: a systematic review and metaanalysis. Familial cancer 2013. 11.
Bronner K, Mesters I, Weiss-Meilnik A, et al. Do individuals with a family history of
cancer? Fam Cancer 2013;12:629-37.
Bujanda L, Sarasqueta C, Zubiaurre L, et al. Low adherence to colonoscopy in the
M AN U
12.
SC
colorectal cancer adhere to medical recommendations for the prevention of colorectal
screening of first-degree relatives of patients with colorectal cancer. Gut 2007;56:17148. 13.
Eliakim R, Fireman Z, Gralnek IM, et al. Evaluation of the PillCam Colon capsule in the
TE D
detection of colonic pathology: results of the first multicenter, prospective, comparative study. Endoscopy 2006;38:963-70. 14.
Rex DK, Adler SN, Aisenberg J, et al. Accuracy of Capsule Colonoscopy in Detecting
15.
EP
Colorectal Polyps in a Screening Population. Gastroenterology 2015. Schoofs N, Deviere J, Van Gossum A. PillCam colon capsule endoscopy compared with
AC C
colonoscopy for colorectal tumor diagnosis: a prospective pilot study. Endoscopy 2006;38:971-7. 16.
Spada C, Hassan C, Munoz-Navas M, et al. Second-generation colon capsule endoscopy compared with colonoscopy. Gastrointest Endosc 2011;74:581-589 e1.
17.
Alarcon-Fernandez O, Ramos L, Adrian-de-Ganzo Z, et al. Effects of colon capsule endoscopy on medical decision making in patients with incomplete colonoscopies. Clin Gastroenterol Hepatol 2013;11:534-40 e1.
17
ACCEPTED MANUSCRIPT
18.
Hassan C, Zullo A, Winn S, et al. Cost-effectiveness of capsule endoscopy in screening for colorectal cancer. Endoscopy 2008;40:414-21. Groth S, Krause H, Behrendt R, et al. Capsule colonoscopy increases uptake of colorectal cancer screening. BMC Gastroenterol 2012;12:80.
20.
RI PT
19.
Zwarenstein M, Treweek S, Gagnier JJ, et al. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ 2008;337:a2390.
Zelen M. Randomized consent designs for clinical trials: an update. Stat Med
SC
21.
1990;9:645-56.
Adamson J, Cockayne S, Puffer S, et al. Review of randomised trials using the post-
M AN U
22.
randomised consent (Zelen's) design. Contemp Clin Trials 2006;27:305-19. 23.
Kakugawa Y, Saito Y, Saito S, et al. New reduced volume preparation regimen in colon capsule endoscopy. World J Gastroenterol 2012;18:2092-8.
Ramos L, Alarcon O, Adrian Z, et al. One-day versus two-day cleansing for colon
TE D
24.
capsule endoscopy: a prospective randomized pilot study. Gastroenterol Hepatol 2014;37:101-6.
Parra-Blanco A, Nicolas-Perez D, Gimeno-Garcia A, et al. The timing of bowel
EP
25.
preparation before colonoscopy determines the quality of cleansing, and is a significant
AC C
factor contributing to the detection of flat lesions: a randomized study. World J Gastroenterol 2006;12:6161-6. 26.
O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. Journal of the National Cancer Institute 2004;96:1420-5.
27.
Rondonotti E, Borghi C, Mandelli G, et al. Accuracy of Capsule Colonoscopy and Computed Tomographic Colonography in Individuals With Positive Results From the
18
ACCEPTED MANUSCRIPT
Fecal Occult Blood Test. Clin Gastroenterol Hepatol 2014. 28.
Hartmann D, Keuchel M, Philipper M, et al. A pilot study evaluating a new low-volume
Spada C, Hassan C, Galmiche JP, et al. Colon capsule endoscopy: European Society of
EP
TE D
M AN U
SC
Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2012;44:527-36.
AC C
29.
RI PT
colon cleansing procedure for capsule colonoscopy. Endoscopy 2012;44:482-6.
19
ACCEPTED MANUSCRIPT
Figure Legends. Figure 1. Randomization and informed consent design
AC C
EP
TE D
M AN U
SC
RI PT
Figure 2. Study Enrollment and screening uptake.
20
ACCEPTED MANUSCRIPT
Table 1. Questionnaire to determine the reason for changing the screening strategy assigned to first degree relatives.
RI PT
Colon Capsule Endoscopy group (prefers colonoscopy): 1. “Fear of colon capsule endoscopy” □ Yes
□ No
□ Yes
SC
2. "The index case or another first-degree relative reported having had an unpleasant experience with colon capsule endoscopy" □ No
experience with colonoscopy" □ Yes
□ No
M AN U
3. "The index case or another first-degree relative reported having had a satisfactory
4. “To avoid a second bowel preparation in the event of a positive result”
□ Yes
□ No
□ Yes
□ No
EP
6. Other (explain).
TE D
5. "Feeling more confident about colonoscopy"
AC C
Colonoscopy group (prefers Colon Capsule Endoscopy): 1. “Fear of colonoscopy” □ Yes
□ No
2. "The index case or another first-degree relative reported having had an unpleasant experience with colonoscopy" □ Yes
□ No
3. "The index case or another first-degree relative reported having had a satisfactory
experience with colon capsule endoscopy"
