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.

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.

Variation in colorectal cancer treatment and survival: a cohort study covering the East Anglia region.

AIM: National guidelines for colorectal cancer management aim to optimize cancer outcomes irrespective of postcode. However, in order to ensure equal performance of cancer services, variation in outcome must be monitored and intelligently assessed. In this study, detailed regional cancer registry data were used to quantify and explore the reasons for variation in colorectal cancer outcomes at nine hospitals in East Anglia. METHOD: We analysed data on colorectal cancers registered by the Eastern Cancer Registry and Information Centre (ECRIC) between 1999 and 2005. Tumours were grouped by site, in keeping with surgical resection. Multivariable Cox regression models were used to identify the effects of patient, disease and treatment variables on an individual's risk of death. RESULTS: After adjusting for demographic, disease and treatment variables there were significant differences in survival among hospitals in emergency admissions with cancer of the right colon, in elective admissions with cancer of the left, sigmoid or recto-sigmoid colon and in emergency admissions with cancer of the rectum. There were also differences among hospitals in terms of perioperative death, nonsurgical management and numbers of nodes examined. For rectal cancers, rates of anterior resection compared with abdominoperineal excision differed, as well as the use of neoadjuvant radiotherapy. CONCLUSION: Detailed analysis of demographic, disease and treatment factors are required when comparing the survival of individuals with colorectal cancer across hospitals. The results imply that cancer management was not consistent across East Anglia in 1999-2005 but the reasons for this are uncertain. Nevertheless, 5-year age-standardized survival with colon cancer in the Anglia Cancer Network region is currently among the best in the UK.

Evaluation of mammographic surveillance services in women aged 40-49 years with a moderate family history of breast cancer: a single-arm cohort study.

BACKGROUND: Women with a significant family history of breast cancer are often offered more intensive and earlier surveillance than is offered to the general population in the National Breast Screening Programme. Up to now, this strategy has not been fully evaluated. OBJECTIVE: To evaluate the benefit of mammographic surveillance for women aged 40-49 years at moderate risk of breast cancer due to family history. The study is referred to as FH01. DESIGN: This was a single-arm cohort study with recruitment taking place between January 2003 and February 2007. Recruits were women aged < 50 years with a family history of breast or ovarian cancer conferring at least a 3% risk of breast cancer between ages 40 and 49 years. The women were offered annual mammography for at least 5 years and observed for the occurrence of breast cancer during the surveillance period. The age group 40-44 years was targeted so that they would still be aged < 50 years after 5 years of surveillance. SETTING: Seventy-four surveillance centres in England, Wales, Scotland and Northern Ireland. PARTICIPANTS: A total of 6710 women, 94% of whom were aged < 45 years at recruitment, with a family history of breast cancer estimated to imply at least a 3% risk of the disease between the ages of 40 and 50 years. INTERVENTIONS: Annual mammography for at least 5 years. MAIN OUTCOME MEASURES: The primary study end point was the predicted risk of death from breast cancer as estimated from the size, lymph node status and grade of the tumours diagnosed. This was compared with the control group from the UK Breast Screening Age Trial (Age Trial), adjusting for the different underlying incidence in the two populations. RESULTS: As of December 2010, there were 165 breast cancers diagnosed in 37,025 person-years of observation and 30,556 mammographic screening episodes. Of these, 122 (74%) were diagnosed at screening. The cancers included 44 (27%) cases of ductal carcinoma in situ. There were 19 predicted deaths in 37,025 person-years in FH01, with an estimated incidence of 6.3 per 1000 per year. The corresponding figures for the Age Trial control group were 204 predicted deaths in 622,127 person-years and an incidence of 2.4 per 1000 per year. This gave an estimated 40% reduction in breast cancer mortality (relative risk = 0.60; 95% confidence interval 0.37 to 0.98; p = 0.04). CONCLUSIONS: Annual mammography in women aged 40-49 years with a significant family history of breast or ovarian cancer is both clinically effective in reducing breast cancer mortality and cost-effective. There is a need to further standardise familial risk assessment, to research the impact of digital mammography and to clarify the role of breast density in this population. TRIAL REGISTRATION: National Research Register N0484114809. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 11. See the HTA programme website for further project information.

