Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

Do risk scores improve use of faecal immunochemical testing for haemoglobin in symptomatic patients in primary care?

AIM: Faecal immunochemical testing (FIT) is used in the detection of colorectal cancer (CRC). FIT is invariably used at a single faecal haemoglobin (f-Hb) concentration threshold. The aim of this observational study was to explore risk scoring models (RSMs) with f-Hb and other risk factors for CRC in symptomatic patients attending primary care, potentially speeding diagnosis and saving endoscopy resources. METHOD: Records of patients completing FIT were linked with The Scottish Cancer Registry and with other databases with symptoms, full blood count and demographic variables, and randomized into derivation and validation cohorts. Stepwise multivariable logistic regression created RSMs assessed in the validation cohort. RESULTS: Of 18 805 unique patients, 9374 and 9431 were in the derivation and validation cohorts, respectively: f-Hb, male sex, increasing age, iron deficiency anaemia and raised systemic immune inflammation index created the final RSM. A risk score threshold of ≥2.363, generating the same number of colonoscopies as a f-Hb threshold of ≥10 µg Hb/g gave improved sensitivity for CRC in both cohorts. A RSM which excluded f-Hb was used to investigate the effect of raising the f-Hb threshold from ≥10 to ≥20 µg Hb/g in those with a low risk score. This approach would have generated 234 fewer colonoscopies but missed four CRCs. CONCLUSION: The RSM conferred no significant benefit to patients with very low f-Hb and CRC. Alternative strategies combining FIT with other variables may be more appropriate for safety-netting of symptomatic patients. Further work to develop and investigate the value of RSM for significant bowel disease other than CRC may also be beneficial.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Faecal haemoglobin concentrations are associated with all-cause mortality and cause of death in colorectal cancer screening.

BACKGROUND: Colorectal cancer (CRC) screening reduces all-cause and CRC-related mortality. New research demonstrates that the faecal haemoglobin concentration (f-Hb) may indicate the presence of other serious diseases not related to CRC. We investigated the association between f-Hb, measured by a faecal immunochemical test (FIT), and both all-cause mortality and cause of death in a population-wide cohort of screening participants. METHODS: Between 2014 and 2018, 1,262,165 participants submitted a FIT for the Danish CRC screening programme. We followed these participants, using the Danish CRC Screening Database and several other national registers on health and population, until December 31, 2018. We stratified participants by f-Hb and compared them using a Cox proportional hazards regression on all-cause mortality and cause of death reported as adjusted hazard ratios (aHRs). We adjusted for several covariates, including comorbidity, socioeconomic factors, demography and prescription medication. RESULTS: We observed 21,847 deaths in the study period. Our multivariate analyses indicated an association relationship between increasing f-Hb and the risk of dying in the study period. This risk increased steadily from aHR 1.38 (95% CI: 1.32, 1.44) in those with a f-Hb of 7.1-11.9 µg Hb/g faeces to 2.20 (95% CI: 2.10, 2.30) in those with a f-Hb ≥60.0 µg Hb/g faeces, when compared to those with a f-Hb ≤7.0 µg Hb/g faeces. The pattern remained when excluding CRC from the analysis. Similar patterns were observed between incrementally increasing f-Hb and the risk of dying from respiratory disease, cardiovascular disease and cancers other than CRC. Furthermore, we observed an increased risk of dying from CRC with increasing f-Hb. CONCLUSIONS: Our findings support the hypothesis that f-Hb may indicate an elevated risk of having chronic conditions if causes for the bleeding have not been identified. The mechanisms still need to be established, but f-Hb may be a potential biomarker for several non-CRC diseases.

Sex variation in colorectal cancer mortality: trends and implications for screening.

