Carlo Senore

Once-Only Sigmoidoscopy in Colorectal Cancer Screening: Follow-up Findings of the Italian Randomized Controlled Trial—SCORE

BACKGROUND A single flexible sigmoidoscopy at around the age of 60 years has been proposed as an effective strategy for colorectal cancer (CRC) screening. METHODS We conducted a randomized controlled trial to evaluate the effect of flexible sigmoidoscopy screening on CRC incidence and mortality. A questionnaire to assess the eligibility and interest in screening was mailed to 236,568 men and women, aged 55-64 years, who were randomly selected from six trial centers in Italy. Of the 56,532 respondents, interested and eligible subjects were randomly assigned to the intervention group (invitation for flexible sigmoidoscopy; n = 17,148) or the control group (no further contact; n = 17,144), between June 14, 1995, and May 10, 1999. Flexible sigmoidoscopy was performed on 9911 subjects. Intention-to-treat and per-protocol analyses were performed to compare the CRC incidence and mortality rates in the intervention and control groups. Per-protocol analysis was adjusted for noncompliance. RESULTS A total of 34,272 subjects (17,136 in each group) were included in the follow-up analysis. The median follow-up period was 10.5 years for incidence and 11.4 years for mortality; 251 subjects were diagnosed with CRC in the intervention group and 306 in the control group. Overall incidence rates in the intervention and control groups were 144.11 and 176.43, respectively, per 100,000 person-years. CRC-related death was noted in 65 subjects in the intervention group and 83 subjects in the control group. Mortality rates in the intervention and control groups were 34.66 and 44.45, respectively, per 100,000 person-years. In the intention-to-treat analysis, the rate of CRC incidence was statistically significantly reduced in the intervention group by 18% (rate ratio [RR] = 0.82, 95% confidence interval [CI] = 0.69 to 0.96), and the mortality rate was non-statistically significantly reduced by 22% (RR = 0.78; 95% CI = 0.56 to 1.08) compared with the control group. In the per-protocol analysis, both CRC incidence and mortality rates were statistically significantly reduced among the screened subjects; CRC incidence was reduced by 31% (RR = 0.69; 95% CI = 0.56 to 0.86) and mortality was reduced by 38% (RR = 0.62; 95% CI = 0.40 to 0.96) compared with the control group. CONCLUSION A single flexible sigmoidoscopy screening between ages 55 and 64 years was associated with a substantial reduction of CRC incidence and mortality.

Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer

CONTEXT Computed tomographic (CT) colonography has been recognized as an alternative for colorectal cancer (CRC) screening in average-risk individuals, but less information is available on its performance in individuals at increased risk of CRC. OBJECTIVE To assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in asymptomatic individuals at increased risk of CRC using unblinded colonoscopy as the reference standard. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, cross-sectional study. Individuals at increased risk of CRC due to either family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests (FOBTs) were recruited in 11 Italian centers and 1 Belgian center between December 2004 and May 2007. Each participant underwent CT colonography followed by colonoscopy on the same day. MAIN OUTCOME MEASURES Sensitivity and specificity of CT colonography in detecting individuals with advanced neoplasia (ie, advanced adenoma or CRC) 6 mm or larger. RESULTS Of 1103 participants, 937 were included in the final analysis: 373 cases in the family-history group, 343 in the group with personal history of adenomas, and 221 in the FOBT-positive group. Overall, CT colonography identified 151 of 177 participants with advanced neoplasia 6 mm or larger (sensitivity, 85.3%; 95% confidence interval [CI], 79.0%-90.0%) and correctly classified results as negative for 667 of 760 participants without such lesions (specificity, 87.8%; 95% CI, 85.2%-90.0%). The positive and negative predictive values were 61.9% (95% CI, 55.4%-68.0%) and 96.3% (95% CI, 94.6%-97.5%), respectively; after group stratification, a significantly lower negative predictive value was found for the FOBT-positive group (84.9%; 95% CI, 76.2%-91.3%; P < .001). CONCLUSIONS In a group of persons at increased risk for CRC, CT colonography compared with colonoscopy resulted in a negative predictive value of 96.3% overall. When limited to FOBT-positive persons, the negative predictive value was 84.9%.

