First results from five multidisciplinary diagnostic centre (MDC) projects for non-specific but concerning symptoms, possibly indicative of cancer.

BACKGROUND: Patients with non-specific symptoms often experience longer times to diagnosis and poorer clinical outcomes than those with site-specific symptoms. This paper reports initial results from five multidisciplinary diagnostic centre (MDC) projects in England, piloting rapid referral for patients with non-specific symptoms. METHODS: The evaluation covered MDC activity from 1st December 2016 to 31st July 2018, with projects using a common dataset. Logistical regression analyses were conducted, with a diagnosis of any cancer as the dependent variable. Exploratory analysis was conducted on presenting symptoms and diagnoses of cancer, and on comparisons within these groupings. RESULTS: In total, 2961 patients were referred into the MDCs and 241 cancers were diagnosed. The pathway detected cancers across a broad range of tumour sites, including several rare and less common cancers. An association between patient age and cancer was identified (p < 0.001). GP 'clinical suspicion' was identified as a strong predictor of cancer (p = 0.006), with a reduced association with cancer observed in patients with higher numbers of GP consultation before referral (p = 0.008). CONCLUSIONS: The MDC model diagnoses cancer in patients with non-specific symptoms, with a conversion rate of 8%, demonstrating the diagnostic potential of a non-site-specific symptomatic referral pathway.

The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

Likely effect of adding flexible sigmoidoscopy to the English NHS Bowel Cancer Screening Programme: impact on colorectal cancer cases and deaths.

BACKGROUND: From 2013, once-only flexible sigmoidoscopy (FS) at age 55 is being phased into the England National Health Service Bowel Cancer Screening Programme (NHSBCSP), augmenting biennial guaiac faecal occult blood testing (gFOBT) at ages 60-74. Here, we project the impact of this change on colorectal cancer (CRC) cases and deaths prevented in England by mid-2030. METHODS: We simulated the life-course of English residents reaching age 55 from 2013 onwards. Model inputs included population numbers, invitation rates and CRC incidence and mortality rates. The impact of gFOBT and FS alone on CRC incidence and mortality were derived from published trials, assuming an uptake of 50% for FS and 57% for gFOBT. For FS plus gFOBT, we assumed the gFOBT effect to be 75% of the gFOBT alone impact. RESULTS: By mid-2030, 8.5 million individuals will have been invited for once-only FS screening. Adding FS to gFOBT screening is estimated to prevent an extra 9627 (-10%) cases and 2207 (-12%) deaths by mid-2030. If FS uptake is 38% or 71%, respectively, an extra 7379 (-8%) or 13 689 (-15%) cases and 1691 (-9%) or 3154 (-17%) deaths will be prevented by mid-2030. CONCLUSIONS: Adding once-only FS at age 55 to the NHSBCSP will prevent ∼10,000 CRC cases and ∼2000 CRC deaths by mid-2030 if FS uptake is 50%. In 2030, one cancer was estimated to be prevented per 150 FS screening episodes, and one death prevented per 900 FS screening episodes. The actual reductions will depend on the FS invitation schedule and uptake rates.

Translation of research results to simple estimates of the likely effect of a lung cancer screening programme in the United Kingdom.

BACKGROUND: There is considerable interest in the possibility of provision of lung cancer screening services in many developed countries. There is, however, no consensus on the target population or optimal screening regimen. METHODS: In this paper, we demonstrate the use of published results on lung cancer screening and natural history parameters to estimate the likely effects of annual and biennial screening programmes in different risk populations, in terms of deaths prevented and of human costs, including screening episodes, further investigation rates and overdiagnosis. RESULTS: Annual screening with the UK Lung Screening Study eligibility criteria was estimated to result in 956 lung cancer deaths prevented and 457 overdiagnosed cancers from 330,000 screening episodes. Biennial screening would result in 802 lung cancer deaths prevented and 383 overdiagnosed cancers for 180,000 screening episodes. INTERPRETATION/CONCLUSION: The predictions suggest that the intervention effect could justify the human costs. The evidence base for low-dose CT screening for lung cancer pertains almost entirely to annual screening. The benefit of biennial screening is subject to additional uncertainty but the issue merits further empirical research.