21
ACCEPTED MANUSCRIPT
□ Yes
□ No
4. "Feeling more confident about colon capsule endoscopy" □ Yes
□ No
AC C
EP
TE D
M AN U
SC
RI PT
5. Other (explain).
22
ACCEPTED MANUSCRIPT
Table 2. Demographic data of first-degree relatives in both study groups. CCE1 group
Colonoscopy group
(n=120)
(n=113)
55.1 ± 11.9
54.9 ± 11.2
Mean age ± SD Gender, n (%)
67 (55.8)
Chronic disease, n (%) Alcohol intake > 60 g/d, n (%)
36 (56.3)
0.29
68 (51.5)
8 (11.8)
8 (12.5)
0.90
16 (12.1)
0.38
27.9 ± 5.1
19 (29.7)
0.68
37 (28.0)
9 (14.1)
0.73
20 (15.2)
76 (67.3)
0.97
18 (26.5)
Antiplatelet therapy, aspirin
11 (16.2)
TE D
CRC2 Proband, n (%) 81 (67.5) 56.8 ± 8.7
27.2 ± 4.8
57.2 ± 9.19
96 (80.0)
91 (80.5)
24 (20.0)
22 (19.5)
0.57
0.87
112 (48.1)
157
67.4
57 ± 8.95
187
(80.3)
46
(19.7)
AC C
Two or more
EP
One
121 (51.9)
0.22
32 (47.1)
Smoking, n (%)
Relatives with CRC, n (%)
54.9 ± 11.6
59 (52.2)
28.6 ± 5.5
Mean age ± SD
(n=233)
53 (44.2)
BMI ± SD
Age < 60 years
0.91
SC
Male
54 (47.8)
M AN U
Female
p
RI PT
Category
Total
1
CCE = Colon capsule endoscopy
2
CRC = colorectal cancer
23
ACCEPTED MANUSCRIPT
Table 3.- Diagnostic yield of colon capsule endoscopy (CCE) and colonoscopy according to the
CCE Group
Rate
Subjects
Rate
Most advanced lesion
no.
%
no.
%
Intention-to-screen analysis
113
Non-advanced adenomaω
12
10.6
9
≥ 3 non-advanced adenomas
5
4.4
4
Advanced adenoma
8
7.1
9
Significant lesion§
13
11.5
As-screened analysis
81
Non-advanced adenomaω
16
≥ 3 non-advanced adenomas
4
Advanced adenoma
12
Significant lesion §
16
120
Odds Ratio+
M AN U
Subjects
SC
Colonoscopy Group
RI PT
intention-to-screen and as-screened analyses.*
95% CIξ
P value
0.68
0.27 to 1.68
0.41
3.3
0.74
0.19 to 2.84
0.67
7.5
1.06
0.39 to 2.86
0.92
11.7
1.02
0.45 to 2.26
0.96
5
11.1
0.50
0.17 to 1.49
0.22
4.9
5
11.1
2.41
0.61 to 9.46
0.21
14.8
5
11.1
0.72
0.23 to 2.19
0.56
19.8
11∞
24.4
1.31
0.54 to 3.14
0.54
TE D
7.5
14∞
AC C
19.8
EP
45
*In the intention-to-screen analysis the detection rate was calculated as the number of subjects with true positive results divided by the number of subjects who were eligible to undergo testing. In the as-screened analysis the
24
ACCEPTED MANUSCRIPT
RI PT
detection rate was calculated as the number of positive results divided by the number of subjects who actually underwent screening. Subjects were classified according to the most advanced lesion. +
ξ
CI denotes confidence interval.
ω
One or two adenoma <10 mm in diameter
Significant lesion was defined as polyp ≥ 10 mm, >2 polyps of any size or cancer.
M AN U
§
SC
Odds ratios were adjusted according to age, gender, age (<60 or ≥60 years old) of the index-case at CRC diagnosis, having siblings with CRC or more than one FDR with CRC.
AC C
EP
TE D
∞One CRC was detected in the group of CCE.
25
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Table 1 Supplementary Appendix. Endoscopic Satisfaction Questionnaire: adapted from the GHAA 9 (Group Health Association of America 9) questionnaire:
Please tick the box which best reflects your assessment of the following aspects: 1. How long you waited to get an appointment. □ Very Good
□ Good
□ Fair
□ Poor
RI PT
□ Excellent
2. Length of time spent waiting at the office/hospital for the procedure. □ Very Good
□ Good
□ Fair
□ Poor
SC
□ Excellent
3. The personal manner (courtesy, respect, sensitivity, friendliness) of the physician who performed your procedure. □ Very Good
□ Good
□ Fair
M AN U
□ Excellent
□ Poor
4. The technical skills (thoroughness, carefulness, competence) of the physician who performed your procedure. □ Very Good
□ Good
TE D
□ Excellent
□ Fair
□ Poor
5. The personal manner (courtesy, respect, sensitivity, friendliness) of the nurses and other auxiliary staff.
□ Very Good
EP
□ Excellent
□ Good
□ Fair
□ Poor
6. Adequacy of explanation of what was done for you and all your questions answered. □ Very Good
AC C
□ Excellent
□ Good
□ Fair
□ Poor
□ Good
□ Fair
□ Poor
7. Overall rating of the visit. □ Excellent
□ Very Good
8. Would you have the procedure done again by this physician? □Yes
□ No
9. Would you consider having this procedure again at this facility? □ Yes
□ No
ACCEPTED MANUSCRIPT 10. In case you have undergo both tests (CCE and optical colonoscopy): How would you rate the CCE procedure compared to optical colonoscopy? □ More unpleasant □ Somewhat uncomfortable
RI PT
□ Similar □ Something comfortable □ More comfortable
AC C
EP
TE D
M AN U
satisfaction with the CCE procedure: ______
SC
11. On a scale from 1 to 10 where 10 is the best score, please indicate your level of
S1542-3565(15)00908-8 10.1016/j.cgh.2015.06.032 YJCGH 54356
To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 9 June 2015 Please cite this article as: Adrián-de-Ganzo Z, Alarcón-Fernández O, Ramos L, Gimeno-García A, Alonso-Abreu I, Carrillo M, Quintero E, Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients with Colorectal Cancer, Clinical Gastroenterology and Hepatology (2015), doi: 10.1016/j.cgh.2015.06.032. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Uptake of Colon Capsule Endoscopy vs Colonoscopy for Screening Relatives of Patients with Colorectal Cancer ACCEPTED MANUSCRIPT
Zaida Adrián-de-Ganzo MD, Onofre Alarcón-Fernández MD, Laura Ramos MD, Antonio Gimeno-García MD, PhD, Inmaculada Alonso-Abreu MD, Marta Carrillo MD, PhD, and Enrique Quintero MD, PhD. de
Gastroenterología, Hospital
Universitario
de
Canarias.
