Increased uptake and improved outcomes of bowel cancer screening with a faecal immunochemical test: results from a pilot study within the national screening programme in England.

BACKGROUND: The National Health Service Bowel Cancer Screening Programme (BCSP) in England uses a guaiac-based faecal occult blood test (gFOBt). A quantitative faecal immunochemical test (FIT) for haemoglobin (Hb) has many advantages, including being specific for human blood, detecting Hb at a much lower concentration with a single faecal sample and improved uptake. METHODS: In 2014, a large comparative pilot study was performed within BCSP to establish the acceptability and diagnostic performance of FIT. Over a 6-month period, 40 930 (1 in 28) subjects were sent a FIT (OC-SENSOR) instead of a gFOBt. A bespoke FIT package was used to mail FIT sampling devices to and from FIT subjects. All participants positive with either gFOBt or FIT (cut-off 20 µg Hb/g faeces) were referred for follow-up. Subgroup analysis included cut-off concentrations, age, sex, screening history and deprivation quintile. RESULTS: While overall uptake increased by over 7 percentage points with FIT (66.4% vs 59.3%, OR 1.35, 95% CI 1.33 to 1.38), uptake by previous non-responders almost doubled (FIT 23.9% vs gFOBt 12.5%, OR 2.20, 95% CI 2.10 to 2.29). The increase in overall uptake was significantly higher in men than women and was observed across all deprivation quintiles. With the conventional 20 µg/g cut-off, FIT positivity was 7.8% and ranged from 5.7% in 59-64-year-old women to 11.1% in 70-75-year-old men. Cancer detection increased twofold and that for advanced adenomas nearly fivefold. Detection rates remained higher with FIT for advanced adenomas, even at 180 µg Hb/g. CONCLUSIONS: Markedly improved participation rates were achieved in a mature gFOBt-based national screening programme and disparities between men and women were reduced. High positivity rates, particularly in men and previous non-respondents, challenge the available colonoscopy resource, but improvements in neoplasia detection are still achievable within this limited resource.

A national cluster-randomised controlled trial to examine the effect of enhanced reminders on the socioeconomic gradient in uptake in bowel cancer screening.

BACKGROUND: The NHS Bowel Cancer Screening Programme in England offers biennial guaiac faecal occult blood testing (gFOBt). There is a socioeconomic gradient in participation and socioeconomically disadvantaged groups have worse colorectal cancer survival than more advantaged groups. We compared the effectiveness and cost of an enhanced reminder letter with the usual reminder letter on overall uptake of gFOBt and the socioeconomic gradient in uptake. METHODS: We enhanced the usual reminder by including a heading 'A reminder to you' and a short paragraph restating the offer of screening in simple language. We undertook a cluster-randomised trial of all 168 480 individuals who were due to receive a reminder over 20 days in 2013. Randomisation was based on the day of invitation. Blinding of individuals was not possible, but the possibility of bias was minimal owing to the lack of direct contact with participants. The enhanced reminder was sent to 78 067 individuals and 90 413 received the usual reminder. The primary outcome was the proportion of people adequately screened and its variation by quintile of Index of Multiple Deprivation. Data were analysed by logistic regression with conservative variance estimates to take account of cluster randomisation. RESULTS: There was a small but statistically significant (P=0.001) increase in participation with the enhanced reminder (25.8% vs 25.1%). There was significant (P=0.005) heterogeneity of the effect by socioeconomic status with an 11% increase in the odds of participation in the most deprived quintile (from 13.3 to 14.1%) and no increase in the least deprived. We estimated that implementing the enhanced reminder nationally could result in up to 80 more people with high or intermediate risk colorectal adenomas and up to 30 more cancers detected each year if it were implemented nationally. The intervention incurred a small one-off cost of £78 000 to modify the reminder letter. CONCLUSIONS: The enhanced reminder increases overall uptake and reduces the socioeconomic gradient in bowel cancer screening participation at little additional cost.

Recommendations for a step-wise comparative approach to the evaluation of new screening tests for colorectal cancer.

