Wendy Atkin

Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial.

BACKGROUND Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 years of age can substantially reduce colorectal cancer incidence and mortality. METHODS This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. FINDINGS 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11.2 years (IQR 10.7-11.9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer [538 vs 189]). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0.77, 95% CI 0.70-0.84) and mortality by 31% (0.69, 0.59-0.82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0.67, 0.60-0.76) and mortality by 43% (0.57, 0.45-0.72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0.50, 0.42-0.59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145-277) and 489 (343-852), respectively. INTERPRETATION Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. FUNDING Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed.

The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases.

The grade of a tumour is gauged on the subjective assessment of a number of histopathological parameters. The problems associated with this exercise were viewed from a historical perspective and survival analysis of 447 patients receiving surgery for rectal adenocarcinoma was undertaken. Only deaths from rectal adenocarcinoma were included as events in the survival analysis. Seven grade‐related parameters were scored by one observer. A grading system was constructed using the Cox regression model. The variables in the best‐fitting parsimonious model comprised lymphocytic infiltration, tubule configuration and pattern of growth. Scores were derived from the model and a four grade system was created in which the groups were of similar size. Good reproducibility of the selected histopathological parameters was demonstrated. Grade‐related parameters were then allowed to compete with stage‐related parameters in an overall model of pathological prognostic categories. The parameters selected in the best model were number of affected lymph nodes, the presence of lymphocytic infiltration and extent of spread through bowel wall. A set of five prognostic categories was developed from this model.

Prevention of colorectal cancer by once-only sigmoidoscopy

There is no national screening programme for colorectal cancer in the UK despite the fact that the annual death toll from this disease exceeds that of breast and cervical cancer. Faecal occult blood testing (FOBT) is under evaluation for screening, but screening by sigmoidoscopy is not considered viable. This situation contrasts with the USA where both annual FOBT and screening by flexible sigmoidoscopy every 3 to 5 years are recommended from 50 years old. We seek to demonstrate that most of the benefit from the US screening policy would accrue from a single flexible sigmoidoscopy examination at age 55 to 60 years with appropriate colonoscopic surveillance for the 3% to 5% found to have high-risk adenomas (> or = 1 cm or villous histology). If applied nationally, this screening regimen could prevent about 5500 colorectal cancer cases and 3500 deaths in the UK each year, thus saving 40,000 years of life. We estimate that there would be little net cost to the National Health Service because savings obtained from treating fewer patients would largely offset the cost of screening. We recommend that a randomised trial to evaluate screening by single flexible sigmoidoscopy should start without delay. Such a trial would involve about 120,000 participants, and 15 years of follow-up would be required to obtain a clear answer on mortality, although information on incidence reduction would be available sooner.

Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: A randomized controlled trial

BACKGROUND Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy. METHODS Consecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye). RESULTS Two hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:48-24:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min) in the control group (p < 0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (<5 mm) were detected proximal to the sigmoid colon (p = 0.026) and more patients were identified with 3 or more adenomas (p = 0.002). More non-neoplastic polyps were detected throughout the colon in the dye-spray group (p = 0.003). There were no complications. CONCLUSIONS Dye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.

Surveillance guidelines after removal of colorectal adenomatous polyps

Most colon cancers are assumed to have a premalignant adenomatous polyp phase, therefore colonoscopic detection and polypectomy provides the opportunity for cancer prevention. Some patients who have undergone colonoscopy and have had adenomas removed are at increased risk of developing colorectal cancer (CRC) in the future, and therefore might benefit from colonoscopic surveillance. However, it is important to appreciate that colonoscopy is an invasive and costly procedure with some associated morbidity. It is also an under-resourced procedure in the UK, with a serious lack of fully trained endoscopists. Around one third of the population will develop an adenoma by age 60. Most adenomas are asymptomatic and remain undiagnosed. If colorectal screening is introduced this situation will change dramatically. There are few data on the benefits of colonoscopic surveillance in preventing colorectal cancer after a baseline clearing colonoscopy. It is therefore important that this practice is applied judiciously, balancing the risks and benefits in each individual case. Using published evidence, this guideline recommends appropriate surveillance after adenoma removal. The decision to perform each follow up colonoscopy should also depend on the patient’s wishes, the presence of comorbidity, the patient’s age, and the presence of other risk factors. ### Risk of colorectal cancer and adenomas with advanced pathology (≥1 cm or severely dysplastic) (see fig 1) Figure 1 Surveillance after adenoma removal. Risk can be stratified according to findings at baseline and refined at each subsequent surveillance examination. (Recommendation Grade B) #### Low risk Patients with only 1–2, small (<1 cm) adenomas. Recommendation: no follow up or five yearly until one negative examination . #### Intermediate risk Patients with 3–4 small adenomas or at least one >1 cm Recommendation: three yearly until two consecutive negative examinations . #### High risk If either of the following are detected at any single examination (at baseline or follow up): ≥5 adenomas or ≥3 adenomas at least one of which is ≥1 cm. Recommendation: An extra examination should be undertaken at 12 months before returning …