Reduction in interval cancer rates following the introduction of two-view mammography in the UK breast screening programme.

BACKGROUND: The introduction of two-view mammography at incident (subsequent) screens in the National Health Service Breast Screening Programme (NHSBSP) has led to an increased number of cancers detected at screen. However, the effect of two-view mammography on interval cancer rates has yet to be assessed. METHODS: Routine screening and interval cancer data were collated from all screening programmes in the United Kingdom for women aged 50-64, screened between 1 April 2003 and 31 March 2005. Interval cancer rates were compared based on whether two-view mammography was in use at the last routine screen. RESULTS: The reduction in interval cancers following screening using two-view mammography compared with one view was 0.68 per 1,000 women screened. Overall, this suggests the introduction of two-view mammography at incident screen was accompanied by a 15-20% reduction in interval cancer rates in the NHSBSP. CONCLUSION: The introduction of two-view mammography at incident screens is associated with a reduction in incidence of interval cancers. This is consistent with previous publications on a contemporaneous increase in screen-detected cancers. The results provide further evidence of the benefit of the use of two-view mammography at incident screens.

Evaluation of a service intervention to improve awareness and uptake of bowel cancer screening in ethnically-diverse areas.

BACKGROUND: Uptake of bowel cancer screening is lowest in London, in populations of lower socio-economic status, and in particular ethnic or religious groups. METHODS: We report on the evaluation of two interventions to improve uptake in an area including populations of low socio-economic status and considerable ethnic diversity. The interventions were face-to-face health promotion on bowel cancer screening at invitees' general practice and health promotion delivered by telephone only. Nine large general practices in East London were chosen at random to offer face-to-face health promotion, and nine other large practices to offer telephone health promotion, with 24 practices of similar size as comparators. Data at practice level were analysed by Mann-Whitney-Wilcoxon tests and grouped-logistic regression. RESULTS: There were 2034 invitees in the telephone intervention practices, 1852 in the face-to-face intervention practices and 5227 in the comparison practices. Median gFOBt kit uptake in the target population (aged 59-70) was 46.7% in the telephone practices, 43.8% in the face-to-face practices and 39.1% in the comparison practices. Significant improvements in the odds of uptake were observed following telephone intervention in both males (OR=1.39, 95% CI=1.20-1.61, P<0.001) and females (OR=1.49, 95% CI=1.29-1.73, P<0.001), while the face-to-face intervention mainly impacted uptake in males (OR=1.23, 95% CI=1.10-1.36), P<0.001) but did not lead to a significant increase in females (OR=1.12, 95% CI=0.96-1.29, P=0.2). CONCLUSIONS: Personally delivered health promotion improved uptake of bowel cancer screening in areas of low socio-economic status and high ethnic diversity. The intervention by telephone appears to be the most effective method.

A systematic review of the characteristics associated with recall rates, detection rates and positive predictive values of computed tomography screening for lung cancer.

BACKGROUND: Low-dose computed tomography (LDCT) screening has been shown to reduce mortality from lung cancer but at a substantial cost in diagnostic activity. The objective of this study was to investigate the characteristics of screening programmes associated with recall rates, detection rates and positive predictive values (PPVs). DESIGN: We conducted a systematic review of randomised trials and observational studies on LDCT screening for lung cancer. A meta-regression using random-effect logistic regressions was carried out to assess factors influencing recall rates for further investigation, cancer detection rates and PPVs of recall. RESULTS: We used data from 63 372 prevalent screens from 16 studies of LDCT screening for lung cancer and 79 302 incident screens from nine studies. In univariable analysis, the use of a cut-off size to define nodules warranting further investigation at prevalent screens reduced recall rates [odds ratio (OR) = 0.44, 95% confidence interval (CI) 0.24-0.82 and OR = 0.42, 95% CI 0.21-0.84 for cut-off sizes of 3-4 and 5-8 mm, respectively], without significant changes in detection rates and PPVs. The number of readers (1 or ≥2) was not associated with changes in recall rates, detection rates and PPVs at prevalent and incident screens. Using the volumetry software at incident screens significantly increased the PPV (OR = 5.02, 95% CI 1.65-15.28) as a result of a decrease in recall rates (OR = 0.25, 95% CI 0.12-0.51), without significant changes in detection rates. CONCLUSION: These results highlight the value of using a cut-off size for nodules warranting further investigation with lower recall rates at prevalent screens, whereas the volumetric assessment software at incident screens results in lower recall rates and higher PPVs. The presence of positron emission tomography in the work-up protocol might be associated with lower rates of surgical procedures for benign findings, although this hypothesis deserves further investigation.