BACKGROUND: New screening tests for colorectal cancer continue to emerge, but the evidence needed to justify their adoption in screening programs remains uncertain. METHODS: A review of the literature and a consensus approach by experts was undertaken to provide practical guidance on how to compare new screening tests with proven screening tests. RESULTS: Findings and recommendations from the review included the following: Adoption of a new screening test requires evidence of effectiveness relative to a proven comparator test. Clinical accuracy supported by programmatic population evaluation in the screening context on an intention-to-screen basis, including acceptability, is essential. Cancer-specific mortality is not essential as an endpoint provided that the mortality benefit of the comparator has been demonstrated and that the biologic basis of detection is similar. Effectiveness of the guaiac-based fecal occult blood test provides the minimum standard to be achieved by a new test. A 4-phase evaluation is recommended. An initial retrospective evaluation in cancer cases and controls (Phase 1) is followed by a prospective evaluation of performance across the continuum of neoplastic lesions (Phase 2). Phase 3 follows the demonstration of adequate accuracy in these 2 prescreening phases and addresses programmatic outcomes at 1 screening round on an intention-to-screen basis. Phase 4 involves more comprehensive evaluation of ongoing screening over multiple rounds. Key information is provided from the following parameters: the test positivity rate in a screening population, the true-positive and false-positive rates, and the number needed to colonoscope to detect a target lesion. CONCLUSIONS: New screening tests can be evaluated efficiently by this stepwise comparative approach.

Factors associated with completion of bowel cancer screening and the potential effects of simplifying the screening test algorithm.

BACKGROUND: The primary colorectal cancer screening test in England is a guaiac faecal occult blood test (gFOBt). The NHS Bowel Cancer Screening Programme (BCSP) interprets tests on six samples on up to three test kits to determine a definitive positive or negative result. However, the test algorithm fails to achieve a definitive result for a significant number of participants because they do not comply with the programme requirements. This study identifies factors associated with failed compliance and modifications to the screening algorithm that will improve the clinical effectiveness of the screening programme. METHODS: The BCSP Southern Hub data for screening episodes started in 2006-2012 were analysed for participants aged 60-69 years. The variables included age, sex, level of deprivation, gFOBt results and clinical outcome. RESULTS: The data set included 1,409,335 screening episodes; 95.08% of participants had a definitively normal result on kit 1 (no positive spots). Among participants asked to complete a second or third gFOBt, 5.10% and 4.65%, respectively, failed to return a valid kit. Among participants referred for follow up, 13.80% did not comply. Older age was associated with compliance at repeat testing, but non-compliance at follow up. Increasing levels of deprivation were associated with non-compliance at repeat testing and follow up. Modelling a reduction in the threshold for immediate referral led to a small increase in completion of the screening pathway. CONCLUSIONS: Reducing the number of positive spots required on the first gFOBt kit for referral for follow-up and targeted measures to improve compliance with follow-up may improve completion of the screening pathway.

Tests detecting biomarkers for screening of colorectal cancer: What is on the horizon?

AIM: To identify new and emerging screening tests for colorectal cancer (CRC) that involves detection of various biomarkers like blood, DNA and RNA in samples of faeces, tissue or blood. Current practice: Screening for CRC can be done by bowel visualisation techniques and tests that measure biomarkers. The Bowel Cancer Screening Programme (BCSP) in England uses a guaiac faecal occult blood test. METHODS: The strategy was to search available literature, identify developers and contact them for relevant information. Advice from experts was sought on potential utility and likely impact of identified technologies on the BCSP. RESULTS: Ninety-three companies and five research groups were contacted. Sixty-nine relevant tests were identified. Detailed information was available for 48 tests, of these 73% were CE marked and the remainder were considered as emerging. Forty-nine tests use immunochemical methods to detect occult blood in faeces. Eight, four and two tests detect biomarkers in a sample of blood, or exfoliated cells either shed in faeces or collected from rectal mucosa respectively. Six tests were grouped as 'other tests'. Most of the identified tests are performed manually and give qualitative detection of biomarkers. CONCLUSION: Variation in test performance and characteristics was observed amongst the 69 identified tests. Automated, quantitative FIT with a variable cut off are the preferred approach in the BSCP. However the units used to report FITs results do not enable comparison across products. Tests detecting biomarkers other than occult blood are more specific to neoplasms but have limited sensitivity due to the heterogeneity of cancer. Research is ongoing to identify an optimal panel of biomarkers, simplifying and automating the test, and reducing the cost.

Faecal occult blood testing for colorectal cancer screening: the past or the future.

