Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study.

BACKGROUND: Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. METHODS: We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. FINDINGS: 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. INTERPRETATION: This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. FUNDING: GRAIL Bio UK.

National Cancer Diagnosis Audits for England 2018 versus 2014: a comparative analysis.

BACKGROUND: Timely diagnosis of cancer in patients who present with symptoms in primary care is a quality-improvement priority. AIM: To examine possible changes to aspects of the diagnostic process, and its timeliness, before and after publication of the National Institute for Health and Care Excellence's (2015) guidance on the referral of suspected cancer in primary care. DESIGN AND SETTING: Comparison of findings from population-based clinical audits of cancer diagnosis in general practices in England for patients diagnosed in 2018 or 2014. METHOD: GPs in 1878 (2018) and 439 (2014) practices collected primary care information on the diagnostic pathway of cancer patients. Key measures including patient characteristics, place of presentation, number of pre-referral consultations, use of primary care investigations, and referral type were compared between the two audits by descriptive analysis and regression models. RESULTS: Among 64 489 (2018) and 17 042 (2014) records of a new cancer diagnosis, the percentage of patients with same-day referral (denoted by a primary care interval of 0 days) was higher in 2018 (42.7% versus 37.7%) than in 2014, with similar improvements in median diagnostic interval (36 days versus 40 days). Compared with 2014, in 2018: fewer patients had ≥3 pre-referral consultations (18.8% versus 26.2%); use of primary care investigations increased (47.9% versus 45.4%); urgent cancer referrals increased (54.8% versus 51.8%); emergency referrals decreased (13.4% versus 16.5%); and recorded use of safety netting decreased (40.0% versus 44.4%). CONCLUSION: In the 5-year period, including the year when national guidelines were updated (that is, 2015), there were substantial improvements to the diagnostic process of patients who present to general practice in England with symptoms of a subsequently diagnosed cancer.

Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study.

BACKGROUND: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. METHODS: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. FINDINGS: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995-2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010-14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. INTERPRETATION: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. FUNDING: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network.

Establishing population-based surveillance of diagnostic timeliness using linked cancer registry and administrative data for patients with colorectal and lung cancer.

BACKGROUND: Diagnostic timeliness in cancer patients is important for clinical outcomes and patient satisfaction but, to-date, continuous monitoring of diagnostic intervals in nationwide incident cohorts has been impossible in England. METHODS: We developed a new methodology for measuring the secondary care diagnostic interval (SCDI - first relevant secondary care contact to diagnosis) using linked cancer registration and healthcare utilisation data. Using this method, we subsequently examined diagnostic timeliness in colorectal and lung cancer patients (2014-15) by socio-demographic characteristics, diagnostic route and stage at diagnosis. RESULTS: The approach assigned SCDIs to 94.4% of all incident colorectal cancer cases [median length (90th centile) of 25 (104) days] and 95.3% of lung cancer cases [36 (144) days]. Advanced stage patients had shorter intervals (median, colorectal: stage 1 vs 4 - 34 vs 19 days; lung stage 1&2 vs 3B&4 - 70 vs 27 days). Routinely referred patients had the longest (colorectal: 61, lung: 69 days) and emergency presenters the shortest intervals (colorectal: 3, lung: 14 days). Comorbidities and additional diagnostic tests were also associated with longer intervals. CONCLUSION: This new method can enable repeatable nationwide measurement of cancer diagnostic timeliness in England and identifies actionable variation to inform early diagnosis interventions and target future research.

Diagnosing cancer in primary care: results from the National Cancer Diagnosis Audit.

BACKGROUND: Continual improvements in diagnostic processes are needed to minimise the proportion of patients with cancer who experience diagnostic delays. Clinical audit is a means of achieving this. AIM: To characterise key aspects of the diagnostic process for cancer and to generate baseline measures for future re-audit. DESIGN AND SETTING: Clinical audit of cancer diagnosis in general practices in England. METHOD: Information on patient and tumour characteristics held in the English National Cancer Registry was supplemented by information from GPs in participating practices. Data items included diagnostic timepoints, patient characteristics, and clinical management. RESULTS: Data were collected on 17 042 patients with a new diagnosis of cancer during 2014 from 439 practices. Participating practices were similar to non-participating ones, particularly regarding population age, urban/rural location, and practice-based patient experience measures. The median diagnostic interval for all patients was 40 days (interquartile range [IQR] 15-86 days). Most patients were referred promptly (median primary care interval 5 days [IQR 0-27 days]). Where GPs deemed diagnostic delays to have occurred (22% of cases), patient, clinician, or system factors were responsible in 26%, 28%, and 34% of instances, respectively. Safety netting was recorded for 44% of patients. At least one primary care-led investigation was carried out for 45% of patients. Most patients (76%) had at least one existing comorbid condition; 21% had three or more. CONCLUSION: The findings identify avenues for quality improvement activity and provide a baseline for future audit of the impact of 2015 National Institute for Health and Care Excellence guidance on management and referral of suspected cancer.