BACKGROUND: Colorectal cancer (CRC) screening using faecal tests reduces disease-specific mortality. To investigate mortality and its association with sex, rates in women and men, and in different age ranges, were examined, before and after screening began in Scotland. METHODS: From 1990-99, no structured screening existed. Three pilots ran from 2000 to 2007 and subsequent full roll-out completed in 2009. Crude mortality rates for 1990-2020 were calculated relative to Scottish population estimates, and age-sex standardized rates calculated for all, pre-screening (<50 years), screening (5-74 years) and post-screening (>74 years) age ranges. RESULTS: CRC mortality declined from 1990 to 2020, but not linearly, and differed between sexes. In women, 1990-99 showed a steady decline [average annual percentage change (AAPC): -2.1%, 95% confidence interval (CI): -2.8% to -1.4%], but a less marked decline after 2000 (AAPC: -0.7%, 95% CI: -0.9% to -0.4%). In men, no clear decline was seen from 1990 to 1999 (AAPC: -0.4%, 95% CI: -1.1% to 0.4%), but mortality declined from 2000 to 2020 (AAPC: -1.7%, 95% CI: -1.9% to -1.5%). This pattern was exaggerated in the screening age ranges. For 2000-20, the overall reduction in mortality was less in women and in the screening age range. In the post-screening age range, reductions were smaller, but an increase was seen in the pre-screening age range, greater in women. CONCLUSIONS: CRC mortality fell during 1990-2020, but the decline differed markedly between sexes, indicating a larger beneficial effect of screening on CRC mortality in men compared to women: use of different thresholds for the sexes might lead to equality.

An evaluation of the feasibility of implementing the BeWEL lifestyle intervention programme for people at increased risk of colorectal cancer - from research to real life.

BACKGROUND: The BeWEL randomised controlled trial (RCT) of weight loss in people with colorectal adenomas demonstrated that a significant proportion of people are interested in lifestyle interventions (49%) and clinically relevant changes in body weight were achieved at 12-month follow-up. The current work aimed to assess the feasibility of the BeWEL programme invitation and delivery in a nonresearch setting to assess whether the original results could be replicated. METHODS: The original BeWel programme was modified through the provision of verbal introductions (vs. letter), requirement for people to contact BeWEL team (vs. BeWEL team contacting them), community delivery (vs. home), duration (12 weeks vs. 12 months) and two intervention visits (vs. 3) and inclusion of people with predisposition to colorectal cancer. Eligible people were informed about the BeWel programme from National Health Service (NHS) staff after colonoscopy procedures and invited to contact a dedicated Bowel Cancer UK lifestyle team. RESULTS: Findings demonstrated that programme uptake (10.6% vs. 33%) and retention (71% vs. 93%) was significantly lower than that obtained from the BeWEL RCT. For people who participated in the 3-month programme (n = 21), self-reported weight loss (mean: -7% body weight) was successful, and the programme was well received. CONCLUSIONS: The current approach to engaging clients with the BeWEL programme is unsustainable. Reliance on busy NHS staff to deliver invitations and the need for people to contact the delivery team (due to data protection) may have impacted on uptake. Alternative approaches to supporting weight management in this population should be explored further.

Strategies to minimise the current disadvantages experienced by women in faecal immunochemical test-based colorectal cancer screening.

Currently, women are disadvantaged compared to men in colorectal cancer (CRC) screening, particularly in programmes that use faecal immunochemical tests for haemoglobin (FIT) followed by colonoscopy. Although there is no single cause for all the known disadvantages, many can be attributed to the ubiquitous finding that women have lower faecal haemoglobin concentrations (f-Hb) than men; there are many plausible reasons for this. Generally, a single f-Hb threshold is used in CRC screening programmes, leading to lower positivity for women than men, which causes poorer outcomes for women, including lower CRC detection rate, higher interval cancer (IC) proportion, and higher CRC mortality. Many of the now widely advocated risk scoring strategies do include factors taking account of sex, but these have not been extensively piloted or introduced. Using different f-Hb thresholds for the sexes seems advantageous, but there are difficulties, including deciding which characteristic should be selected to achieve equivalency, for example, positivity, IC proportions, or specificity. Moreover, additional colonoscopy resources, often constrained, would be required. Governments and their agencies should be encouraged to prioritise the allocation of resources to put simple strategies into practice, such as different f-Hb thresholds to create equal positivity in both sexes.

Yield of colorectal cancer at colonoscopy according to faecal haemoglobin concentration in symptomatic patients referred from primary care.

