Øyvind Holme

Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline

BACKGROUND AND AIM This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the choice amongst regimens available for cleansing the colon in preparation for colonoscopy. METHODS This Guideline is based on a targeted literature search to evaluate the evidence supporting the use of bowel preparation for colonoscopy. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendation and the quality of evidence. RESULTS The main recommendations are as follows. (1) The ESGE recommends a low-fiber diet on the day preceding colonoscopy (weak recommendation, moderate quality evidence). (2) The ESGE recommends a split regimen of 4 L of polyethylene glycol (PEG) solution (or a same-day regimen in the case of afternoon colonoscopy) for routine bowel preparation. A split regimen (or same-day regimen in the case of afternoon colonoscopy) of 2 L PEG plus ascorbate or of sodium picosulphate plus magnesium citrate may be valid alternatives, in particular for elective outpatient colonoscopy (strong recommendation, high quality evidence). In patients with renal failure, PEG is the only recommended bowel preparation. The delay between the last dose of bowel preparation and colonoscopy should be minimized and no longer than 4 hours (strong recommendation, moderate quality evidence). (3) The ESGE advises against the routine use of sodium phosphate for bowel preparation because of safety concerns (strong recommendation, low quality evidence).

Effect of Flexible Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality A Randomized Clinical Trial

IMPORTANCE Colorectal cancer is a major health burden. Screening is recommended in many countries. OBJECTIVE To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 100,210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry. INTERVENTIONS Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1:1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp ≥10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention. MAIN OUTCOMES AND MEASURES Colorectal cancer incidence and mortality. RESULTS A total of 98,792 participants were included in the intention-to-screen analyses, of whom 78,220 comprised the control group and 20,572 comprised the screening group (10,283 randomized to receive a flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100,000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100,000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50- to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55- to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups. CONCLUSIONS AND RELEVANCE In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00119912.

Long-Term Colorectal-Cancer Mortality after Adenoma Removal

BACKGROUND Although colonoscopic surveillance of patients after removal of adenomas is widely promoted, little is known about colorectal-cancer mortality among these patients. METHODS Using the linkage of the Cancer Registry and the Cause of Death Registry of Norway, we estimated colorectal-cancer mortality among patients who had undergone removal of colorectal adenomas during the period from 1993 through 2007. Patients were followed through 2011. We calculated standardized incidence-based mortality ratios (SMRs) using rates for the Norwegian population at large for comparison. Norwegian guidelines recommended colonoscopy after 10 years for patients with high-risk adenomas (adenomas with high-grade dysplasia, a villous component, or a size ≥10 mm) and after 5 years for patients with three or more adenomas; no surveillance was recommended for patients with low-risk adenomas. Polyp size and exact number were not available in the registry. We defined high-risk adenomas as multiple adenomas and adenomas with a villous component or high-grade dysplasia. RESULTS We identified 40,826 patients who had had colorectal adenomas removed. During a median follow-up of 7.7 years (maximum, 19.0), 1273 patients were given a diagnosis of colorectal cancer. A total of 398 deaths from colorectal cancer were expected and 383 were observed, for an SMR of 0.96 (95% confidence interval [CI], 0.87 to 1.06) among patients who had had adenomas removed. Colorectal-cancer mortality was increased among patients with high-risk adenomas (expected deaths, 209; observed deaths, 242; SMR, 1.16; 95% CI, 1.02 to 1.31), but it was reduced among patients with low-risk adenomas (expected deaths, 189; observed deaths, 141; SMR, 0.75; 95% CI, 0.63 to 0.88). CONCLUSIONS After a median of 7.7 years of follow-up, colorectal-cancer mortality was lower among patients who had had low-risk adenomas removed and moderately higher among those who had had high-risk adenomas removed, as compared with the general population. (Funded by the Norwegian Cancer Society and others.).