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.

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.

Mammographic breast density by area of residence: possible evidence of higher density in urban areas.

OBJECTIVES: A comparison of mammographic breast densities of women living in London with those of women living in rural and suburban areas. DESIGN AND METHODS: Using the standard four American College of Radiology Breast Imaging Reporting and Data System (BIRADS) categories of mammographic density, 318 mammograms of women from London and 654 mammograms of women from outside the capital aged 27-87 years who had received mammography at the Princess Grace Hospital, London, were assessed for density. The association between having any dense tissue and area of residence was assessed using both ordered and standard logistic regression, giving odds ratio estimates of relative risk of dense tissue adjusting for age. RESULTS: Adjusting for age, London residents had significantly higher levels of density (OR = 1.32, 95% CI 1.04-1.70, p = 0.02). The major difference occurred in the age group 45-54 years and was most strongly manifested as a higher rate in London for density of 25% or more (BIRADS categories 2-4) as compared to almost entirely fatty (BIRADS 1) (OR = 2.22, 95% CI 1.05-4.68, p = 0.035). CONCLUSION: The higher density is likely to be due to a different prevalence of risk factors in the London population. This study cannot ascertain the reason for the higher density in this urban population, but the result is a cause for concern given that screening uptake is lower in London. Increased attention to screening in urban areas and attention to screening quality for dense breast tissue might be prudent.

A case-control study of the impact of the East Anglian breast screening programme on breast cancer mortality.

Although breast cancer screening has been shown to work in randomised trials, there is a need to evaluate service screening programmes to ensure that they are delivering the benefit indicated by the trials. We carried out a case-control study to investigate the effect of mammography service screening, in the NHS breast screening programme, on breast cancer mortality in the East Anglian region of the UK. Cases were deaths from breast cancer in women diagnosed between the ages of 50 and 70 years, following the instigation of the East Anglia Breast Screening Programme in 1989. The controls were women (two per case) who had not died of breast cancer, from the same area, matched by date of birth to the cases. Each control was known to be alive at the time of death of her matched case. All women were known to the breast screening programme and were invited, at least once, to be screened. There were 284 cases and 568 controls. The odds ratio (OR) for risk of death from breast cancer in women who attended at least one routine screen compared to those who did not attend was 0.35 (CI: 0.24, 0.50). Adjusting for self-selection bias gave an estimate of the breast cancer mortality reduction associated with invitation to screening of 35% (OR=0.65, 95% CI: 0.48, 0.88). The effect of actually being screened was a 48% breast cancer mortality reduction (OR=0.52, 95% CI: 0.32, 0.84). The results suggest that the National Breast Screening Programme in East Anglia is achieving a reduction in breast cancer deaths, which is at least consistent with the results from the randomised controlled trials of mammographic screening.

Effects of specialisation on treatment and outcomes in screen-detected breast cancers in Wales: cohort study.

Volume-outcome relationships have been found for management of symptomatic but not for screen-detected, breast cancers. The study included 2705 patients with breast cancer detected by the Welsh breast cancer-screening programme from its inception in 1989 to 1997. Survival was tracked until 1999. Data validity was assessed for 10% of subjects. Hospitals' and surgeons' annual patient volumes were calculated as indices of specialisation. Effects of hospital and surgeon volumes on survival were estimated using Cox regression. Surgeons' and hospitals' volumes ranged from 1 to 90, and 1 to 86 patients, respectively. Patients managed by higher volume surgeons survived significantly longer (adjusted hazards ratio for a volume difference of 10 patients per year=0.90 (95% confidence intervals 0.84-0.97)). The adjusted hazard ratio for breast cancer survival was similar (0.91 (95% confidence intervals 0.82-1.00)). This association decreased over time. Patients of higher volume surgeons were significantly more likely to have axillary surgery and impalpable excision biopsies and were less likely to have mastectomy or radiotherapy. Surgeons' specialisation in management of screen-detected breast cancers was associated with longer survival, but this effect appeared to decrease over time.