Instituto
RI PT
Servicio
Universitario de Tecnologías Biomédicas (ITB) & Centro de Investigación Biomédica de Canarias (CIBICAN). Departamento de Medicina Interna. Universidad de La
SC
Laguna. Tenerife. España Grant support.
M AN U
This study was supported by a grant from the European Capsule Endoscopy Group (ECEG), by a grant from Caja Canarias Banca Cívica and by funds of the Department of Internal Medicine of La Laguna University. Abbreviations.
CCR: colorectal cancer
TE D
CCE: colon capsule endoscopy
CI: confidence intervals
AC C
OR: odds ratios
EP
FDR: first-degree relatives
Disclosures: None of the authors have any potential conflict of interest to disclose.
Author Contributions
Enrique Quintero was responsible for the conception and design of the trial. Zaida Adrián-de-Ganzo and Enrique Quintero took responsibility for the integrity of the data,
1
ACCEPTED MANUSCRIPT performed the analysis and interpretation of the results and were involved in the drafting of the article. Zaida Adrián-de-Ganzo, Onofre Alarcón, Antonio Z Gimeno-García, Laura Ramos, Inmaculada Alonso-Abreu and Marta Carrillo were involved in the acquisition of data. All the authors performed a critical revision of the article for
RI PT
important intellectual content and gave their final approval of the manuscript submitted.
Acknowledgements.
SC
The authors gratefully acknowledge Dr. Victor Abraira and Dr. Alfonso Muriel (Unidad de Bioestadística, Hospital Ramón y Cajal, Madrid) for assistance on the statistical
Correspondence: Enrique Quintero M.D. Department of Gastroenterology.
M AN U
analysis and critical reading of the manuscript.
TE D
Hospital Universitario de Canarias. Ctra. Ofra S/N La Cuesta,
38320 La Laguna, Tenerife, Spain.
EP
Email: [email protected]
AC C
Word count: 3,993 words
2
ACCEPTED MANUSCRIPT
ABSTRACT Background & Aims: The efficacy of screening colonoscopy in first-degree relatives (FDRs) of patients with colorectal cancer (CRC) is limited by suboptimal uptake. We compared
RI PT
screening uptake of colon capsule endoscopy (CCE) vs colonoscopy in this population.
Methods: We performed a prospective study of 329 asymptomatic FDRs of patients with CRC who were randomly assigned to groups examined by CCE (PillCam, 2nd generation;
SC
n=165) or colonoscopy (n=164) at a tertiary hospital in Spain, from July 2012 through December 2013. Crossover was permitted for patients who did not wish to undergo the
M AN U
assigned procedure. Subjects assigned to CCE who had a significant lesion (polyp ≥10 mm, >2 polyps of any size, or CRC) were invited to undergo colonoscopy. Results: One-hundred twenty subjects in the CCE group and 113 in the colonoscopy group were eligible for inclusion. In the intention-to-screen analysis, uptake was similar between
TE D
groups (55.8% CCE vs 52.2% colonoscopy; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.51−1.44; P=.57); 57.4% of subjects crossed-over from the CCE group and 30.2% crossed-over from the colonoscopy group (OR, 3.11; 95% CI, 1.51−6.41; P=.002).
EP
Unwillingness to repeat bowel preparation in the case of a positive result was the main reason that subjects assigned to the CCE group crossed over; fear of colonoscopy was the reason that
AC C
most patients in this group crossed over. A significant lesion was detected in 14 subjects (11.7%) in the CCE group and 13 subjects (11.5%) in the colonoscopy group (OR, 1.02; 95% CI, 0.45−2.26; P=.96).
Conclusion: In a prospective study, similar numbers of FDRs of patients with CRC assigned to undergo CCE or colonoscopy agreed to participate, but most preferred to undergo colonoscopy. CCE was as effective as colonoscopy in detecting significant lesions; it could be a valid rescue strategy for subjects who reject screening colonoscopy.
3
ACCEPTED MANUSCRIPT
ClinicalTrials.gov number NCT01557101.
RI PT
KEY WORDS: participation; colon cancer; colon capsule-2; detection; tumor
INTRODUCTION.
Family history is a major risk-factor for developing CRC.1 Risk increases two to five-fold in FDR of patients with CRC if the index-case is younger than 60 years or when 2, 3
Based on this premise, clinical practice guidelines
SC
there are two or more FDR affected.
M AN U
empirically recommend colonoscopy every five years, starting at the age of 40 or ten years less than the index-case at first diagnosis, as the first-line screening strategy in this setting.4-6
Colonoscopy is the gold standard procedure for detecting CRC and advanced adenomas. The advantage of colonoscopy over other screening tests is that polypectomy can
TE D
be performed, thus breaking the adenoma-carcinoma sequence and reducing subsequent development of CRC. However, it is far from being an ideal screening technique: it fails to identify as many as 12% of advanced adenomas and 5% of CRC, 7,
8
it is an invasive or
EP
procedure that carries an increased risk for complications, especially bleeding
perforation following caecal polypectomy,9 and screening uptake is suboptimal with
AC C
participation rates below 40% in the familial risk population. 10-12 For these reasons, alternative-screening strategies are currently under investigation. Colon capsule endoscopy (CCE) is a minimally invasive tool with similar accuracy
for detecting advanced neoplasia as optical colonoscopy.13-16 Currently, CCE is used in clinical practice as an alternative diagnostic tool in patients with non- occlusive, incomplete optical colonoscopy.17 Recently, it has been suggested that CCE may be cost-effective as compared to colonoscopy if it is able to increase CRC screening uptake by 20%. 18 In a pilot
4
ACCEPTED MANUSCRIPT
study in which all individuals were invited to undergo CCE followed by colonoscopy, the authors reported a four-fold higher screening uptake for CCE than for colonoscopy, with both techniques showing the same diagnostic yields for detecting adenomas. However,
RI PT
there are no prospective, randomized, controlled studies comparing CRC screening uptake between colonoscopy and CCE.
To test the hypothesis that CCE may improve CRC screening uptake in the familial-
SC
risk population, we designed a pragmatic, prospective, randomized open trial to compare
M AN U
screening uptake of colonoscopy versus CCE in screening naïve FDR of patients with CRC.