Screening for colorectal cancer (CRC) reduces CRC mortality; many countries have implemented population-based CRC screening programmes and many more are poised to do so. Whilst several different CRC screening modalities are available, choice will be influenced by cost, available resources (e.g. high-quality colonoscopy) and acceptability of the test by the invited population. For CRC screening, no screening test has so far surpassed the practicality, affordability and effectiveness of tests for the presence of blood in faeces (faecal occult blood tests, FOBt). The results of several large FOBt-based randomised controlled trials provide the best clinical evidence to support their use in population-based CRC screening. This review considers the current options for CRC screening and the future for FOBt.

Colorectal cancer screening uptake over three biennial invitation rounds in the English bowel cancer screening programme.

OBJECTIVE: To examine patterns of colorectal cancer (CRC) screening uptake over three biennial invitation rounds in the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) in England. METHODS: We analysed data from the BCSP's Southern Hub for individuals (n=62,099) aged 60-64 years at the time of first invitation to screening with a follow-up period that allowed for two further biennial invitations. Data on sex, age and a neighbourhood-level measure of socioeconomic deprivation were used in the analysis. Outcomes included uptake of guaiac-based faecal occult blood (gFOB) test screening, inadequate gFOB screening (≥1 test kit(s) returned but failed to complete further gFOB tests needed to reach a conclusive test result), test positivity, compliance with follow-up examinations (usually colonoscopy) and diagnostic outcomes. RESULTS: Overall gFOB uptake was 57.4% in the first, 60.9% in the second and 66.2% in third biennial invitation round. This resulted in 70.1% of the initial cohort having responded at least once, 60.7% at least twice and 44.4% three times. Participation in the first round was strongly predictive of participation in the second round ('Previous Responders': 86.6% vs. 'Previous Non-Responders': 23.1%). Participation in the third round was highest among 'Consistent Screeners' (94.5%), followed by 'Late Entrants' (78.0%), 'Dropouts' (59.8%) and 'Consistent Non-Responders' (14.6%). Socioeconomic inequalities in uptake were observed across the three rounds, but sex inequalities decreased over rounds. Inadequate gFOB screening was influenced by screening history and socioeconomic deprivation. Screening history was the only significant predictor of follow-up compliance. CONCLUSIONS: Screening history is associated with overall gFOB uptake, inadequate gFOB screening and follow-up compliance. Socioeconomic deprivation is also consistently associated with lower gFOB uptake and inadequate gFOB screening. Improving regular screening among identified 'at-risk' groups is important for the effectiveness of CRC screening programmes.

Advances in Fecal Occult Blood Tests: the FIT revolution.

UNLABELLED: There is a wide choice of fecal occult blood tests (FOBTs) for colorectal cancer screening. GOAL: To highlight the issues applicable when choosing a FOBT, in particular which FOBT is best suited to the range of screening scenarios. Four scenarios characterize the constraints and expectations of screening programs: (1) limited colonoscopy resource with a need to constrain test positivity rate; (2) a priority for maximum colorectal neoplasia detection with little need to constrain colonoscopy workload; (3) an "adequate" endoscopy resource that allows balancing the benefits of detection with the burden of service provision; and (4) a need to maximize participation in screening. Guaiac-based FOBTs (gFOBTs) have significant deficiencies, and fecal immunochemical tests (FITs) for hemoglobin have emerged as better tests. gFOBTs are not sensitive to small bleeds, specificity can be affected by diet or drugs, participant acceptance can be low, laboratory quality control opportunities are limited, and they have a fixed hemoglobin concentration cutoff determining positivity. FITs are analytically more specific, capable of quantitation and hence provide flexibility to adjust cutoff concentration for positivity and the balance between sensitivity and specificity. FITs are clinically more sensitive for cancers and advanced adenomas, and because they are easier to use, acceptance rates are high. CONCLUSIONS: FOBT must be chosen carefully to meet the needs of the applicable screening scenario. Quantitative FIT can be adjusted to suit Scenarios 1, 2 and 3, and for each, they are the test of choice. FITs are superior to gFOBT for Scenario 4 and gFOBT is only suitable for Scenario 1.

Tests and investigations for colorectal cancer screening.