Uptake, yield of neoplasia, and adverse effects of flexible sigmoidoscopy screening

Background—A multicentre randomised controlled trial to evaluate screening by “once only” flexible sigmoidoscopy (FS) for prevention of bowel cancer is in progress. Aims—To pilot the trial protocol examining rates of attendance, yield of neoplasia, and adverse effects. Subjects—A total of 3540 subjects aged 55–64 years in Welwyn Garden City (WGC) and 19 706 in Leicester (LE). Methods—Subjects responding positively to an “interest in screening” questionnaire were randomised to invitation for screening or control arms. Small polyps were removed during screening. Colonoscopy was undertaken for high risk polyps (more than two adenomas, size at least 1 cm, villous histology, severe dysplasia, or malignancy). The remainder were discharged. Results—In WGC and LE respectively, 59% and 61% indicated an interest in screening, of which 74% and 75% attended. Adenomas were detected in 10% and 9%, respectively, and cancers in 7 per 1000 (in both centres), 55% at Dukes’s stage A. The colonoscopy referral rate was 6% in both centres. Mild, short lived bleeding occurred in 3%. One person died following surgery. Conclusions—Compliance rates, yield of adenomas, and referral rate for colonoscopy were as expected, but cancer detection rates were higher. Adverse effects following sigmoidoscopy or colonoscopy were mild and transient, but there was one postoperative death. A randomised trial is necessary to evaluate fully the risks and benefits of this intervention.

CT colonography: effect of experience and training on reader performance

The purpose of this paper was to investigate the effect of radiologist experience and increasing exposure to CT colonography on reader performance. Three radiologists of differing general experience (consultant, research fellow, trainee) independently analysed 100 CT colonographic datasets. Readers had no prior experience of CT colonography and received feedback and training after the first 50 cases from an independent experienced radiologist. Diagnostic performance and reporting times were compared for the first and second 50 datasets and compared with the results of a radiologist experienced in CT colonography. Before training only the consultant reader achieved statistical equivalence with the reference standard for detection of larger polyps. After training, detection rates ranged between 25 and 58% for larger polyps. Only the trainee significantly improved after training (P=0.007), with performance of other readers unchanged or even worse. Reporting times following training were reduced significantly for the consultant and fellow (P<0.001 and P=0.03, respectively), but increased for the trainee (P<0.001). In comparison to the consultant reader, the odds of detection of larger polyps was 0.36 (CI 0.16, 0.82) for the fellow and 0.36 (CI 0.14, 0.91) for the trainee. There is considerable variation in the ability to report CT colonography. Prior experience in gastrointestinal radiology is a distinct advantage. Competence cannot be assumed even after directed training via a database of 50 cases.

An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome

The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.