Evaluation of disease activity in IBD at the time of diagnosis by the use of clinical, biochemical, and fecal markers

Abstract Objective. The present population based adult cohort was part of a new prospective study of patients with inflammatory bowel disease (IBD) in South-Eastern Norway, the Inflammatory Bowel South-Eastern Norway II study, investigating disease characteristics in an attempt to improve our knowledge regarding factors related to early clinical phenotype and disease activity. Material and methods. Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days were examined at the local hospital. Colonoscopy with biopsies was performed and blood and stool samples were taken. Results. In ulcerative colitis (UC) patients, the median Simple Clinical Colitis Activity Index (SCCAI) was 4 (range 0–10) in mild and 6 (range 0–14) in patients with moderate or severe endoscopic activity of inflammation (p = 0.002). The calprotectin concentration in feces was significantly related to the SCCAI (p = 0.034) and the Mayo endoscopic subscore (p = 0.031). There was a significant association between the C-reactive protein (CRP) value, leucocytes and thrombocytes and the SCCAI, but only leucocytes were significantly associated with the Mayo endoscopic subscore. In Crohns disease (CD) patients, there was no statistical significant association between the Harvey-Bradshaw Index (HBI) and the endoscopic grade of mucosal inflammation (p = 0.8). The calprotectin concentration in feces was significantly related to the endoscopic activity score (p = 0.004), but not to the HBI (p = 0.5). HBI was significantly related to the CRP value (p = 0.047) and thrombocytes (p = 0.03). Conclusions . In UC, both biochemical and fecal markers are related to disease activity and extent of disease, whereas in CD, the fecal calprotectin concentration is a reliable marker of mucosal affection, but not for systemic disease activity.

Long-term risk of colorectal cancer in individuals with serrated polyps

Objective Although serrated polyps may be precursors of colorectal cancer (CRC), prospective data on the long-term CRC risk in individuals with serrated polyps are lacking. Design In a population-based randomised trial, 12 955 individuals aged 50–64 years were screened with flexible sigmoidoscopy, while 78 220 individuals comprised the control arm. We used Cox models to estimate HRs with 95% CIs for CRC among individuals with ≥1 large serrated polyp (≥10 mm in diameter), compared with individuals with adenomas at screening, and to population controls, and multivariate logistic regression to assess polyp risk factors for CRC. Results A total of 103 individuals had large serrated polyps, of which 81 were included in the analyses. Non-advanced adenomas were found in 1488 individuals, advanced adenomas in 701. Median follow-up was 10.9 years. Compared with the control arm, the HR for CRC was 2.5 (95% CI 0.8 to 7.8) in individuals with large serrated polyps, 2.0 (95% CI 1.3 to 2.9) in individuals with advanced adenomas and 0.6 (95% CI 0.4 to 1.1) in individuals with non-advanced adenomas. A large serrated polyp was an independent risk factor for CRC, adjusted for histology, size and multiplicity of concomitant adenomas (OR 3.3; 95% CI 1.3 to 8.6). Twenty-three large serrated polyps found at screening were left in situ for a median of 11.0 years. None developed into a malignant tumour. Conclusions Individuals with large serrated polyps have an increased risk of CRC, comparable with individuals with advanced adenomas. However, this risk may not be related to malignant growth of the serrated polyp. Trial registration number The Norwegian Colorectal Cancer Screening trial is registered at clinicaltrials.gov (NCT00119912).

Current status of screening for colorectal cancer

BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. A well-defined precursor lesion (adenoma) and a long preclinical course make CRC a candidate for screening. This paper reviews the current evidence for the most important tests that are widely used or under development for population-based screening. MATERIAL AND METHODS In this narrative review, we scrutinized all papers we have been aware of, and carried out searches in PubMed and Cochrane library for relevant literature. RESULTS Two screening methods have been shown to reduce CRC mortality in randomised trials: repetitive faecal occult blood testing (FOBT) reduces CRC mortality by 16%; once-only flexible sigmoidoscopy (FS) by 28%. FS screening also reduces CRC incidence (by 18%), FOBT does not. Colonoscopy screening has a potentially larger effect on CRC incidence and mortality, but randomised trials are lacking. New screening methods are on the horizon but need to be tested in large clinical trials before implementation in population screening. CONCLUSIONS FS screening reduces CRC incidence and CRC mortality by removal of adenomas; FOBT reduces CRC mortality by early detection of cancer. Several other tests are available, but none has been evaluated in randomised trials. Screening strategies differ considerably across countries.