Worldwide, colorectal (CRC) is the third most common form of cancer, after lung and breast cancer, and the fourth most common cause of cancer death, although in developed countries CRC incidence is higher and it accounts for an even higher proportion of cancer deaths. Successful treatment of early-stage CRC confers substantial survival advantage, and there is now overwhelming evidence that screening average-risk individuals for CRC reduces the incidence and disease-specific mortality. In spite of considerable research for new biomarkers for CRC, the detection of blood in faeces remains the most effective screening tool. The best evidence to date for population-based CRC screening comes from randomised-controlled trials that used a guaiac-based faecal occult blood test (gFOBt) as the first-line screening modality, whereby test-positive individuals are referred for follow-up investigations, usually colonoscopy. A major innovation in the last ten years or so has been the development of other more analytically sensitive and specific screening techniques for blood in faeces. The faecal immunochemical test for haemoglobin (FIT) confers substantial benefits over gFOBt in terms of analytical sensitivity, specificity and practicality and FIT are now recommended for CRC screening by the European guidelines for quality assurance in colorectal cancer screening and diagnosis. The challenge internationally is to develop high quality CRC screening programmes for which uptake is high. This is especially important for developing countries witnessing an increase in the incidence of CRC as populations adopt more westernised lifestyles. This review describes the tests available for CRC screening and how they are being used worldwide. The reader will gain an understanding of developments in CRC screening and issues that arise in choosing the most appropriate screening test (or tests) for organised population-based screening internationally and optimising the performance of the chosen test (or tests). Whilst a wide range of literature has been cited, this is not a systematic review. The authors provide FOBT CRC screening for a population of 14.6 million in the south of England and the senior author (SPH) was the lead author of the European guidelines for quality assurance in colorectal cancer screening and diagnosis and leads the World Endoscopy Organization Colorectal Cancer Committee's Expert Working Group on 'FIT for Screening'.

Patient attitudes towards faecal immunochemical testing for haemoglobin as an alternative to colonoscopic surveillance of groups at increased risk of colorectal cancer.

OBJECTIVES: To examine attitudes towards an annual faecal immunochemical test for haemoglobin (FIT) versus three-yearly colonoscopic surveillance of individuals at intermediate risk of colorectal cancer (CRC). SETTING: A London hospital. METHODS: Five semi-structured discussion groups were conducted with 28 adults (aged 60-74, 61% female) with different levels of CRC risk and experience of colonoscopy or colonoscopic surveillance. Information was presented sequentially using a step-by-step discussion guide. Results were analyzed using thematic analysis. RESULTS: When evaluating FIT in the context of a surveillance programme, all respondents readily made comparisons with related tests that they had been exposed to previously. Those with no experience of surveillance were enthusiastic about an annual FIT to replace three-yearly colonoscopy, because they felt that the higher testing frequency could improve detection of advanced lesions. Those with experience of colonoscopic surveillance did not perceive FIT to be as accurate as colonoscopy, and therefore either preferred colonoscopy on its own or wanted an annual FIT in addition to three-yearly colonoscopy. CONCLUSIONS: FIT may be well-received as an additional method of surveillance for new patients at intermediate risk of CRC. More research is required to better understand potential barriers associated with FIT surveillance for patients with experience of colonoscopic surveillance.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 3. The Women's Health Initiative: unopposed estrogen.

BACKGROUND: Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed. OBJECTIVE: To evaluate the evidence for unopposed estrogen. METHODS: In a related article (Part 2) the authors apply generally accepted causal criteria to the findings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the findings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study. RESULTS: In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an 'intention-to-treat' analysis (95% CI 0.59-1.01) and 0.67 (95% CI 0.47-0.97) in an 'as treated' analysis; after 10.7 years the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the 'as treated' analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed. In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed. CONCLUSIONS: The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women's Health Initiative: estrogen plus progestogen.

BACKGROUND: Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy (HRT) with estrogen plus progestogen is now an established cause of breast cancer. For unopposed estrogen therapy the evidence in the three studies is conflicting: the CR and MWS have reported increased risks in estrogen users, while the WHI has not. The authors have previously reviewed the findings in the CR (Part 1). OBJECTIVE: To evaluate the evidence for causality in the WHI studies. METHODS: Using generally accepted causal criteria, in this paper (Part 2) the authors evaluate the findings in the WHI for estrogen plus progestogen; in a related paper (Part 3) the authors evaluate the findings for unopposed estrogen. An evaluation of the MWS (Part 4), and of trends in breast cancer incidence following publication of the WHI findings in 2002 (Part 5) will follow. RESULTS: For estrogen plus progestogen the findings did not adequately satisfy the criteria of bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION: HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Part 1. The Collaborative Reanalysis.