AIM: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). The aim of this study was to examine the diagnostic yield of colonoscopy by faecal haemoglobin (f-Hb) concentration in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). METHOD: In three Scottish NHS Boards, FIT kits (HM-JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by general practitioners to guide referrals for patients with lower GI symptoms (laboratory data studied for 12 months from December 2015 onwards in Tayside, 18 months from June 2018 onwards in Fife and 5 months from September 2018 onwards in Greater Glasgow and Clyde). Cases of CRC diagnosed at colonoscopy were ascertained from colonoscopy and pathology records. RESULTS: Four thousand eight hundred and forty one symptomatic patients who underwent colonoscopy after FIT submission were included. Of the 2166 patients (44.7%) with f-Hb <10 µg Hb/g faeces (µg/g), 14 (0.6%) were diagnosed with CRC, with a number needed to scope (NNS) of 155. Of the 2675 patients (55.3%) with f-Hb ≥10 µg/g, 252 were diagnosed with CRC (9.4%) with a NNS of 11. Of the 705 patients with f-Hb ≥400 µg/g, 158 (22.4%) were diagnosed with CRC with a NNS of 5. Over half of those diagnosed with CRC with f-Hb <10 µg/g had coexisting anaemia. CONCLUSION: Symptomatic patients with f-Hb ≥10 µg/g should undergo further investigation for CRC, while higher f-Hb concentrations could be used to triage for urgency during the COVID-19 recovery phase. Patients with f-Hb <10 µg/g and without anaemia are very unlikely to be diagnosed with CRC and the majority need no further investigation.

The impact of hypothetical PErsonalised Risk Information on informed choice and intention to undergo Colorectal Cancer screening colonoscopy in Scotland (PERICCS)-a randomised controlled trial.

BACKGROUND: There is currently no existing evidence on the effects of personalised risk information on uptake of colonoscopy following first line screening for colorectal cancer. This study aimed to measure the impact of providing risk information based on faecal haemoglobin concentration to allow a fully informed choice around whether or not to undergo colonoscopy. METHODS: Two thousand seven hundred sixty-seven participants from the Scottish Bowel Screening Programme (SBoSP) database, who had not recently been invited for screening, were randomised to receive one of three types of hypothetical risk information materials: (1) numerical risk information (risk categories of one in 40, one in 1600 and one in 3500), (2) categorical risk information (highest, moderate and lowest risk), or (3) positive screening result letter (control group). The primary outcome was the impact of the risk materials on intention to undergo colonoscopy, to allow comparison with the current colonoscopy uptake of 77% for those with a positive screening result in the SBoSP. Secondary outcomes were knowledge, attitudes and emotional responses to the materials. RESULTS: Four hundred thirty-four (15.7%) agreed to participate with 100 from the numerical risk group (69.0%), 104 from the categorical risk group (72.2%) and 104 from the control group (71.7%) returning completed materials. Intention to undergo colonoscopy was highest in the highest risk groups for the numerical and categorical study arms (96.8% and 95.3%, respectively), but even in the lowest risk groups was > 50% (58.1% and 60.7%, respectively). Adequate knowledge of colorectal screening and the risks and benefits of colonoscopy was found in ≥ 98% of participants in all three arms. All participants reported that they found the information easy-to-understand. 19.1%, 24.0% and 29.6% of those in the numerical, categorical and control group, respectively, reported that they found the information distressing (p > 0.05). CONCLUSIONS: Applying the risk categories to existing SBoSP data shows that if all participants were offered an informed choice to have colonoscopy, over two thirds of participants would intend to have the test. Equating to an increase in the number of screening colonoscopies from approx. 14,000 to 400,000 per annum, this would place an unmanageable demand on colonoscopy services, with a very small proportion of cancers and pre-cancers detected. However, the response to the materials were very positive, suggesting that providing risk information to those in lowest and moderate risk groups along with advice that colonoscopy is not currently recommended may be an option. Future research would be required to examine actual uptake. TRIAL REGISTRATION: Date applied 1 December 2017 ISRCTN number 14254582 .

Faecal haemoglobin distributions by sex, age, deprivation and geographical region: consequences for colorectal cancer screening strategies.