Rationale and design of the European Polyp Surveillance (EPoS) trials.

BACKGROUND Current guidelines recommend surveillance colonoscopies after polyp removal depending on the number and characteristics of polyps, but there is a lack of evidence supporting the recommendations. This report outlines the rationale and design of two randomized trials and one observational study investigating evidence-based surveillance strategies following polyp removal. Study design and endpoints: The EPoS studies started to recruit patients in April 2015. EPoS study I randomizes 13 746 patients with low-risk adenomas (1 - 2 tubular adenomas size < 10 mm, low-grade dysplasia) to surveillance after 5 and 10 years, or 10 years only. EPoS study II randomizes 13 704 patients with high-risk adenomas (3 - 10 adenomas or adenoma ≥ 10 mm in diameter, or adenoma with high-grade dysplasia, or > 25 % villous features) to surveillance after 3, 5, and 10 years, or 5 and 10 years only. EPoS study III offers surveillance after 5 and 10 years to patients with serrated polyps ≥ 10 mm in diameter at any location, or serrated polyps ≥ 5 mm in diameter proximal to the splenic flexure. All polyps are removed before patients enter the trials. The primary end point is colorectal cancer incidence after 10 years. We assume a colorectal cancer risk of 1 % for patients in EPoS I, and 2 % for patients in EPoS II. Using a noninferiority hypothesis with an equivalence interval of 0.5 % for EPoS I and 0.7 % for EPoS II, the trials are 90 % powered to uncover differences larger than the equivalence intervals. For EPoS III, no power analyses have been performed. CONCLUSIONS The present trials aim to develop evidence-based strategies for polyp surveillance, thereby maximizing effectiveness and minimizing resources. TRIAL REGISTRATION ClinicalTrials.gov (NCT02319928).

Effectiveness of flexible sigmoidoscopy screening in men and women and different age groups: pooled analysis of randomised trials

Objective To compare the effectiveness of flexible sigmoidoscopy in screening for colorectal cancer by patient sex and age. Design Pooled analysis of randomised trials (the US Prostate, Lung, Colorectal and Ovarian cancer screening trial (PLCO), the Italian Screening for Colon and Rectum trial (SCORE), and the Norwegian Colorectal Cancer Prevention trial (NORCCAP)). Data sources Aggregated data were pooled from each randomised trial on incidence of colorectal cancer and mortality stratified by sex, age at screening, and colon subsite (distal v proximal). Eligibility criteria for selecting studies Invited individuals aged 55-74 (PLCO), 55-64 (SCORE), and 50-64 (NORCCAP). Individuals were randomised to receive flexible sigmoidoscopy screening once only (SCORE and NORCCAP) or twice (PLCO), or receive usual care (no intervention). Results 287 928 individuals were included in the pooled analysis; 115 139 randomised to screening and 172 789 to usual care. Compliance rates were 58%, 63%, and 87% in SCORE, NORCCAP, and PLCO, respectively. Median follow-up was 10.5 to 12.1 years. Screening reduced the incidence of colorectal cancer in men (relative risk 0.76; 95% confidence interval 0.70 to 0.83) and women (0.83; 0.75 to 0.92). No difference in the effect of screening was seen between men younger than 60 and those older than 60. Screening reduced the incidence of colorectal cancer in women younger than 60 (relative risk 0.71; 95% confidence interval 0.59 to 0.84), but not significantly in those aged 60 or older (0.90; 0.80 to 1.02). Colorectal cancer mortality was significantly reduced in both younger and older men, and in women younger than 60. Screening reduced colorectal cancer incidence to a similar extent in the distal colon in men and women, but there was no effect of screening in the proximal colon in older women with a significant interaction between sex and age group (P=0.04). Conclusion Flexible sigmoidoscopy is an effective tool for colorectal cancer screening in men and younger women. The benefit is smaller and not statistically significant for women aged over 60; alternative screening methods that more effectively detect proximal tumours should be considered for these women.