Audit of negative assessments in a breast-screening programme in women who later develop breast cancer-implications for survival.

The aim of this study was to examine observed short-term survival, to estimate future survival, and to assess the impact on survival of amending procedures to avoid false negatives in women recalled for further assessment due to a suspicious screening mammogram. From the start of screening in the seven centres in the East Anglian region, 1 April 1989 to 31 December 1999, 503493 women from a total population of 2.2 million were screened, 25346 were recalled for an assessment and 3689 were diagnosed with breast cancer. Of the 21657 women given a negative result at these assessments, 193 women were subsequently diagnosed with 194 breast tumours at the site previously assessed. These women were followed up for survival, with survival analysis adjusting for host and tumour attributes. We also predicted long-term survival using the pathological features of the tumours diagnosed. From previous estimates of tumour progression rates, we estimated the reduction in incidence of advanced tumours and the potential saving of lives had unsatisfactory assessments been carried out within guidelines. There were 17 deaths, 15 in women who had unsatisfactory assessments. Five-year survival was estimated at 93% (95% CI: 88-97%) for breast cancer and 91% (95% CI: 86-95%) for all cause deaths. Women with positive nodes and/or larger tumours had significantly worse survival. Twenty years survival for women with unsatisfactory assessments was estimated at 66% (35 deaths) and predicted a potential saving of 7-9 lives (14-18% reduction in expected fatality within this special tumour population) had original assessments been carried out within current guidelines. This retrospective audit of a small and special tumour population shows a potential reduction in breast cancer deaths of 18%, had current guidelines been available for the original assessments. Increased use of percutaneous biopsy in recent years should address the problem.

An audit of assessment procedures in women who develop breast cancer after a negative result.

OBJECTIVES: A case audit was undertaken to determine the extent to which the early diagnosis of cancer could be improved by better adherence to screening guidelines, and to estimate the effect that this might have on breast cancer survival. Although affecting only a small proportion of the cancers of the screening programme, this exercise had an educational function for screening radiologists. SETTING: The East Anglian breast screening programme, a group of seven centres offering screening to a total population of 2.2 million inhabitants. Women were screened every three years between the ages of 50 and 64. METHODS: Adherence to the guidelines of the UK National Breast Screening Programme (as published in 2001) was tested in women assessed between the start of screening on 1 April 1989 and 31 December 1999, in cases where the screen was negative but who were subsequently diagnosed with breast cancer. RESULTS: In this period the programme screened 503,493 women, recalled 25,346 and diagnosed 3689 with cancer. 194 cancers in 193 women were reviewed, comprising those cancers that arose at the site of the lesion previously assessed. 96 women (49.5%) had calcifications, 48 (24.7%) had opacities. 139 of 194 cases were judged to have been inadequately assessed. A recurring theme showed that biopsies not undertaken or with false negative findings led to failure to diagnose lesions which were subsequently shown to be cancer. Microcalcifications and opacities were more likely to have been inadequately assessed than spiculate masses, parenchymal deformities, or asymmetric densities. In the earliest time period (1989-1993), there were a larger proportion of inadequately assessed cases than in the period 1994-1999. CONCLUSION: Scrupulous adherence to good guidelines will result in a greater proportion of cancers being diagnosed. Failure to perform effective percutaneous biopsy was the usual cause of missed diagnoses. Although an infrequent occurrence this may have an effect on subsequent survival from breast cancer.