Objectives Faecal immunochemical tests for haemoglobin (FIT) are becoming widely used in colorectal cancer (CRC) screening and assessment of symptomatic patients. Faecal haemoglobin concentration (f-Hb) thresholds are used to guide subsequent investigation. We established the distributions of f-Hb in a large screening population by sex, age, deprivation and geography. Methods Single estimates of f-Hb were documented for all individuals participating in the first 18 months of the Scottish Bowel Screening Programme (SBoSP). The distributions of f-Hb were generated for all participants, all men and women, and men and women by age quintile and deprivation quintile. Distributions were also generated by geographical region for all participants, men and women, and by deprivation. Comparisons of f-Hb distributions with those found in a pilot evaluation of FIT and three other countries were performed. Results f-Hb was documented for 887,248 screening participants, 422,385 men and 464,863 women. f-Hb varied by sex, age, deprivation quintile and geographical region. The f-Hb distributions by sex and age differed between the SBoSP and the pilot evaluation and the three other countries. Conclusions f-Hb is higher in men than in women and increases with age and deprivation in both sexes. f-Hb also varies by geographical region, independently of deprivation, and by country. The f-Hb distribution estimated by pilot evaluation may not represent the population distribution. Decision limits have advantages over reference intervals. Use of partitioned f-Hb thresholds for further investigation, based on the data generated, has advantages and disadvantages, as do risk scores based on a spectrum of influencing variables.

Comparing uptake across breast, cervical and bowel screening at an individual level: a retrospective cohort study.

BACKGROUND: We investigated demographic and clinical predictors of lower participation in bowel screening relative to breast and cervical screening. METHODS: Data linkage study of routinely collected clinical data from 430,591 women registered with general practices in the Greater Glasgow & Clyde Health Board. Participation in the screening programmes was measured by attendance at breast or cervical screening or the return of a bowel screening kit. RESULTS: 72.6% of 159,993 women invited attended breast screening, 80.7% of 309,899 women invited attended cervical screening and 61.7% of 180,408 women invited completed bowel screening. Of the 68,324 women invited to participate in all three screening programmes during the study period, 52.1% participated in all three while 7.2% participated in none. Women who participated in breast (OR = 3.34 (3.21, 3.47), p < 0.001) or cervical (OR = 3.48 (3.32, 3.65), p < 0.001) were more likely to participate in bowel screening. CONCLUSION: Participation in bowel screening was lower than breast or cervical for this population although the same demographic factors were associated with uptake, namely lower social deprivation, increasing age, low levels of comorbidity and prior non-malignant neoplasms. As women who complete breast and cervical are more likely to also complete bowel screening, interventions at these procedures to encourage bowel screening participation should be explored.

Appraisal of the faecal haemoglobin, age and sex test (FAST) score in assessment of patients with lower bowel symptoms: an observational study.

BACKGROUND: Many patients present in primary care with lower bowel symptoms, but significant bowel disease (SBD), comprising colorectal cancer (CRC), advanced adenoma (AA), or inflammatory bowel disease (IBD), is uncommon. Quantitative faecal immunochemical tests for haemoglobin (FIT), which examine faecal haemoglobin concentrations (f-Hb), assist in deciding who would benefit from colonoscopy. Incorporation of additional variables in an individual risk-score might improve this approach. We investigated if the published f-Hb, age and sex test score (FAST score) added value. METHODS: Data from the first year of routine use of FIT in primary care in one NHS Board in Scotland were examined: f-Hb was estimated using one HM-JACKarc FIT system (Kyowa Medex Co., Ltd., Tokyo, Japan) with a cut-off for positivity ≥10 µg Hb/g faeces. 5660 specimens were received for analysis in the first year. 4072 patients were referred to secondary care: 2881 (70.6%) of these had returned a FIT specimen. Of those referred, 1447 had colonoscopy data as well as the f-Hb result (group A): 2521 patients, also with f-Hb, were not immediately referred (group B). The FAST score was assessed in both groups. RESULTS: 1196 (41.7%) of patients who returned a specimen for FIT analysis had f-Hb ≥10 µg Hb/g faeces. In group A, 252 of 296 (85.1%) with SBD had f-Hb > 10 µg Hb/g faeces, as did 528 of 1151 (45.8%) without SBD. Using a FAST score > 2.12, which gives high clinical sensitivity for CRC, only 1143 would have been referred for colonoscopy (21.0% reduction in demand): 286 of 296 (96.6%) with SBD had a positive FAST score, as did 857 of 1151 (74.5%) without SBD. However, one CRC, five AA and four IBD would have been missed. In group B, although 95.2% had f-Hb < 10 µg Hb/g faeces, 1371 (53.7%) had FAST score ≥ 2.12: clinical rationale led to only 122 of group B completing subsequent bowel investigations: a FAST score > 2.12 was found in 13 of 15 (86.7%) with SBD. CONCLUSIONS: The performance characteristics of the FAST score did not seem to enhance the utility of f-Hb alone. Locally-derived formulae might confer desired benefits.