Water exchange versus carbon dioxide insufflation in unsedated colonoscopy: A multicenter randomized controlled trial

BACKGROUND AND STUDY AIMS Compared with air insufflation, water exchange and carbon dioxide (CO2) insufflation have been shown to reduce colonoscopy discomfort; however, head-to-head studies of the two methods are lacking. We aimed to compare water exchange and CO2 insufflation directly with regard to pain during primary unsedated colonoscopy. METHODS Patients willing to undergo unsedated colonoscopy at three centers in Norway and Poland were randomized 1:1 to water exchange or CO2 insufflation during colonoscope insertion. Patients were blinded to group allocation. The primary end point was the proportion of patients reporting moderate or severe procedural pain on a 4-point verbal rating scale (VRS-4) at discharge. Secondary outcomes included the proportion of patients reporting no pain on the VRS-4. RESULTS A total of 473 patients were randomized. A discharge pain questionnaire was completed by 226 of 234 patients (97 %) in the water exchange group versus 226 of 239 patients (95 %) in the CO2 group (P = 0.37). Moderate or severe pain was reported by 47 of 226 patients (21 %) in the water exchange group versus 60 of 226 patients (27 %) in the CO2 group (P = 0.15). No pain was reported by 100 of 226 patients (44 %) and 69 of 226 patients (31 %) in the water exchange and CO2 groups, respectively (P = 0.003). On-demand sedation was used in 15 patients (6 %) in each group (P = 0.95). CONCLUSIONS There was no significant reduction in moderate or severe pain in a comparison of water exchange with CO2 insufflation. The secondary outcome of no pain was significantly more frequent in the water exchange group. Clinical trials registry number: NCT01633333.

Long-term lifestyle changes after colorectal cancer screening: randomised controlled trial

Objective There is uncertainty whether cancer screening affects participant incentives for favourable lifestyle. The present study investigates long-term effects of colorectal cancer (CRC) screening on lifestyle changes. Design In 1999–2001, men and women drawn from the population registry were randomised to screening for CRC by flexible sigmoidoscopy (‘invited-to-screening’ arm) or to no-screening (control arm) in the Norwegian Colorectal Cancer Prevention trial. A subgroup of 3043 individuals in the ‘invited-to-screening’ and 2819 in the control arm, aged 50–55 years, randomised during 2001 had their lifestyle assessed by a questionnaire at inclusion and after 11 years (42% of cohort). The outcome was 11-year changes in lifestyle factors (body weight, smoking status, physical exercise, selected dietary habits) and in total lifestyle score (0–4 points, translating to the number of lifestyle recommendations adhered to). We compared outcomes in the two randomisation arms and attendees with positive versus negative findings. Results Total lifestyle scores improved in both arms. The improvement was smaller in the ‘invited-to-screening’ arm (score 1.43 at inclusion; 1.58 after 11 years) compared with the control arm (score 1.49 at inclusion; 1.67 after 11 years); adjusted difference −0.05 (95% CI −0.09 to −0.01; p=0.03). The change in the score was less favourable in screening attendees with a positive compared with negative screening result; adjusted difference −0.16 (95% CI −0.25 to −0.08; p<0.001). Conclusions The present study suggests that possible unfavourable lifestyle changes after CRC screening are modest. Lifestyle counselling may be considered as part of cancer screening programmes. Trial registration number NCT00119912.