Performance measures for lower gastrointestinal endoscopy: a European Society of Gastrointestinal Endoscopy (ESGE) Quality Improvement Initiative

The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology (UEG) have identified quality of endoscopy as a major priority and we described our rationale for this in a first manuscript that also addressed the methodology of the quality initiative process.1 The identification of upper gastrointestinal (UGI) performance measures presents a considerable challenge, in contrast to the situation with colonoscopy for instance, where several performance measures (inspection time, adenoma detection rate, and interval cancers, among others) have been identified over the last decade.2,3 Following the Quality in UGI Endoscopy meeting held in Lisbon in 2013, it was clear that there was a need to identify performance measures for the UGI tract, and that quality standards could be identified although there is a paucity of evidence. This lack of evidence helps however to identify research priorities for the development of clinical trials that will further validate and substantiate the implementation of performance measures. The aim therefore of the UGI working group was twofold: (a) to identify performance measures for UGI endoscopy; (b) to identify the evidence or absence of evidence that would develop the research priorities in this field. We used an innovative methodology to facilitate the quality initiative process, which combined a thorough search and standardized evaluation of the available evidence for each clinical question, followed by a Delphi process (http://is.njit.edu/pubs/delphibook/delphibook.pdf) using an online platform.4,5 This online platform permitted iterative rounds of modification and comment by all members of the UGI working group until agreement was reached on the performance measure. We now report these newly identified performance measures.

A randomized trial of smoking cessation interventions in general practice in Italy.

The purpose of this study was to examine the effectiveness of different practice-based approaches to assist patients of primary care physicians to quit smoking and sustain cessation. Forty-four nonsmoking general practitioners volunteered for the study. After a period of training, they randomized 923 smoking clients, unselected for motivation toward quitting, to four different intervention groups: (i) minimal intervention, consisting of one single counselling session and a brief handout on quitting techniques; (ii) repeated counselling including reinforcing sessions at Months 1, 3, 6, and 9; (iii) repeated counselling and use of nicotine gum; and (iv) repeated counselling and spirometry. Biochemically validated smoking status was assessed at six and 12 months after recruitment. The proportion of verified quitters at 12 months was 4.8 percent among subjects randomized to the minimal intervention group, compared to 5.5 percent, 7.5 percent, and 6.5 percent among those randomized to the three repeated-counselling groups. In no treatment group was the outcome significantly different from that for one-time counselling at the (P<0.05) level. Lack of power, contamination, and low attendance at reinforcing sessions should be taken into account in interpreting the results.

Efficacy and safety of endoscopic resection of large colorectal polyps: a systematic review and meta-analysis

Objective To assess the efficacy and safety of endoscopic resection of large colorectal polyps. Design Relevant publications were identified in MEDLINE/EMBASE/Cochrane Central Register for the period 1966–2014. Studies in which ≥20 mm colorectal neoplastic lesions were treated with endoscopic resection were included. Rates of postendoscopic resection surgery due to non-curative resection or adverse events, as well as the rates of complete endoscopic removal, invasive cancer, adverse events, recurrence and mortality, were extracted. Study quality was ascertained according to Newcastle-Ottawa Scale. Forest plot was produced based on random effect models. I2 statistic was used to describe the variation across studies due to heterogeneity. Meta-regression analysis was also performed. Results 50 studies including 6442 patients and 6779 large polyps were included in the analyses. Overall, 503 out of 6442 patients (pooled rate: 8%, 95% CI 7% to 10%, I2=78.6%) underwent surgery due to non-curative endoscopic resection, and 31/6442 (pooled rate: 1%, 95% CI 0.7% to 1.4%, I2=0%) to adverse events. Invasive cancer at histology, non-curative endoscopic resection, synchronous lesions and recurrence accounted for 58%, 28%, 2.2% and 5.9% of all the surgeries, respectively. Endoscopic perforation occurred in 96/6595 (1.5%, 95% CI 1.2% to 1.7%) polyps, while bleeding in 423/6474 (6.5%, 95% CI 5.9% to 7.1%). Overall, 5334 patients entered in surveillance, 502/5836 (8.6%, 95% CI 7.9% to 9.3%) being lost at follow-up. Endoscopic recurrence was detected in 735/5334 patients (13.8%, 95% CI 12.9% to 14.7%), being an invasive cancer in 14/5334 (0.3%, 95% CI 0.1% to 0.4%). Endoscopic treatment was successful in 664/735 cases (90.3%, 95% CI 88.2% to 92.5%). Mortality related with management of large polyps was reported in 5/6278 cases (0.08%, 95% CI 0.01% to 0.15%). Conclusions Endoscopic resection of large polyps appeared to be an extremely effective and safe intervention. However, an adequate endoscopic surveillance is necessary for its long-term efficacy.