The impact of personalised risk information compared to a positive/negative result on informed choice and intention to undergo colonoscopy following colorectal Cancer screening in Scotland (PERICCS) - a randomised controlled trial: study protocol.

BACKGROUND: In Scotland a new, easier to complete bowel screening test, the Faecal Immunochemical Test (FIT), has been introduced. This test gives more accurate information about an individual's risk of having colorectal cancer (CRC), based on their age and gender, and could lead to fewer missed cancers compared to the current screening test. However, there is no evidence of the effect on colonoscopy uptake of providing individuals with personalised risk information following a positive FIT test. The objectives of the study are: 1) To develop novel methods of presenting personalised risk information in an easy-to-understand format using infographics with involvement of members of the public 2) To assess the impact of different presentations of risk information on informed choice and intention to take up an offer of colonoscopy after FIT 3) To assess participants' responses to receiving personal risk information (knowledge, attitudes to screening/risk, emotional responses including anxiety). METHODS: Adults (age range 50-74) registered on the Scottish Bowel Screening database will be invited by letter to take part. Consenting participants will be randomised to one of three groups to receive hypothetical information about their risk of cancer, based on age, gender and faecal haemoglobin concentration: 1) personalised risk information in numeric form (e.g. 1 in 100) with use of infographics, 2) personalised information described as 'highest', 'moderate' or 'lowest' risk with use of infographics, and 3) as a 'positive' test result, as is current practice. Groups will be compared on informed choice, intention to have a colonoscopy, and satisfaction with their decision. Follow-up semi-structured qualitative interviews will be conducted, by telephone, with a small number of consenting participants (n = 10 per group) to explore the acceptability/readability and any potential negative impact of the risk information, participants' understanding of risk factors, attitudes to the different scenarios, and reasons for reported intentions. DISCUSSION: Proving personalised risk information and allowing patient choice could lead to improved detection of CRC and increase patient satisfaction by facilitating informed choice over when/whether to undergo further invasive screening. However, we need to determine whether/how informed choice can be achieved and assess the potential impact on the colonoscopy service. TRIAL REGISTRATION: The trial is registered on www.isrctn.com on 08/12/2017. Registration no: ISRCTN14254582.

Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality.

OBJECTIVE: An association between detectable faecal haemoglobin (f-Hb) and both the risk of death from colorectal cancer (CRC) and all-cause mortality has been reported. We set out to confirm or refute this observation in a UK population and to explore the association between f-Hb, as indicated by a positive guaiac faecal occult blood test (gFOBT) result, and different causes of death. DESIGN: All individuals (134 192) who participated in gFOBT screening in Tayside, Scotland between 29/03/2000 and 29/03/2016 were studied by linking their test result (positive or negative) with mortality data from the National Records of Scotland database and following to 30/03/2016. RESULTS: Those with a positive test result (n=2714) had a higher risk of dying than those with a negative result, from CRC: HR 7.79 (95% CI 6.13 to 9.89), p<0.0001, (adjusted for, gender, age, deprivation quintile and medication that can cause bleeding) and all non-CRC causes: HR 1.58 (95% CI 1.45 to 1.73), p<0·0001.· In addition, f-Hb detectable by gFOBT was significantly associated with increased risk of dying from circulatory disease, respiratory disease, digestive diseases (excluding CRC), neuropsychological disease, blood and endocrine disease and non-CRC. CONCLUSION: The presence of detectable f-Hb is associated with increased risk of death from a wide range of causes.