The expanding role of primary care in cancer control.

The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise­from epidemiologists, psychologists, policy makers, and cancer specialists­has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care­its continuous, coordinated, and comprehensive care for individuals and families­are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development.

The International Cancer Benchmarking Partnership: an international collaboration to inform cancer policy in Australia, Canada, Denmark, Norway, Sweden and the United Kingdom.

The International Cancer Benchmarking Partnership (ICBP) was initiated by the Department of Health in England to study international variation in cancer survival, and to inform policy to improve cancer survival. It is a research collaboration between twelve jurisdictions in six countries: Australia (New South Wales, Victoria), Canada (Alberta, British Columbia, Manitoba, Ontario), Denmark, Norway, Sweden, and the United Kingdom (England, Northern Ireland, Wales). Leadership is provided by policymakers, with academics, clinicians and cancer registries forming an international network to conduct the research. The project currently has five modules examining: (1) cancer survival, (2) population awareness and beliefs about cancer, (3) attitudes, behaviours and systems in primary care, (4) delays in diagnosis and treatment, and their causes, and (5) treatment, co-morbidities and other factors. These modules employ a range of methodologies including epidemiological and statistical analyses, surveys and clinical record audit. The first publications have already been used to inform and develop cancer policies in participating countries, and a further series of publications is under way. The module design, governance structure, funding arrangements and management approach to the partnership provide a case study in conducting international comparisons of health systems that are both academically and clinically robust and of immediate relevance to policymakers.

Knowledge of lung cancer symptoms and risk factors in the U.K.: development of a measure and results from a population-based survey.

OBJECTIVES: To develop and validate a lung cancer awareness measure (Lung CAM) and explore the demographical and social predictors of lung cancer awareness in the general population. METHODS STUDY 1: Symptoms and risk factors for lung cancer were identified from the medical literature and health professional expertise in an iterative process. Test-retest reliability, internal reliability, item analyses, construct validity and sensitivity to changes in awareness of the Lung CAM were assessed in three samples (total N=191). RESULTS STUDY 1: The Lung CAM demonstrated good internal (Cronbach's α=0.88) and test-retest reliability (r=0.81, p<0.001). Validity was supported by lung cancer experts scoring higher than equally educated controls (t(106)=8.7, p<0.001), and volunteers randomised to read lung cancer information scoring higher than those reading a control leaflet (t(81)=3.66, p<0.001). METHODS STUDY 2: A population-based sample of 1484 adults completed the Lung CAM in a face-to-face, computer-assisted interview. RESULTS STUDY 2: Symptom awareness was low (average recall of one symptom) and there was little awareness of risk factors other than smoking. Familiarity with cancer, and being from a higher socioeconomic group, were associated with greater awareness. CONCLUSIONS: Using a valid and reliable tool for assessing awareness showed the UK population to have low awareness of lung cancer symptoms and risk factors. Interventions to increase lung cancer awareness are needed to improve early detection behaviour.

Assessing awareness of colorectal cancer symptoms: measure development and results from a population survey in the UK.

BACKGROUND: This paper describes the development of a Cancer Awareness Measure for colorectal (CRC) cancer (Bowel/Colorectal CAMa) (study 1) and presents key results from a population-representative survey using the measure (study 2). METHODS: STUDY 1: Items were taken from the literature and reviewed by expert groups. A series of three validation studies assessed reliability and validity of the measure. To establish test-retest reliability, 49 people over 50 years of age completed the Bowel/Colorectal CAM on two occasions (range 9-14 days, mean 13.5 days). Construct validity was assessed by comparing responses from bowel cancer experts (n = 16) and the lay public (n = 35). Lastly, a brief intervention study tested sensitivity to change with participants (n = 70) randomly allocated to be given a control leaflet or an intervention leaflet and their responses were compared. STUDY 2: 1520 respondents completed the Bowel/Colorectal CAM in a population survey carried out by TNS-British Market Research Bureau International (TNS-BMRB) in March 2010. RESULTS: STUDY 1: Internal reliability (Cronbach's alpha = 0.84) was high. Test-retest reliability was over r = 0.7 for warning signs, risk factors and age people are first invited for screening, but lower (between 0.6 and 0.7) for other items (lifetime risk, awareness of bowel cancer screening, age at risk). Bowel cancer experts achieved higher scores than equally educated controls (54.7 [4.3] vs. 42.9 [5.7]; P < 0.001) demonstrating the measure has construct validity and intervention participants showed higher knowledge than controls (51.4 [5.9] vs. 42.9 [5.7]; P < 0.001) suggesting the measure is sensitive to change. STUDY 2: Respondents recalled on average, one CRC sign and one risk factor. There was particularly low prompted awareness of the signs 'lump in the abdomen' (64%) and 'tiredness' (50%) and several lifestyle risk factors for CRC, e.g. exercise (37%).Respondents from more affluent groups had consistently higher knowledge of signs and risk factors compared to those from more deprived groups. CONCLUSIONS: The Bowel/Colorectal CAM meets accepted psychometric criteria for reliability and construct validity and should therefore provide a useful tool for assessment of CRC awareness. The population survey revealed low awareness of several CRC signs and risk factors and emphasises the importance of continuing public education, particularly about the link between lifestyle behaviours and CRC.