A telephone reminder intervention to improve breast screening information and access.

OBJECTIVES: In the UK, women aged 50-70 are offered breast cancer screening every three years. Screening participation rates in London have been particularly low. Low rates have been associated with low socio-economic status, and some ethnic groups have been observed to be underserved by cancer screening. This paper reports on a telephone reminder intervention in London Newham, an area of high deprivation and ethnic diversity. STUDY DESIGN: Observational study of planned intervention. METHODS: Women invited for breast screening were telephoned to confirm receipt of the invitation letter, remind invitees of their upcoming appointment, and to provide further information. Aggregate data at general practice level on invitation to and attendance at breast screening and on numbers reached by telephone were analysed by logistic regression. RESULTS: For the 29 participating GP practices (10,928 invitees) overall uptake in 2010 was higher compared to the previous screening round in 2007 (67% vs. 51%; p < 0.001). On average 59% of invitees were reached by the reminder calls. A 10% increase in women reached resulted in an 8% increase in the odds of women attending their screening appointment (95% CI: 5%-11%), after adjusting for 2007 attendance rates. Practices with a higher proportion of South Asian women were associated with a larger uptake adjusted for 2007 uptake and population reached by the telephone intervention, (4% increase in odds of attendance per 10% increase in South Asian population, CI 1%-7%, p = 0.003) while practices with a higher proportion of black women were associated with a smaller uptake similarly adjusted. (11% decrease in odds of attendance per 10% increase in black population, CI 9%-16%, p < 0.001). CONCLUSIONS: A language- and culture-sensitive programme of reminder calls substantially improved breast cancer screening uptake.

A randomised trial of weekend and evening breast screening appointments.

BACKGROUND: There is a need to research interventions that improve access to and convenience of breast cancer screening services. METHODS: We conducted a randomised trial comparing invitations to out-of-hours appointments with standard office hour appointments. Women who were to be invited for routine breast screening were randomised (3 : 1 : 1 : 1) to one of these screening invitations: standard office hour appointment, office hour appointment with the option to change to an out-of-hours appointment, weekday evening appointment, or weekend appointment. RESULTS: A total of 9410 women were invited to an office hour, 3519 to an office hour with the option to change, 3271 to a weekday evening, and 3162 to a weekend appointment. The offer of an initial out-of-hours appointment was associated with a non-significant decrease in attendance rates (73.7% vs 74.1%). The highest attendance was observed in the group offered an initial office hour appointment with the option to change to out-of-hours (76.1% vs 73.3% for standard office hour, P=0.001), with 7% of invitees exercising the option to change. CONCLUSION: The optimum strategy for improving attendance at breast screening is to offer a traditional office hour appointment and including in the letter of invitation an option to change to an evening or weekend appointment if wished.

Reduction in rate of node metastases with breast screening: consistency of association with tumor size.

Population screening has brought about changes in both the incidence and mortality rates of patients with breast cancer. Large numbers of small screen-detected tumors have inspired discussions about overdiagnosis based on potential biological differences between screen-detected and symptomatic cancers. In the current systematic review, we analyzed the relation and the interaction of tumor size and nodal status in correlation with screening. Smaller tumors were more frequently screen detected (pT1 78.5 %) than symptomatic (pT1 61.7 %, p < 0.001), with a RR of 1.6 (95 % CI 1.4-1.8, n = 41,209). In the screened population, pT1 tumors were also more frequent (68.5 vs 49.9 %, n = 51,171, p < 0.001). Positive lymph nodes were less frequent in screen-detected tumors (26.8 vs 46.3 %, n = 43,705, p < 0.001) as well as in screened populations as a whole (24.1 vs 44.9 %, n = 49,581, p < 0.001). The relation between size and nodal status was not different between the screen-detected and the symptomatic tumors [pT2+N+ OR 2.42 (95 % CI 1.69-3.48) vs OR 2.91 (95 % CI 2.41-3.51)], suggesting that biological differences, if present, are small. In this systematic review, we confirmed both the association of screening with smaller tumor size at presentation and the consequent reduction in lymph node metastases.