METHODS. Subjects
The study was conducted in a tertiary hospital serving approximately 375.000
TE D
inhabitants between July 2012 and December 2013. Consecutive patients with nonsyndromic CRC diagnosed during the previous two years were interviewed at the high-risk CRC clinic of our hospital. The trial registered as ClinicalTrials.gov number NCT01557101
EP
complied with the CONSORT extension for pragmatic trials.19 Inclusion criteria were: asymptomatic FDR ≥40 years of age or ten years less
AC C
than the youngest relative with CRC. Exclusion criteria were: previous CRC screening; history of colorectal neoplasia or inflammatory bowel disease; hereditary CRC; gastrointestinal surgery; pregnancy; allergy or other severe comorbidity (mean life expectancy of <5 years) or major limitation of physical activity (performance status ≥2); and contraindication for bisacodyl, polyethylen glycol or phosphates.
Information and Randomization
5
ACCEPTED MANUSCRIPT
To analyze screening uptake under real-life practice conditions we used the Zelen design.20 Briefly, participants in the two arms of the study are randomized before giving informed consent and have the opportunity to refuse their allotted strategy, and ¨crossover” to
RI PT
the alternative strategy is permitted (Figure 1). This design ensures the inclusion of all eligible subjects whereas the conventional randomization design (informed consent signed before randomization) includes only subjects consenting to participate. The Zelen design helps to
SC
reduce selection bias by preventing belief in the effectiveness of the intervention by physicians or participants and improves recruitment rates by reducing drop-out rates from the
M AN U
reference group.21
At the initial interview with the index-case, a gastroenterologist provided detailed verbal and written information about the study. After obtaining signed informed consent to accept familial participation, a one-generation family history of cancer was taken to identify
TE D
all FDR that met no exclusion criteria. Then, randomization (1:1) of eligible FDR was performed using a computer generated random sequence with sealed envelopes to one of the two study groups: Group 1: screening by CCE and colonoscopy in the event of a significant
EP
lesion (polyp ≥10 mm in diameter, >2 polyps of any size, or CRC); and Group 2: screening with optical colonoscopy. Sealed envelopes were prepared for eligible FDR in the family and
AC C
given to the index-case for their delivery. The envelopes contained a leaflet with detailed information about the trial, the strategy allocated, the informed consent document to participate in the study and a contact telephone number to arrange an appointment at the High Risk CRC Clinic. The possibility of changing group was not mentioned in the information leaflet, to minimize as much as possible crossover in both arms. In that event, a structured questionnaire was used to determine the reason for crossover between the assigned strategies (Table 1).
6
ACCEPTED MANUSCRIPT
Subjects assigned to CCE received information about the procedure (bowel preparation, duration and possible adverse events) and were told that they would be scheduled to undergo colonoscopy in the event of positive result. By contrast, subjects
RI PT
assigned to colonoscopy received detailed information about the technique (bowel cleansing, sedation, advantages of polypectomy in the event of polyp detection, and possible complications). Specific informed consent for the agreed strategy (CCE or conventional
SC
colonoscopy) was sought before the procedure. Both screening procedures were free of charge. The Clinical Research Ethics Committee of our center approved the study protocol
M AN U
and all authors had access to the study data and reviewed and approved the final manuscript
Colon capsule endoscopy.
CCE was performed with second-generation PillCam™ CCE system (PillCam® colon
TE D
capsule, Given Imaging Inc, Yoqneam, Israel) previously described. 13 Colon cleanliness for CCE was scheduled in one-day, low-volume preparation, as previously described, to facilitate adherence to screening. 22, 23 Colon cleanliness was graded for the following colonic
EP
segments: right colon, transverse colon, left colon and rectum, and classified using a validated 4-point scale as previously described:13 (1) excellent (no material or liquid material covering
AC C
<10% of the mucosal surface in each location), good (liquid material or mucus covering >10% of the mucosal surface), fair (solid material impossible to suction, covering <10% of the mucosal surface) or poor (solid material covering >10% of the mucosal surface). In the current study a colon preparation rated as “excellent” or “good” was considered as “adequate” whereas colon cleansing rated as “fair” and “poor” was classified as “inadequate”. CCE readings were performed by one independent blinded observer (AG or OA), as previously described.23 Polyp size was estimated by using the polyp size estimation
7
ACCEPTED MANUSCRIPT
tool included in the RAPID software (Given Imaging Ltd, Yoqneam, Israel, version 7.0). CCE findings were collected and a global lesion evaluation for each patient was recorded as: negative examination (no polyps or CCR), polyps, CRC or miscellaneous (diverticula,
RI PT
angiomas, inflammation or hemorrhoids). CCE examination was considered to be valid when the capsule was excreted (or hemorrhoidal plexus was observed), had adequate colonic cleansing or a significant lesion was detected. Subjects with an incomplete CCE
SC
exploration due to poor bowel cleansing were scheduled for optical colonoscopy. Colonoscopy
M AN U
Colonoscopies were carried out by experienced endoscopists as previously described.24 The endoscopic report contained the parameters for quality assessment (caecal intubation, quality of cleanliness for each colorectal segment, number of polyps identified, removed and recovered for histological examination and immediate complications).
TE D
Colonoscopy was considered complete if the cecum was reached and bowel cleansing was good or excellent.24 Colon cleansing was defined as inadequate when less than 90% of colorectal mucosa could be properly evaluated due to the presence of faeces. Patients with
colonoscopy.