Medical or surgical treatment for chronic gastrooesophageal reflux? A systematic review of published evidence of effectiveness.

OBJECTIVE: To compare the effectiveness of medical (antacids, histamine antagonists and proton pump inhibitors) and surgical (fundoplication) treatment of chronic GORD. SUBJECTS: Patients with objective (endoscopic or pH) evidence of chronic reflux reported in 6 randomised trials and 3 cohort studies, 1966-1999. METHODS: Systematic review of comparative studies identified from electronic searches, citations, manual searches of journals, and correspondence with authors and experts. MAIN OUTCOME MEASURES: Improvements in prevalence or severity of symptoms, oesophagitis, pH reflux duration, lower oesophageal sphincter pressure, patients' satisfaction, and side-effects. RESULTS: Improved outcomes were more common after surgical than medical treatment with significant differences in objective outcomes in 5/6 randomised trials and in 2/3 cohort studies. Subjective outcomes (symptoms and patients' satisfaction) were also more common among surgical patients in all but one study that assessed them. Odds ratios for improvement with surgical rather than medical treatment ranged from 1.2 to 200, and numbers needed to treat ranged from 1.2 to 58, where these could be calculated. Studies were too heterogeneous for meta-analysis. CONCLUSIONS: In trials of chronic severe GORD, surgery is consistently more effective than medical treatment in relieving symptoms and objective oesophagitis, although omeprazole can give similar symptom relief with adjustment of the dose.

Two populations of tyrosine hydroxylase-positive cells occur in the spinal cord of the chick embryo and hatchling.

The existence of tyrosine hydroxylase (TH)-containing neurons in the spinal cord of the chick embryo was investigated by anti-TH immunocytochemistry. Two populations of intensely immunostained cells were observed along the entire extent of the cord, beginning late in chick embryogenesis. One group of TH-positive cells was particularly numerous and found ventral to the central canal. The other group, which was smaller in number, was located along the superficial and lateral border of the dorsal horn of the spinal cord. When examined by the glyoxylic acid histofluorescence technique, cells could be visualized only very infrequently ventral to the central canal, and not at all within the dorsal horn. However, after pretreatment of hatchlings with the catecholamine synthesis precursor L-DOPA, cells ventral to the canal were readily observed by histofluorescence, while the dorsally located cells seldom visualized. Since these populations of TH-positive cells appear to only partially express the catecholaminergic phenotype, these cells may provide a model in which factors regulating the expression of neurotransmitter phenotypes can be examined in neurons of the developing CNS.

Analysis of the change in number of serotonergic neurons in the chick spinal cord during embryonic development.

The existence of serotonin (5-HT)-containing neurons in the spinal cord of the chick embryo was examined by anti-5-HT immunocytochemistry. The first immunoreactive cells were observed in embryos at 7 days of incubation (E7) and were initially located within the floor plate of the early spinal cord. By E9, immunostained cells occurred throughout the length of the spinal cord and were frequently encountered in most transverse sections of the cord. When examined at later embryonic ages of E12, 17 and at hatching (E21 or 22), the 5-HT cells became progressively more difficult to find with the advancing age of the embryos. To determine if this population of spinal cord 5-HT neurons actually diminished during development, a detailed quantitative analysis was undertaken to estimate the number of 5-HT cells in the cord of chick embryos at different ages. The results of this investigation demonstrated that the size of the 5-HT neuronal population rose rapidly from E7 and plateaued (at approximately 3500 neurons) between E9 and E12. As anticipated, the number of 5-HT cells at E17 decreased at all cord levels. Surprisingly, however, the number of spinal cord 5-HT neurons at hatching increased (depending on the cord level) either back to, or above, the counts estimated for the earlier ages of E9 and E12. Therefore, cells expressing the 5-HT phenotype in the spinal cord of the chick embryo persist throughout the period of embryonic development, rather than appear transiently.(ABSTRACT TRUNCATED AT 250 WORDS)