BACKGROUND Concern that hormone replacement therapy (HRT) may cause breast cancer has existed since the time it was introduced, and based on evidence in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that causality is now established. OBJECTIVE To evaluate the evidence for causality in the three studies. Methods Using generally accepted causal criteria, in this paper the authors begin with an evaluation of the CR. Analogous evaluations of the WHI and MWS will follow. RESULTS The findings in the CR did not adequately satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, dose/duration-response, internal consistency, external consistency or biological plausibility. CONCLUSION HRT may or may not increase the risk of breast cancer, but the CR did not establish that it does.

The epidemiology of Guillain-Barré syndrome worldwide. A systematic literature review.

BACKGROUND: This systematic literature review of the epidemiology of Guillain-Barré syndrome (GBS) identifies trends in incidence rates by age, study method and cause of disease. It is important to have a reliable estimate of incidence to determine and investigate any changes: no previous systematic reviews of GBS have been found. METHODS: After critical assessment of the reliability of the reported data, incidence rates were extracted from all relevant papers published between 1980 and 2008, identified through searches of Medline, Embase and Science Direct. RESULTS: Sixty-three papers were included in this review; these studies were prospective, retrospective reviews of medical records or retrospective database studies. Ten studies reported on the incidence in children (0-15 years old), and found the annual incidence to be between 0.34 and 1.34/100,000. Most studies investigated populations in Europe and North America and reported similar annual incidence rates, i.e. between 0.84 and 1.91/100,000. A decrease in incidence over the time between the 1980s and 1990s was found. Up to 70% of cases of GBS were caused by antecedent infections. CONCLUSIONS: Our best estimate of the overall incidence of GBS was between 1.1/100,000/year and 1.8/100,000/year. The incidence of GBS increased with age after 50 years from 1.7/100,000/year to 3.3/100,000/year.

The incidence of autoimmune thyroid disease: a systematic review of the literature.

OBJECTIVE: To undertake a systematic review of literature published between 1980 and 2008 on the incidence of autoimmune thyroid disease. DESIGN: All relevant papers found through searches of Medline, EMBASE and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. RESULTS: The reported incidence of autoimmune hypothyroidism varied between 2.2/100 000/year (males) and 498.4/100 000/year (females) and for autoimmune hyperthyroidism, incidence ranged from 0.70/100 000/year (Black males) to 99/100 000/year (Caucasian females). Higher incidence rates were found in women compared to men for all types of autoimmune thyroid disease. The majority of studies included in the review investigated Caucasian populations mainly from Scandinavia, Spain, the UK and the USA. It is possible that nonautoimmune cases were included in the incidence rates reported here, which would give an overestimation in the incidence rates of autoimmune disease presented. CONCLUSION: To our knowledge this is the most comprehensive systematic review of autoimmune thyroid disease conducted in the past two decades. Studies of incidence of autoimmune thyroid disease have only been conducted in a small number of mainly western countries. Our best estimates of the incidence of hypothyroidism is 350/100 000/year in women and 80/100 000/year in men; the incidence of hyperthyroidism is 80/100 000/year in women and 8/100 000/year in men.

Venous thromboembolism and cyproterone acetate in men with prostate cancer: a study using the General Practice Research Database.

OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE) associated with the use of cyproterone acetate (CPA) amongst men with prostate cancer. PATIENTS AND METHODS: Using data from the General Practice Research Database, cases of VTE were identified amongst men with prostate cancer. Four controls with no evidence of a VTE were selected for each case. The time from diagnosis of prostate cancer to first hormonal treatment, and from first hormonal treatment to VTE, was compared for different treatments. Adjusted risk estimates for VTE were derived from further analysis using a nested case-control study design amongst all men with advanced prostate cancer, qualified by evidence of hormonal treatment. RESULTS: The time between diagnosis and first treatment was significantly shorter for men first treated with CPA than for men first treated with a luteinizing hormone releasing hormone (LHRH) analogue (adjusted hazard ratio 1.33, 95% confidence interval, CI, 1.06-1.67). When the first treatment was CPA, the treatment-free period after diagnosis was significantly shorter for men who later had a VTE than for those who did not. The case-control study yielded an adjusted risk estimate for VTE amongst CPA users that was significantly higher than amongst men who were prescribed an LHRH analogue or who had had an orchidectomy (adjusted odds ratio 5.23, 95% CI 3.12-8.79). CONCLUSION: There was a greater risk of VTE associated with CPA, which might be due to differences in disease severity between users of different products. The clinical significance of this finding is unclear.