Identifying and managing patients at low risk of bowel cancer in general practice

All NHS patients who are suspected to have bowel cancer by their general practitioner should now be seen by a specialist within two weeks. The government introduced this policy in July 2000 in response to concerns that some patients had to wait too long for an outpatient appointment. However, this new policy could distort referral patterns either by increasing the referral of patients with transient symptoms or by increasing the delay for cancer patients presenting with non-typical symptoms. Unless general practitioners act as efficient gatekeepers, specialist services could become overloaded. We explain the basis for the governments guidelines for referral and discuss how to manage patients at low risk of cancer. The Department of Health has developed guidelines to help general practitioners decide which patients require fast track referral and which can safely be treated and monitored in general practice (table).1 2 View this table: Department of Health criteria for high and low risk of bowel cancer The guidelines were based on data from relevant studies, which were assigned levels of evidence by established methods.3 The grading system for the higher risk symptoms was similar to that used to grade recommendations for hypertension, thrombosis, and diabetes.4–6 The high prevalence of rectal bleeding,7 8 changes in bowel habit,9 and abdominal pain10 in the community relative to the incidence of bowel cancer means that most patients with these symptoms are at very low risk of cancer. Many of these symptoms are transient or cause no alarm, and over 80% of patients do not seek medical advice.7–11 Of those who do, only 40-50% are referred to hospital.7 8 The risk of cancer in patients with rectal bleeding, for example, varies from 1:700 in the community8 to 1:30 in primary care,12 and 1:16 …

Options for screening for colorectal cancer.

Unlike other types of cancer, there are several options for screening for colorectal cancer (CRC). The most extensively examined method, faecal occult blood testing (FOBT), has been shown, in three large randomized trials, to reduce mortality from CRC by up to 20% if offered biennally and possibly more if offered every year. Recently published data from the US trial suggest that CRC incidence rates are also reduced by up to 20%, but only after 18 years. In this study, the number of positive slides was associated with the positive predictive value both for CRC and adenomas larger than 1 cm, suggesting that the reduction in CRC incidence was caused by the identification and removal of large adenomas. In this respect, this study supports the concept that removing adenomas prevents CRC. More efficient methods of detecting adenomas include the use of colonoscopy or flexible sigmoidoscopy (FS). Considerable evidence exists from case-control and uncontrolled cohort studies to suggest that endoscopic screening by sigmoidoscopy reduces incidence of distal colorectal cancer. However, in the absence of evidence from a randomized trial, several countries have been reluctant to introduce endoscopic screening. Three trials are currently in progress (in the UK, Italy and the US) to address this issue. Two of these trials are examining the hypothesis that a single FS screen at around age 55-64 might be a cost-effective and acceptable method for reducing CRC incidence rates. Recruitment and screening are now complete in both studies and the first analysis of results on incidence rates is expected in 2004. Colonoscopy screening at 10-year intervals has recently been endorsed in the US on the basis that the reductions in incidence observed with distal CRC screening can be extrapolated to the proximal colon. However, data are lacking and a pilot study for a trial of the acceptability and efficacy of colonoscopy screening is in progress in the US. It has also been suggested that FOBT testing should be used to detect proximal CRC missed by sigmoidoscopy screening, but the small amount of published data suggest that supplementing FS with FOBT offers very little advantage over FS alone. Other forms of CRC screening are under investigation and represent exciting options for the future. Extraction of DNA from stool is now feasible and a number of research groups have shown high sensitivity for CRC using a panel of DNA markers including mutations in k-ras, APC, p53 and BAT26. Data so far indicate that, with the exception of k-ras, these markers are highly specific and therefore represent a significant improvement over FOBT. Whether these tests will replace or supplement existing methods of screening has yet to be determined. It has been suggested that BAT26, which is a marker of microsatellite instability, a feature of proximal sporadic CRC, might be a useful adjunct to sigmoidoscopy screening. Others have suggested that a test for occult blood should be included with the DNA markers to further increase sensitivity. It is not yet known how sensitive these markers are for adenomas--it is only by detecting adenomas that CRC incidence rates can be reduced. A final exciting new option for screening is virtual colonoscopy (VC), which by screening out people without neoplasia allows colonoscopy to be reserved for patients requiring a therapeutic intervention. The sensitivity of VC for large adenomas and CRC appears to be high, although results vary by centre and there is a steep learning curve. Sensitivity for small adenomas is low, but perhaps it is less essential to find such lesions. Some groups have suggested that virtual colonoscopy might be a useful option for investigating patients who test positive with stool-based screening tests. Whichever CRC screening method is finally chosen (and there is no reason why several methods should not ultimately be available), high quality endoscopy resources will always be required to investigate and treat neoplastic lesions detected.