EP
incomplete colonoscopy because of poor bowel preparation were re-scheduled to
AC C
Adenomas ≥10 mm in diameter, with tubulovillous architecture, high-grade
dysplasia or intramucosal carcinoma were classified as advanced adenomas. Invasive cancer was considered when malignant cells were observed beyond the muscularis mucosa. Tumor staging was performed according to the classification system of the American Joint Committee on Cancer 25 and patients were classified according to the most advanced lesion. Data collection Demographic characteristics of participants, kinship, degree of bowel cleanliness for
8
ACCEPTED MANUSCRIPT
each procedure, colonoscopy and CCE completion, colonoscopy or CCE findings, reason for failure and reason for crossover between the assigned groups was recorded. The level of patient satisfaction and potential procedure-related adverse effects were assessed using a
RI PT
questionnaire administered by telephone interview two weeks later (Supplementary Table 1). Sample Size
We hypothesized that uptake of CCE screening should be at least 20% higher
SC
than that of colonoscopy, on the basis that this is the minimal estimated difference that would make CCE cost-effective.18 Assuming a participation rate of 38% for colonoscopy12 and of
M AN U
58% for CCE screening, with an alpha risk of 0.05 and a beta risk of 0.20 in a two -sided test, 108 subjects in each arm of the study were needed to find a statistically significant difference.
TE D
Statistical Analysis.
The primary objective of this study was to compare screening uptake of CCE versus optical colonoscopy in FDR of patients with CRC. Screening uptake was defined as
EP
number of invited subjects screened by CCE or colonoscopy as a proportion of eligible subjects. The principal analysis consisted of an intention-to-screen comparison of the uptake
AC C
proportions between both study arms (subjects were analyzed according to their randomly assigned strategy, irrespective of whether they actually received it or not). The detection rate of neoplastic lesions (number of subjects with true positive results divided by the number of subjects who actually underwent testing) was based on as-screened analyses (subjects that underwent screening by colonoscopy or CCE, independently to their randomly assigned strategy). Statistical comparisons for secondary endpoints (efficacy of each procedure to
9
ACCEPTED MANUSCRIPT
explore the entire colon, and acceptance of each strategy) were performed according to asscreened analysis. Comparisons between groups were carried out by logistic-regression analysis and reported as odds ratios (OR) with 95% confidence intervals (CI). Continuous
RI PT
variables were expressed as means and standard deviation. Categorical variables were expressed as frequencies and percentages. Chi-square test was used to compare categorical variables. Differences with a P value <0.05 were considered statistically significant. Data
M AN U
SC
were analyzed using SPSS version 15.0 (SPSS Inc., Chicago, IL).
RESULTS.
Three hundred twenty nine FDR of 84 index-cases were prospectively randomized to undergo either CCE (n=165) or colonoscopy (n=164). Of these, 45 (27.7%) and 51 subjects (31.1%) were excluded from the CCE and colonoscopy groups, respectively
TE D
(Figure 2). Finally, the eligible population comprised 233 FDR (121 female, median age 55 years, range 31 to 78 years) who were assigned to CCE (n=120) or colonoscopy (n=113). As shown in Table 2, there were no statistically significant differences between the
EP
two groups in age, gender, body mass index (BMI), smoking or alcohol abuse and
AC C
demographic characteristics of the index-case.
Screening uptake and crossover rates. Among the 120 eligible FDR that were assigned to undergo CCE, 52 (43.3%)
declined to be screened and 68 (56.6%) agreed to participate in the study. Overall, 29 (24.2%) accepted the assigned strategy and 28 (23.3%) finally underwent CCE, whereas 39 (32.5%) that declined CCE were offered colonoscopy and actually did so. Among the 113 eligible FDR that were invited to undergo colonoscopy, 50 (44.2%) declined and 63
10
ACCEPTED MANUSCRIPT
(55.8%) agreed to participate. Of these, 44 (38.9%) accepted the assigned strategy and 42 (37.1%) finally underwent colonoscopy, whereas 19 (16.8%) that declined colonoscopy were offered CCE and 17 (15.0%) actually did so (Figure 2). Consequently, the crossover rate
group (30.2%) (OR 3.11; 95% CI, 1.51-6.41; P=0.002).
RI PT
between groups was significantly higher in the CCE group (57.4%) than in the colonoscopy
According to the intention-to-screen analysis, screening uptake was similar in the
SC
CCE group (n=67, 55.8%) compared to the colonoscopy group (n=59, 52.2%) (OR 0.86; 95% CI, 0.51-1.44; P=0.57). Overall, of the 233 eligible subjects, 45 (19.3%) underwent
M AN U
CCE whereas 81 (34.7%) completed colonoscopy.
The reasons for declining to be screened by CCE was “to avoid a second bowel preparation in the event of a positive result” in 35/39 (89.7%) subjects, "feeling more confident about colonoscopy" in three (7.7%) subjects and "the index case or another first-
TE D
degree relative reported having had an unpleasant experience" in one (2.6%) subject. Among FDR assigned to colonoscopy, the reason for rejecting that option was “fear of colonoscopy”
EP
in 19/19 (100%) of cases.
Efficacy for detecting colorectal neoplasia.
AC C
Table 3 shows the efficacy of the two strategies to detect colorectal neoplasia according to the intention-to-screen and as-screened analyses. No statistical differences between the two groups were observed regarding the detection rate of significant lesions.
Completion of CCE and colonoscopy. Overall, the mean average CCE recording time was 373±265 minutes and the mean capsule recording time in the colon was 215±231 minutes. CCE was excreted in
11
ACCEPTED MANUSCRIPT
33/45 subjects (73.3%) within 10 hours. In 12 subjects (26.7%) the capsule was not excreted or did not reach the rectum. Of these, CCE was considered valid in four subjects who had an advanced adenoma (n=2) or three non-advanced adenomas (n=2), and
RI PT
an optical colonoscopy was indicated and completed. The overall cleansing rate was inadequate in 9/45 additional subjects (20%), but the procedure was considered valid in two cases with positive findings (one had advanced adenoma and one had three non- advanced
SC
adenomas) and an optical colonoscopy was completed. Therefore, in 30 subjects (66.6%) CCE was considered complete, whereas in 15 subjects (33.4%) in whom the capsule did not
M AN U
reach the rectum or had inadequate cleansing it was considered inadequate and a colonoscopy was scheduled. In the colonoscopy group, the overall cleansing rate was adequate and colonoscopy was complete in 66/81 subjects (81.5%). The remaining 15
TE D
subjects (18.5%) with inadequate bowel preparation were re-scheduled for colonoscopy.
Satisfaction level and adverse events.