High Rate of Advanced Adenoma Detection in 4 Rounds of Colorectal Cancer Screening With the Fecal Immunochemical Test

BACKGROUND & AIMS Few data have been published on the performance of colorectal cancer (CRC) screens that use multiple rounds of the fecal immunochemical test (FIT). We evaluated outcomes of 4 screening rounds in over 7 years in an Italian population-based program. METHODS We conducted a prospective cohort study of 2959 average-risk subjects, aged 50-74 years, who were invited for the first screening round in 2001. We assessed the participation rate, the yield of advanced adenomas and CRC detected in the screening examinations, and we collected information about interval CRCs, with a follow-up period of 8.5 years. RESULTS Participation in each round varied from 56% to 63%; 48.1% of eligible subjects attended all 4 invitations. The positive predictive value of the FIT for advanced neoplasia (CRC or advanced adenoma) was 40% at the first round, and approximately 33% in the subsequent rounds. This decrease was attributable mainly to a decrease in the detection of CRC, although a high rate of advanced adenomas (range, 0.8%-1.7%) was observed over all rounds. To find one advanced neoplasia in the study period the number of people that needed to be screened was 28, and the number of tests needed was 74. CONCLUSIONS About 60% of invited individuals participated in every single round of FIT screening for CRC, but less than 50% attended all 4 tests. A high detection rate of advanced adenomas in all rounds indicates that FIT screening could have a higher impact on incidence of CRC than the guaiac fecal occult blood test.

Comparing different strategies for colorectal cancer screening in italy: Predictors of patients participation

OBJECTIVES:The objective of this study was to study predictors of patients’ participation in colorectal cancer (CRC) screening.METHODS:Men and women, aged 55–64 years, were randomized to the following: (i) biennial fecal occult blood test (FOBT) delivered by mail (n=2,266); (ii) FOBT delivered by a general practitioner (GP)/screening facility (n=5,893); (iii) “once-only” sigmoidoscopy (FS) (n=3,650); (iv) FS followed by FOBT for screenees with negative FS (n=10,867); and (v) patients choice between FS and FOBT (n=3,579). A stratified (by screening arm) random sample of attenders and nonattenders was contacted by trained interviewers 4 months after the initial invitation. Subjects giving their consent were administered a questionnaire (available online) investigating perceptions of individual CRC risk, attitudes toward prevention, adoption of health protective behaviors, and reasons for attendance/nonattendance. Adjusted prevalence odds ratios (ORs) were computed by multivariable logistic regression.RESULTS:The response rate was 71.9% (701 of 975) among nonattenders and 88.9% (773 of 870) among attenders. Adjusting for screening arm, center, gender, age, and education, participation was significantly higher among people who consulted their GP before undergoing screening (OR: 4.24; 95% confidence interval (CI): 3.11–5.78), who mentioned one first-degree relative with CRC (OR: 3.62; 95% CI: 2.02–6.49), who reported regular physical activity (OR: 1.85; 95% CI: 1.33–2.55), and who read the mailed information (letter only: OR: 1.85; 95% CI: 1.23–2.78; letter+leaflet: OR: 3.18; 95% CI: 2.12–4.76). People who considered screening to be ineffective (OR: 0.12; 95% CI: 0.08–0.19), those who considered it to be effective but reported even moderate levels of anxiety (OR: 0.32; 95% CI: 0.23–0.45), and those who mentioned previous knowledge of CRC screening tests were less likely to accept the invitation (OR: 0.49; 95% CI: 0.34–0.70).CONCLUSIONS:Adoption of health protective behaviors is associated with a higher attendance rate, whereas anxiety represents a strong barrier, even among people who deemed screening to be effective. Increasing the proportion of people who consult their GP when making a decision regarding screening might enhance participation.

Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy.

Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M 
(2012) Histopathology 61, 562–575

Acceptability and side-effects of colonoscopy and sigmoidoscopy in a screening setting

Objective Quantitative information on adverse reactions associated with colorectal cancer (CRC) screening tests is useful to estimate the balance between benefit and risk in different strategies. Setting Six Italian screening centres. Methods Thirty-day active follow-up (interview about side-effects and acceptability of the screening procedure and review of hospital admissions) among average-risk people undergoing flexible sigmoidoscopy (FS), total colonoscopy (TC), fecal immunochemical test (FIT) in a multicentre randomized trial of CRC screening. Multivariable logistic models were used to assess determinants of completion rate and self-reported pain. Results The attendance rate following the first invitation and mail reminder was 28.2% (1696/6018) in the FS and 23.0% (1382/6021) in the TC arm. Response rate to the 30-day follow-up questionnaire was 88.6% (1502/1696) among people undergoing FS, and 86.7% (1198/1382) among those undergoing TC. The proportion of people complaining of serious reactions following bowel preparation (odds ratio [OR], 5.17; 95% confidence interval [CI] 3.70–7.24) or reporting severe pain immediately after the exam (OR, 1.86; 95% CI 1.47–2.34) was higher for TC than for FS. The most common post-procedural complaints were abdominal distension and pain. People mentioning pain or bowel distension following preparation were more likely to report severe pain both after FS (OR, 2.13; 95% CI 1.52–2.97) and TC (OR: 2.03; 95% CI 1.41–2.90). The 30-day hospitalization rate was similar after FS, TC and FIT. Conclusions Screenees reported higher pain levels after TC than FS. The proportion of people complaining of severe side effects after discharge was similar. Bowel preparation was poorly tolerated by people undergoing TC. Subjects’ reactions to the bowel preparation was predictive of post-procedural discomfort. A commitment of at least 48 hours was required of people undergoing TC, compared with 3–4 for FS.

Colon capsule versus CT colonography in patients with incomplete colonoscopy: a prospective, comparative trial

Objective In case of incomplete colonoscopy, several radiologic methods have traditionally been used, but more recently, capsule endoscopy was also shown to be accurate. Aim of this study was to compare colon capsule endoscopy (CCE) and CT colonography (CTC) in a prospective cohort of patients with incomplete colonoscopy. Design Consecutive patients with a previous incomplete colonoscopy underwent CCE and CTC followed by colonoscopy in case of positive findings on either test (polyps/mass lesions ≥6 mm). Clinical follow-up was performed in the other cases to rule out missed cancer. CTC was performed after colon capsule excretion or 10–12 h postingestion. Since the gold standard colonoscopy was performed only in positive cases, diagnostic yield and positive predictive values of CCE and CTC were used as study end-points. Results 100 patients were enrolled. CCE and CTC were able to achieve complete colonic evaluation in 98% of cases. In a per-patient analysis for polyps ≥6 mm, CCE detected 24 patients (24.5%) and CTC 12 patients (12.2%). The relative sensitivity of CCE compared to CTC was 2.0 (95% CI 1.34 to 2.98), indicating a significant increase in sensitivity for lesions ≥6 mm. Of larger polyps (≥10 mm), these values were 5.1% for CCE and 3.1% for CTC (relative sensitivity: 1.67 (95% CI 0.69 to 4.00)). Positive predictive values for polyps ≥6 mm and ≥10 mm were 96% and 85.7%, and 83.3% and 100% for CCE and CTC, respectively. No missed cancer occurred at clinical follow-up of a mean of 20 months. Conclusions CCE and CTC were of comparable efficacy in completing colon evaluation after incomplete colonoscopy; the overall diagnostic yield of colon capsule was superior to CTC. Trial registration number NCT01525940.