Explaining the difference in prognosis between screen-detected and symptomatic breast cancers.

BACKGROUND: We analysed 10-year survival data in 19,411 women aged 50-64 years diagnosed with invasive breast cancer in the West Midlands region of the United Kingdom. The aim was to estimate the survival advantage seen in cases that were screen detected compared with those diagnosed symptomatically and attribute this to shifts in prognostic variables or survival differences specific to prognostic categories. METHODS: We studied tumour size, histological grade and the Nottingham Prognostic Index in very narrow categories and investigated the distribution of these prognostic factors within screen-detected and symptomatic tumours. We also adjusted for lead time bias. RESULTS: The unadjusted 10-year breast cancer survival in screen-detected cases was 85.5% and in symptomatic cases 62.8%; after adjustment for lead time bias, survival in the screen-detected cases was 79.3%. Within narrow categories of prognostic variables, survival differences were small, indicating that the majority of the survival advantage of screen detection is due to differences in the distributions of size and node status. CONCLUSION: Our results suggested that a combination of lead time with size and node status in 10 categories explained almost all (97%) of the survival advantage. Only a small proportion remained to be explained by biological differences, manifested as length bias or overdiagnosis.

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening.

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone. METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively). RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases. CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.

Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease.

BACKGROUND: Molecular profiling has identified at least four subtypes of invasive breast carcinoma, which exhibit distinct clinical behaviour. There is good evidence now that DCIS represents the non-obligate precursor to invasive breast cancer and therefore it should be possible to identify similar molecular subtypes at this stage. In addition to a limited five-marker system to identify molecular subtypes in invasive breast cancer, it is evident that other biological molecules may identify distinct tumour subsets, though this has not been formally evaluated in DCIS. METHODS: Tissue microarrays were constructed for 188 cases of DCIS. Immunohistochemistry was performed to examine the expression patterns of oestrogen receptor (ER), progesterone receptor (PR), Her2, EGFR, cytokeratin (CK) 5/6, CK14, CK17, CK18, ß4-integrin, ß6-integrin, p53, SMA, maspin, Bcl-2, topoisomerase IIα and P-cadherin. Hierarchical clustering analysis was undertaken to identify any natural groupings, and the findings were validated in an independent sample series. RESULTS: Each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups, in particular, the triple negative and basal-like phenotype is very uncommon in DCIS. Hierarchical cluster analysis identified three main subtypes of DCIS determined largely by ER, PR, Her2 and Bcl-2, and this classification is related to conventional prognostic indicators. These subtypes were confirmed in an analysis on independent series of DCIS cases. CONCLUSION: This study indicates that DCIS may be classified in a similar manner to invasive breast cancer, and determining the relative frequency of different subtypes in DCIS and invasive disease may shed light on factors determining disease progression. It also demonstrates a role for Bcl-2 in classifying DCIS, which has recently been identified in invasive breast cancer.

Mammographic density and its interaction with other breast cancer risk factors in an Asian population.

BACKGROUND: Joint effects of mammographic density and other risk factors on breast cancer risk remain unclear. METHODS: From The Singapore Breast Screening Project, we selected 491 cases and 982 controls. Mammographic density was measured quantitatively. Data analysis was by conditional logistic regression. RESULTS: Density was a significant risk factor, adjusting for other factors. Density of 76-100% had an odds ratio of 5.54 (95% CI 2.38-12.90) compared with 0-10%. Density had significant interactions with body mass index and oral contraceptive use (P=0.02). CONCLUSIONS: Percent density increases breast cancer risk in addition to effects of other risk factors, and modifies the effects of BMI and OCs.

UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancer.

The UK Lung Screen (UKLS) is a randomised controlled trial of the use of low-dose multidetector CT for lung cancer screening. It completed the Health Technology Appraisal (HTA)-funded feasibility stage in October 2009 and the pilot UKLS will be initiated in early 2011. The pilot will randomise 4000 subjects to either low-dose CT screening or no screening. The full study, due to start in September 2012, if progression criteria are met, will randomise a further 28,000 subjects from seven centres in the UK. Subjects will be selected if they have sufficient risk of developing lung cancer according to the Liverpool Lung Project risk model. The UKLS employs the 'Wald Single Screen Design', which was modelled in the UKLS feasibility study. This paper describes the modelling of nodule management in UKLS by using volumetric analysis with a single initial screen design and follow-up period of 10 years. This modelling has resulted in the development and adoption of the UKLS care pathway, which will be implemented in the planned CT screening trial in the UK.

The impact of digital mammography on screening a young cohort of women for breast cancer in an urban specialist breast unit.

OBJECTIVE: To compare the diagnostic performance of full-field digital mammography (FFDM) with screen-film mammography (SFM) in a corporate screening programme including younger women. METHODS: Data were available on 14,946 screening episodes, 5010 FFDM and 9936 SFM. Formal analysis was by logistic regression, adjusting for age and calendar year. FFDM is compared with SFM with reference to cancer detection rates, cancers presenting as clustering microcalcifications, recall rates and PPV of recall. RESULTS: Overall detection rates were 6.4 cancers per thousand screens for FFDM and 2.8 per thousand for SFM (p < 0.001). In women aged 50+ cancer detection was significantly higher for FFDM at 8.6 per thousand vs. 4.0 per thousand, (p = 0.002). In women <50, cancer detection was also significantly higher for FFDM at 4.3 per thousand vs. 1.4 per thousand, (p = 0.02). Cancers detected as clustering microcalcifications increased from 0.4 per thousand with SFM to 2.0 per thousand with FFDM. Rates of assessment recall were higher for FFDM (7.3% vs. 5.0%, p < 0.001). FFDM provided a higher PPV for assessment recall, (32 cancers/364 recalls, 8.8%) than SFM, (28 cancers/493 recalls, 5.7%). CONCLUSIONS: Cancer detection rates were significantly higher for FFDM than for SFM, especially for women <50, and cancers detected as clustering microcalcifications.

Potential surrogate endpoints in cancer research--some considerations and examples.

We present an introductory survey of the use of surrogates in cancer research, in particular in clinical trials. The concept of a surrogate endpoint is introduced and contrasted with that of a biomarker. It is emphasized that a surrogate endpoint is not universal for an indication but will depend on the mechanism of treatment. We discuss the measures of validity of a surrogate and give examples of both cancer surrogates and biomarkers on the path to surrogacy. Circumstances in which a surrogate endpoint may actually be preferred to the clinical endpoint are described. We provide pointers to the recent substantive literature on surrogates.

Comparison of discriminatory power and accuracy of three lung cancer risk models.

BACKGROUND: Three lung cancer (LC) models have recently been constructed to predict an individual's absolute risk of LC within a defined period. Given their potential application in prevention strategies, a comparison of their accuracy in an independent population is important. METHODS: We used data for 3197 patients with LC and 1703 cancer-free controls recruited to an ongoing case-control study at the Harvard School of Public Health and Massachusetts General Hospital. We estimated the 5-year LC risk for each risk model and compared the discriminatory power, accuracy, and clinical utility of these models. RESULTS: Overall, the Liverpool Lung Project (LLP) and Spitz models had comparable discriminatory power (0.69), whereas the Bach model had significantly lower power (0.66; P=0.02). Positive predictive values were highest with the Spitz models, whereas negative predictive values were highest with the LLP model. The Spitz and Bach models had lower sensitivity but better specificity than did the LLP model. CONCLUSION: We observed modest differences in discriminatory power among the three LC risk models, but discriminatory powers were moderate at best, highlighting the difficulty in developing effective risk models.