Ethnic disparities in knowledge of cancer screening programmes in the UK.

OBJECTIVE: The aim of the study was to examine awareness of the three National Cancer Screening Programmes (breast, cervical, bowel) among white and ethnic minority groups in the UK. SETTING: Data were from two surveys in which the screening questions were added: (i) the Office of National Statistics (ONS) Opinions Survey, carried out in September and October 2008; and (ii) the Ethnibus™ survey of the main ethnic minority groups in England, conducted in October and November 2008. METHODS: The ONS sample consisted of 2216 adults selected using stratified probability sampling to obtain a population-representative sample. The Ethnibus™ sample was obtained by quota sampling and included 1500 adults from the six largest ethnic minority groups in England (Indian, Pakistani, Bangladeshi, Caribbean, African and Chinese). Participants completed questions on awareness of cancer screening programmes as part of the wider Cancer Awareness Measure (CAM) in home-based, face-to-face interviews. RESULTS: Awareness of breast and cervical cancer screening was high in the white ONS participants (89% breast and 84% cervical), lower in the ONS ethnic minority sample (74% for both breast and cervical) and lowest in the Ethnibus™ sample (69% breast and 66% cervical). Ethnic disparities persisted after controlling for age, gender and occupational group. In both groups, knowledge of breast and cervical screening was lower among men and more socioeconomically deprived groups. Awareness of the new bowel cancer screening programme was less than 30% in both white and ethnic minority groups. CONCLUSIONS: Ethnic disparities in knowledge of breast and cervical cancer screening should be addressed. Strategies to engage ethnic minority and socioeconomically deprived groups in bowel cancer screening should be instigated to avoid the emergence of disparities.

UK Food Standards Agency Workshop Report: an investigation of the relative contributions of diet and sunlight to vitamin D status.

The UK Food Standards Agency (FSA) convened an international group of scientific experts to review three Agency-funded projects commissioned to provide evidence for the relative contributions of two sources, dietary vitamin D intake and skin exposure to UVB rays from sunlight, to vitamin D status. This review and other emerging evidence are intended to inform any future risk assessment undertaken by the Scientific Advisory Committee on Nutrition. Evidence was presented from randomised controlled trials to quantify the amount of vitamin D required to maintain a serum 25-hydroxy vitamin D (25OHD) concentration >25 nmol/l, a threshold that is regarded internationally as defining the risk of rickets and osteomalacia. Longitudinal evidence was also provided on summer sunlight exposure required to maintain 25OHD levels above this threshold in people living in the British Isles (latitude 51 degrees-57 degrees N). Data obtained from multi-level modelling of these longitudinal datasets showed that UVB exposure (i.e. season) was the major contributor to changes in 25OHD levels; this was a consistent finding in two Caucasian groups in the north and south of the UK, but was less apparent in the one group of British women of South Asian origin living in the south of the UK. The FSA-funded research suggested that the typical daily intake of vitamin D from food contributed less than UVB exposure to average year-round 25OHD levels in both Caucasian and Asian women. The low vitamin D status of Asian women has been acknowledged for some time, but the limited seasonal variation in Asian women is a novel finding. The Workshop also considered the dilemma of balancing the risks of vitamin D deficiency (from lack of skin exposure to sunlight in summer) and skin cancer (from excessive exposure to sunlight with concomitant sunburn and erythema). Cancer Research UK advises that individuals should stay below their personal sunburn threshold to minimise their skin cancer risk. The evidence suggests that vitamin D can be produced in summer at the latitude of the UK, with minimal risk of erythema and cell damage, by exposing the skin to sunlight for a short period at midday, when the intensity of UVB is at its daily peak. The implications of the new data were discussed in the context of dietary reference values for vitamin D for the general population aged 4-64 years. Future research suggestions included further analysis of the three FSA-funded studies as well as new research.