No major complications were registered during capsule ingestion or transit period,
EP
nor during colonoscopy. Only one patient (2.2%) in the CCE group and three (3.7%) in the colonoscopy group had discrete abdominal discomfort during the procedure. Nine out of
AC C
11 (81.8%) subjects undergoing CCE and colonoscopy were satisfied with the technique and considered that CCE was less unpleasant than colonoscopy. No subjects reported any longterm secondary effects related with CCE or colonoscopy.
DISCUSSION.
12
ACCEPTED MANUSCRIPT
In the current study we aimed to determine whether CCE would improve screening uptake of optical colonoscopy in FDR of patients with CRC. Contrary to expectations, the study failed to support this hypothesis and screening uptake was similar between CCE
RI PT
and colonoscopy in FDR of patients with CRC. The higher crossover rate from the CCE group to the colonoscopy group suggests better acceptance of screening colonoscopy. This finding runs counter to those of two recent pilot studies on screening modalities which
SC
suggested that CCE is about four-fold better accepted than optical colonoscopy26 or computed tomographic colonoscopy.27 However, these studies had important methodological
M AN U
flaws for the assessment of screening uptake. They were designed as single-arm studies rather than randomized trials, which makes it difficult to assess the adherence to each strategy separately, and sample size was small.
One of the main findings of our study was that the crossover rate in individuals
TE D
assigned to CCE was three-fold higher than in those assigned to colonoscopy, which definitively contributed to low CCE adherence rate. The main reason for low CCE uptake in this study is probably the fact that subjects knew they would have to undergo a second bowel
EP
preparation and colonoscopy on another day in the event of a positive CCE finding. In fact, “to avoid a second bowel preparation in the event of a positive result” was the most
AC C
frequent answer (89%) given by individuals assigned to CCE who decided to take the alternative test. Although we assumed a higher screening uptake in the CCE group, it is possible that a more complex family history (i.e. having more than one FDR with CRC) led to CCE rejection because of higher risk perception. This group of patients might therefore have been more predisposed to undergo conventional colonoscopy. In our opinion, logistical difficulties impede same-day CCE and optical colonoscopy in the screening setting. The main problem is prolonged duration of the procedure which 13
ACCEPTED MANUSCRIPT
requires two hours for bowel preparation, about nine hours for transit time, no less than 3 hours for data downloading to the RAPID workstation and about 90 minutes for reading and reporting the results. In total, the whole process takes no less than 15 hours which makes it
RI PT
very difficult to program optical colonoscopy on the same day in patients with a positive CCE result. We are aware that this may have influenced CCE uptake. Another factor that could have contributed to low adherence to CCE was the “good experience” of the index-case
SC
with colonoscopy, as we systematically use intravenous sedation in all colonoscopies. However, this is also expected to occur in real clinical practice and should be considered as a
M AN U
factor that could reduce the overall adherence to CCE screening.
Apart from individual perceptions on the procedure, CCE has two additional drawbacks for use as a screening procedure. Firstly, between 20-35% of cases (in our study 33%) have an incomplete examination due to inadequate bowel preparation, not
17,
23,
26
16,
TE D
allowing the capsule to reach the hemorrhoid plexus or because of technical problems. 13,
Therefore, a significant proportion of examinations need rescheduling to
colonoscopy. Secondly, at least in Spain, CCE is about two-fold more expensive than
EP
colonoscopy. Although we did not analyze costs in the current study, CCE is very unlikely to be cost -effective nowadays for CRC screening; a recent study has shown that screening
AC C
uptake should be at least 20% higher than that of colonoscopy to be cost-effective,17 which was not the case in our study. Taking into account these circumstances, it seems reasonable for now not to recommend CCE as a first-line screening option in FDR of patients with CRC. Our study has several strengths. It is the first randomized controlled trial comparing the uptake of CCE with colonoscopy for CRC screening and it was designed as a pragmatic study, allowing crossover between groups. In addition, randomization was performed before informed consent was signed, to minimize selection bias.
14
ACCEPTED MANUSCRIPT
We are also aware of the study limitations. First, apart from individual perceptions on the screening techniques, we did not evaluate other potential causes for non-adherence (i.e. socio-economic status or index-case influence on the final decision of their respective
RI PT
relatives). Second, we cannot provide accurate information on the reasons for declining screening in subjects who did not attend the appointment at our high-risk CRC clinic because Spanish law does not allow recording data of individuals without their signed
SC
informed consent. Third, the low performance of CCE in terms of completeness and cleansing level observed in our study could be influenced by the low-volume preparation
M AN U
used. However, it has been reported that cleansing quality was similar between low-volume and high-volume preparations28 and the proportion of poor cleansing in our study was similar to that of other studies.16,
17, 23, 26
In addition, the evidence supporting the benefit of high-
volume preparation regimens recommended by a recent guideline is low (Evidence level 4;
TE D
Grade of recommendation D).29
The efficacy of CCE with respect to the final diagnosis of a significant lesion deserves comment. Although our study was not powered to assess diagnostic yield, the
EP
intention-to-screen and as-screened analysis showed that CCE was as effective as colonoscopy for detecting significant lesions. This result is in line with two recent
AC C
multicenter studies that compared the diagnostic capacity of CCE and colonoscopy for detecting colorectal neoplasia. 14, 16 In conclusion, our study showed that screening uptake of CCE was about the same as
that of colonoscopy in FDR of patients with CRC. Interestingly, the crossover rate was markedly higher in subjects invited to CCE than in those invited to colonoscopy, suggesting better acceptance of colonoscopy. For these reasons, colonoscopy should still be considered the first-choice screening strategy in the familial risk population, leaving
15
ACCEPTED MANUSCRIPT
CCE as a rescue technique for those individuals unwilling to undergo colonoscopy.
REFERENCES Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer
RI PT
1.
for individuals with a family history: a meta-analysis. European journal of cancer 2006;42:216-27.
Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance:
SC
2.
clinical guidelines and rationale-Update based on new evidence. Gastroenterology
3.
M AN U
2003;124:544-60.
Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001;96:2992-3003.
4.
Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance
TE D
after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2012;143:844-57. 5.