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. RESULTS: Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders. CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.

A review of sex-related differences in colorectal cancer incidence, screening uptake, routes to diagnosis, cancer stage and survival in the UK.

BACKGROUND: Colorectal cancer (CRC) is an illness strongly influenced by sex and gender, with mortality rates in males significantly higher than females. There is still a dearth of understanding on where sex differences exist along the pathway from presentation to survival. The aim of this review is to identify where actions are needed to improve outcomes for both sexes, and to narrow the gap for CRC. METHODS: A cross-sectional review of national data was undertaken to identify sex differences in incidence, screening uptake, route to diagnosis, cancer stage at diagnosis and survival, and their influence in the sex differences in mortality. RESULTS: Overall incidence is higher in men, with an earlier age distribution, however, important sex differences exist in anatomical site. There were relatively small differences in screening uptake, route to diagnosis, cancer staging at diagnosis and survival. Screening uptake is higher in women under 69 years. Women are more likely to present as emergency cases, with more men diagnosed through screening and two-week-wait. No sex differences are seen in diagnosis for more advanced disease. Overall, age-standardised 5-year survival is similar between the sexes. CONCLUSIONS: As there are minimal sex differences in the data from routes to diagnosis to survival, the higher mortality of colorectal cancer in men appears to be a result of exogenous and/or endogenous factors pre-diagnosis that lead to higher incidence rates. There are however, sex and gender differences that suggest more targeted interventions may facilitate prevention and earlier diagnosis in both men and women.

Development of an evidence-based brief 'talking' intervention for non-responders to bowel screening for use in primary care: stakeholder interviews.

BACKGROUND: Bowel cancer is the third most common cause of cancer death worldwide. Bowel screening has been shown to reduce mortality and primary care interventions have been successful in increasing uptake of screening. Using evidence-based theory to inform the development of such interventions has been shown to increase their effectiveness. This study aimed to develop and refine a brief evidence-based intervention for eligible individuals whom have not responded to their last bowel screening invitation (non-responders), for opportunistic use by primary care providers during routine consultations. METHODS: The development of a brief intervention involving a conversation between primary care providers and non-responders was informed by a multi-faceted model comprising: research team workshop and meetings to draw on expertise; evidence from the literature regarding barriers to bowel screening and effective strategies to promote informed participation; relevant psychological theory, and intervention development and behaviour change guidance. Qualitative telephone interviews with 1) bowel screening stakeholders and 2) patient non-responders explored views regarding the acceptability of the intervention to help refine its content and process. RESULTS: The intervention provides a theory and evidence-based tool designed to be incorporated within current primary care practice. Bowel screening stakeholders were supportive of the intervention and recognised the importance of the role of primary care. Interviews highlighted the importance of brevity and simplicity to incorporate the intervention into routine clinical care. Non-responders similarly found the intervention acceptable, valuing a holistic approach to their care. Moreover, they expected their primary care provider to encourage participation. CONCLUSIONS: A theory-based brief conversation for use in a primary care consultation was acceptable to bowel screening stakeholders and potential recipients, reflecting a health promoting primary care ethos. Findings indicate that it is appropriate to test the intervention in primary care in a feasibility study.

The fecal hemoglobin concentration, age and sex test score: Development and external validation of a simple prediction tool for colorectal cancer detection in symptomatic patients.