Sunbed use in children aged 11-17 in England: face to face quota sampling surveys in the National Prevalence Study and Six Cities Study.

OBJECTIVES: To quantify the use of sunbeds in young people across England, identify geographical variation, and explore patterns of use, including supervision. DESIGN: Two random location sampling surveys. SETTING: National Prevalence Study in England; Six Cities Study in Liverpool, Stoke/Stafford, Sunderland, Bath/Gloucester, Oxford/Cambridge, and Southampton. PARTICIPANTS: 3101 children aged 11-17 in the National Prevalence study and 6209 in the Six Cities study. RESULTS: In the National Prevalence Study 6.0% (95% confidence interval 5.1% to 6.8%) of those aged 11-17 had used a sunbed. Use was higher in girls than in boys (8.6% (7.2% to 10.0%) v 3.5% (2.6% to 4.4%), respectively), in those aged 15-17 compared with those aged 11-14 (11.2% (9.5% to 12.9%) v 1.8% (1.2% to 2.4%), respectively), and in those from lower rather than higher social grades (7.6% (5.7% to 9.5%) v 5.4% (4.5% to 6.3%), respectively). Sunbed use was higher in the "north" (11.0%, 8.9% to 13.0%) than in the "midlands" (4.2%, 2.5% to 5.8%) and the "south" (4.2%, 3.3% to 5.2%). In the Six Cities Study, sunbed use was highest in Liverpool and Sunderland (20.0% (17.5% to 22.4%) and 18.0% (15.6% to 20.3%), respectively), with rates especially high in girls, those aged 15-17, or from lower social grades. Mean age of first use was 14, and 38.4% (34.7% to 42.1%) of children used a sunbed at least once a week. Nearly a quarter (23.0%, 19.8% to 26.1%) of children had used a sunbed at home (including home of friends/relatives), and 24.7% (21.0% to 28.4%) said they had used sunbeds unsupervised in a tanning/beauty salon or gym/leisure centre. CONCLUSIONS: Sunbed use by children is widespread in England, is often inadequately supervised, and is a health risk. National legislation is needed to control sunbed outlets.

The launch of Cancer Research UK's 'Reduce the Risk' campaign: baseline measurements of public awareness of cancer risk factors in 2004.

AIM: This national survey sought to establish levels of awareness of cancer risk factors and awareness of what individuals could do to reduce their own risk status. METHOD: Cross-sectional interview data comprising a national representative sample of 4,233 individuals aged 15 years or over across Great Britain. RESULTS: There were high levels of awareness of the role of smoking in the development of cancer, but only modest awareness of alcohol intake, being overweight, physical inactivity and older age. Recognition of the role of viral infection in cancer risk was very poor. Although two-thirds of respondents thought that cancer risk could be modified through lifestyle changes, those most in need of making lifestyle changes were less likely to be aware of what they could do to reduce their cancer risk. CONCLUSION: This survey highlights the need to increase awareness of overweight, alcohol, infections and exercise in the development of cancer, particularly amongst younger people and those from more socio-economically deprived backgrounds.

Public awareness regarding UV risks and vitamin D--the challenges for UK skin cancer prevention campaigns.

Since 1970s, incidence rates for malignant melanoma have been among the fastest rising of all cancers in the UK. Compared to other cancers, melanoma affects disproportionately more young people, and non-melanoma skin cancers are the most commonly diagnosed, with over 100,000 new cases estimated in the UK annually. Government targets to reduce skin cancer incidence have led working groups and prevention campaigns to be set up in the belief that moderating UV exposure will help. An increased awareness of skin cancer has clearly played a role in curbing mortality from the disease, but translating knowledge into behaviour change in this context is a slow and complex process, and campaigns need to be sustained if they are to impact on incidence. A growing body of literature suggesting a cancer protective role for vitamin D and sun exposure presents further challenges for skin cancer prevention campaigns, no more so than when exaggerated claims for the health benefits of sunbathing make the media spotlight. The UK population tend to need little encouragement to make the most of sunshine, and this is especially true for the younger generation who most need to take care. Public health messages to avoid the midday sun, not to burn and to protect children should not adversely affect outdoor activity or population vitamin D levels, but it is important that they are targeted to those most at risk and are consistent. More research is required to establish optimal levels of vitamin D and how to safely achieve them in a heterogeneous population. In the meantime, hasty alterations of public health messages are likely to prove counterproductive.