Davila RE, Rajan E, Baron TH, et al. ASGE guideline: colorectal cancer screening and
6.
EP
surveillance. Gastrointestinal endoscopy 2006;63:546-57. Castells A, Marzo-Castillejo M, Mascort JJ, et al. [Clinical practice guideline.
AC C
Prevention of colorectal cancer. 2009 update. Asociacion Espanola de Gastroenterologia]. Gastroenterologia y hepatologia 2009;32:717 e1-58. 7.
Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology 1997;112:24-8.
8.
Pickhardt PJ, Nugent PA, Mysliwiec PA, et al. Location of adenomas missed by optical colonoscopy. Ann Intern Med 2004;141:352-9.
9.
Rutter MD, Nickerson C, Rees CJ, et al. Risk factors for adverse events related to
16
ACCEPTED MANUSCRIPT
polypectomy in the English Bowel Cancer Screening Programme. Endoscopy 2014;46:90-7. 10.
Ait Ouakrim D, Lockett T, Boussioutas A, et al. Screening participation for people at
RI PT
increased risk of colorectal cancer due to family history: a systematic review and metaanalysis. Familial cancer 2013. 11.
Bronner K, Mesters I, Weiss-Meilnik A, et al. Do individuals with a family history of
cancer? Fam Cancer 2013;12:629-37.
Bujanda L, Sarasqueta C, Zubiaurre L, et al. Low adherence to colonoscopy in the
M AN U
12.
SC
colorectal cancer adhere to medical recommendations for the prevention of colorectal
screening of first-degree relatives of patients with colorectal cancer. Gut 2007;56:17148. 13.
Eliakim R, Fireman Z, Gralnek IM, et al. Evaluation of the PillCam Colon capsule in the
TE D
detection of colonic pathology: results of the first multicenter, prospective, comparative study. Endoscopy 2006;38:963-70. 14.
Rex DK, Adler SN, Aisenberg J, et al. Accuracy of Capsule Colonoscopy in Detecting
15.
EP
Colorectal Polyps in a Screening Population. Gastroenterology 2015. Schoofs N, Deviere J, Van Gossum A. PillCam colon capsule endoscopy compared with
AC C
colonoscopy for colorectal tumor diagnosis: a prospective pilot study. Endoscopy 2006;38:971-7. 16.
Spada C, Hassan C, Munoz-Navas M, et al. Second-generation colon capsule endoscopy compared with colonoscopy. Gastrointest Endosc 2011;74:581-589 e1.
17.
Alarcon-Fernandez O, Ramos L, Adrian-de-Ganzo Z, et al. Effects of colon capsule endoscopy on medical decision making in patients with incomplete colonoscopies. Clin Gastroenterol Hepatol 2013;11:534-40 e1.
17
ACCEPTED MANUSCRIPT
18.
Hassan C, Zullo A, Winn S, et al. Cost-effectiveness of capsule endoscopy in screening for colorectal cancer. Endoscopy 2008;40:414-21. Groth S, Krause H, Behrendt R, et al. Capsule colonoscopy increases uptake of colorectal cancer screening. BMC Gastroenterol 2012;12:80.
20.
RI PT
19.
Zwarenstein M, Treweek S, Gagnier JJ, et al. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ 2008;337:a2390.
Zelen M. Randomized consent designs for clinical trials: an update. Stat Med
SC
21.
1990;9:645-56.
Adamson J, Cockayne S, Puffer S, et al. Review of randomised trials using the post-
M AN U
22.
randomised consent (Zelen's) design. Contemp Clin Trials 2006;27:305-19. 23.
Kakugawa Y, Saito Y, Saito S, et al. New reduced volume preparation regimen in colon capsule endoscopy. World J Gastroenterol 2012;18:2092-8.
Ramos L, Alarcon O, Adrian Z, et al. One-day versus two-day cleansing for colon
TE D
24.
capsule endoscopy: a prospective randomized pilot study. Gastroenterol Hepatol 2014;37:101-6.
Parra-Blanco A, Nicolas-Perez D, Gimeno-Garcia A, et al. The timing of bowel
EP
25.
preparation before colonoscopy determines the quality of cleansing, and is a significant
AC C
factor contributing to the detection of flat lesions: a randomized study. World J Gastroenterol 2006;12:6161-6. 26.
O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. Journal of the National Cancer Institute 2004;96:1420-5.
27.
Rondonotti E, Borghi C, Mandelli G, et al. Accuracy of Capsule Colonoscopy and Computed Tomographic Colonography in Individuals With Positive Results From the
18
ACCEPTED MANUSCRIPT
Fecal Occult Blood Test. Clin Gastroenterol Hepatol 2014. 28.
Hartmann D, Keuchel M, Philipper M, et al. A pilot study evaluating a new low-volume
Spada C, Hassan C, Galmiche JP, et al. Colon capsule endoscopy: European Society of
EP
TE D
M AN U
SC
Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2012;44:527-36.
AC C
29.
RI PT
colon cleansing procedure for capsule colonoscopy. Endoscopy 2012;44:482-6.
19
ACCEPTED MANUSCRIPT
Figure Legends. Figure 1. Randomization and informed consent design
AC C
EP
TE D
M AN U
SC
RI PT
Figure 2. Study Enrollment and screening uptake.
20
ACCEPTED MANUSCRIPT
Table 1. Questionnaire to determine the reason for changing the screening strategy assigned to first degree relatives.