Prediction models for colorectal cancer (CRC) detection in symptomatic patients, based on easily obtainable variables such as fecal haemoglobin concentration (f-Hb), age and sex, may simplify CRC diagnosis. We developed, and then externally validated, a multivariable prediction model, the FAST Score, with data from five diagnostic test accuracy studies that evaluated quantitative fecal immunochemical tests in symptomatic patients referred for colonoscopy. The diagnostic accuracy of the Score in derivation and validation cohorts was compared statistically with the area under the curve (AUC) and the Chi-square test. 1,572 and 3,976 patients were examined in these cohorts, respectively. For CRC, the odds ratio (OR) of the variables included in the Score were: age (years): 1.03 (95% confidence intervals (CI): 1.02-1.05), male sex: 1.6 (95% CI: 1.1-2.3) and f-Hb (0-<20 µg Hb/g feces): 2.0 (95% CI: 0.7-5.5), (20-<200 µg Hb/g): 16.8 (95% CI: 6.6-42.0), ≥200 µg Hb/g: 65.7 (95% CI: 26.3-164.1). The AUC for CRC detection was 0.88 (95% CI: 0.85-0.90) in the derivation and 0.91 (95% CI: 0.90-093; p = 0.005) in the validation cohort. At the two Score thresholds with 90% (4.50) and 99% (2.12) sensitivity for CRC, the Score had equivalent sensitivity, although the specificity was higher in the validation cohort (p < 0.001). Accordingly, the validation cohort was divided into three groups: high (21.4% of the cohort, positive predictive value-PPV: 21.7%), intermediate (59.8%, PPV: 0.9%) and low (18.8%, PPV: 0.0%) risk for CRC. The FAST Score is an easy to calculate prediction tool, highly accurate for CRC detection in symptomatic patients.

Perceived diagnostic delay and cancer-related distress: a cross-sectional study of patients with colorectal cancer.

OBJECTIVE: This study aimed to examine the effect of perceived diagnostic delay on cancer-related distress and determine whether fear of cancer-recurrence and quality of life mediate this relationship. METHODS: Cross-sectional study in which 311 colorectal cancer (CRC) survivors in Scotland completed a survey, which included questions on cancer-related distress (IES-R), perceived diagnostic delay, quality of life (trial outcome index of the FACT-C: FACT-C TOI) and fear of cancer recurrence. Fifteen patients withheld consent to data matching with medical records, leaving a sample size of 296. Participants were an average of 69 years old (range 56 to 81) and between 3.5 and 12 years post-diagnosis. Multiple regressions were used to test predictors of distress and regression and bootstrapping to test for mediation. RESULTS: Perceived diagnostic delay was correlated with higher cancer-related distress, while objective markers of diagnostic delay (disease stage at diagnosis and treatment received) were not. Some of the relationship between perceived diagnostic delay and cancer-related distress was mediated by quality of life, but not by fear of cancer recurrence. CONCLUSIONS: Perceived diagnostic delay was associated with higher cancer-related distress among CRC survivors. While poorer quality of life partly explained such associations, fear of cancer recurrence, stage at diagnosis and treatment did not. The exact features of diagnostic delay that are associated with cancer-related distress remain unclear. Future research should examine the experiences patients go through prior to diagnosis that may increase distress, in an effort to improve our understanding of the factors affecting emotional wellbeing among CRC survivors. Copyright © 2016 John Wiley & Sons, Ltd.

Understanding of a negative bowel screening result and potential impact on future symptom appraisal and help-seeking behaviour: a focus group study.

BACKGROUND: Colorectal cancer (CRC) screening using a faecal occult blood test (FOBt) has the potential to reduce cancer-related mortality. Symptom vigilance remains crucial as a proportion of cancers will be diagnosed between screening rounds. A negative FOBt has the potential to influence how participants respond to future symptoms of CRC. OBJECTIVE: To explore (i) understanding of a negative FOBt and (ii) the potential impact of a negative FOBt upon future symptom appraisal and help-seeking behaviour. DESIGN: Qualitative methodology utilizing focus groups with participants who received a negative FOBt within the National Bowel Cancer Screening Programme in Coventry and Lothian. Topics explored included: experience of screening participation, interpretation and understanding of a negative result, symptom awareness and attitudes towards help-seeking. RESULTS: Four broad themes were identified: (i) emotional response to a negative FOBt, (ii) understanding the limitations of FOBt screening, (iii) symptom knowledge and interpretation and (iv) over-reassurance from a negative FOBt. Participants were reassured by a negative FOBt, but there was variability in the extent to which the result was interpreted as an "all clear". Some participants acknowledged the residual risk of cancer and the temporal characteristic of the result, while others were surprised that the result was not a guarantee that they did not have cancer. DISCUSSION AND CONCLUSIONS: Participants recognized that reassurance from a negative FOBt could lead to a short-term delay in help-seeking if symptoms developed. Screening programmes should seek to emphasize the importance of the temporal nature of FOBt results with key messages about symptom recognition and prompt help-seeking behaviour.