RI PT
Colon Capsule Endoscopy group (prefers colonoscopy): 1. “Fear of colon capsule endoscopy” □ Yes
□ No
□ Yes
SC
2. "The index case or another first-degree relative reported having had an unpleasant experience with colon capsule endoscopy" □ No
experience with colonoscopy" □ Yes
□ No
M AN U
3. "The index case or another first-degree relative reported having had a satisfactory
4. “To avoid a second bowel preparation in the event of a positive result”
□ Yes
□ No
□ Yes
□ No
EP
6. Other (explain).
TE D
5. "Feeling more confident about colonoscopy"
AC C
Colonoscopy group (prefers Colon Capsule Endoscopy): 1. “Fear of colonoscopy” □ Yes
□ No
2. "The index case or another first-degree relative reported having had an unpleasant experience with colonoscopy" □ Yes
□ No
3. "The index case or another first-degree relative reported having had a satisfactory
experience with colon capsule endoscopy"
21
ACCEPTED MANUSCRIPT
□ Yes
□ No
4. "Feeling more confident about colon capsule endoscopy" □ Yes
□ No
AC C
EP
TE D
M AN U
SC
RI PT
5. Other (explain).
22
ACCEPTED MANUSCRIPT
Table 2. Demographic data of first-degree relatives in both study groups. CCE1 group
Colonoscopy group
(n=120)
(n=113)
55.1 ± 11.9
54.9 ± 11.2
Mean age ± SD Gender, n (%)
67 (55.8)
Chronic disease, n (%) Alcohol intake > 60 g/d, n (%)
36 (56.3)
0.29
68 (51.5)
8 (11.8)
8 (12.5)
0.90
16 (12.1)
0.38
27.9 ± 5.1
19 (29.7)
0.68
37 (28.0)
9 (14.1)
0.73
20 (15.2)
76 (67.3)
0.97
18 (26.5)
Antiplatelet therapy, aspirin
11 (16.2)
TE D
CRC2 Proband, n (%) 81 (67.5) 56.8 ± 8.7
27.2 ± 4.8
57.2 ± 9.19
96 (80.0)
91 (80.5)
24 (20.0)
22 (19.5)
0.57
0.87
112 (48.1)
157
67.4
57 ± 8.95
187
(80.3)
46
(19.7)
AC C
Two or more
EP
One
121 (51.9)
0.22
32 (47.1)
Smoking, n (%)
Relatives with CRC, n (%)
54.9 ± 11.6
59 (52.2)
28.6 ± 5.5
Mean age ± SD
(n=233)
53 (44.2)
BMI ± SD
Age < 60 years
0.91
SC
Male
54 (47.8)
M AN U
Female
p
RI PT
Category
Total
1
CCE = Colon capsule endoscopy
2
CRC = colorectal cancer
23
ACCEPTED MANUSCRIPT
Table 3.- Diagnostic yield of colon capsule endoscopy (CCE) and colonoscopy according to the
CCE Group
Rate
Subjects
Rate
Most advanced lesion
no.
%
no.
%
Intention-to-screen analysis
113
Non-advanced adenomaω
12
10.6
9
≥ 3 non-advanced adenomas
5
4.4
4
Advanced adenoma
8
7.1
9
Significant lesion§
13
11.5
As-screened analysis
81
Non-advanced adenomaω
16
≥ 3 non-advanced adenomas
4
Advanced adenoma
12
Significant lesion §
16
120
Odds Ratio+
M AN U
Subjects
SC
Colonoscopy Group
RI PT
intention-to-screen and as-screened analyses.*
95% CIξ
P value
0.68
0.27 to 1.68
0.41
3.3
0.74
0.19 to 2.84
0.67
7.5
1.06
0.39 to 2.86
0.92
11.7
1.02
0.45 to 2.26
0.96
5
11.1
0.50
0.17 to 1.49
0.22
4.9
5
11.1
2.41
0.61 to 9.46
0.21
14.8
5
11.1
0.72
0.23 to 2.19
0.56
19.8
11∞
24.4
1.31
0.54 to 3.14
0.54
TE D
7.5
14∞
AC C
19.8
EP
45
*In the intention-to-screen analysis the detection rate was calculated as the number of subjects with true positive results divided by the number of subjects who were eligible to undergo testing. In the as-screened analysis the
24
ACCEPTED MANUSCRIPT
RI PT
detection rate was calculated as the number of positive results divided by the number of subjects who actually underwent screening. Subjects were classified according to the most advanced lesion. +
ξ
CI denotes confidence interval.
ω
One or two adenoma <10 mm in diameter
Significant lesion was defined as polyp ≥ 10 mm, >2 polyps of any size or cancer.
M AN U
§
SC
Odds ratios were adjusted according to age, gender, age (<60 or ≥60 years old) of the index-case at CRC diagnosis, having siblings with CRC or more than one FDR with CRC.
AC C
EP
TE D
∞One CRC was detected in the group of CCE.
25
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Table 1 Supplementary Appendix. Endoscopic Satisfaction Questionnaire: adapted from the GHAA 9 (Group Health Association of America 9) questionnaire:
Please tick the box which best reflects your assessment of the following aspects: 1. How long you waited to get an appointment. □ Very Good
□ Good
□ Fair
□ Poor
RI PT
□ Excellent
2. Length of time spent waiting at the office/hospital for the procedure. □ Very Good
□ Good
□ Fair
□ Poor
SC
□ Excellent
3. The personal manner (courtesy, respect, sensitivity, friendliness) of the physician who performed your procedure. □ Very Good
□ Good
□ Fair
M AN U
□ Excellent
□ Poor
4. The technical skills (thoroughness, carefulness, competence) of the physician who performed your procedure. □ Very Good
□ Good
TE D
□ Excellent
□ Fair
□ Poor
5. The personal manner (courtesy, respect, sensitivity, friendliness) of the nurses and other auxiliary staff.
□ Very Good
EP
□ Excellent
□ Good
□ Fair
□ Poor
6. Adequacy of explanation of what was done for you and all your questions answered. □ Very Good
AC C
□ Excellent
□ Good
□ Fair
□ Poor
□ Good
□ Fair
□ Poor
7. Overall rating of the visit. □ Excellent
□ Very Good
8. Would you have the procedure done again by this physician? □Yes
□ No
9. Would you consider having this procedure again at this facility? □ Yes
□ No
ACCEPTED MANUSCRIPT 10. In case you have undergo both tests (CCE and optical colonoscopy): How would you rate the CCE procedure compared to optical colonoscopy? □ More unpleasant □ Somewhat uncomfortable
RI PT
□ Similar □ Something comfortable □ More comfortable
AC C
EP
TE D
M AN U
satisfaction with the CCE procedure: ______
SC
11. On a scale from 1 to 10 where 10 is the best score, please indicate your level of