Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial.

BACKGROUND: The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40-48 years on breast cancer mortality. METHODS: We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39-41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151. FINDINGS: 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8-24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58-0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79-1·22]; p=0·86). INTERPRETATION: Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality. FUNDING: National Institute for Health Research Health Technology Assessment programme.

A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. OBJECTIVE: To determine whether PSA screening decreases PCa mortality for up to 16yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. DESIGN, SETTING, AND PARTICIPANTS: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), selected from population registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. RESULTS AND LIMITATIONS: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently. CONCLUSIONS: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level. PATIENT SUMMARY: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer.

Comparing CISNET Breast Cancer Incidence and Mortality Predictions to Observed Clinical Trial Results of Mammography Screening from Ages 40 to 49.

BACKGROUND: The UK Age trial compared annual mammography screening of women ages 40 to 49 years with no screening and found a statistically significant breast cancer mortality reduction at the 10-year follow-up but not at the 17-year follow-up. The objective of this study was to compare the observed Age trial results with the Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer model predicted results. METHODS: Five established CISNET breast cancer models used data on population demographics, screening attendance, and mammography performance from the Age trial together with extant natural history parameters to project breast cancer incidence and mortality in the control and intervention arm of the trial. RESULTS: The models closely reproduced the effect of annual screening from ages 40 to 49 years on breast cancer incidence. Restricted to breast cancer deaths originating from cancers diagnosed during the intervention phase, the models estimated an average 15% (range across models, 13% to 17%) breast cancer mortality reduction at the 10-year follow-up compared with 25% (95% CI, 3% to 42%) observed in the trial. At the 17-year follow-up, the models predicted 13% (range, 10% to 17%) reduction in breast cancer mortality compared with the non-significant 12% (95% CI, -4% to 26%) in the trial. CONCLUSIONS: The models underestimated the effect of screening on breast cancer mortality at the 10-year follow-up. Overall, the models captured the observed long-term effect of screening from age 40 to 49 years on breast cancer incidence and mortality in the UK Age trial, suggesting that the model structures, input parameters, and assumptions about breast cancer natural history are reasonable for estimating the impact of screening on mortality in this age group.

The contribution of a negative colorectal screening test result to symptom appraisal and help-seeking behaviour among patients subsequently diagnosed with an interval colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) screening programmes using a guaiac faecal occult blood test (gFOBt) reduce CRC mortality. Interval cancers are diagnosed between screening rounds: reassurance from a negative gFOBt has the potential to influence the pathway to diagnosis of an interval colorectal cancer. METHODS: Twenty-six semi-structured face-to-face interviews were carried out in Scotland and England, with individuals diagnosed with an interval colorectal cancer following a negative gFOBt result. RESULTS: Participants reported they were reassured by a negative gFOBt, interpreting their result as an "all clear". Therefore, most did not suspect cancer as a possible cause of symptoms and many did not recall their screening result during symptom appraisal. Among those who did consider cancer, and did think about their screening test result, reassurance from a negative gFOBt led some to "downplay" the seriousness of their symptoms with some interviewees explicitly stating that their negative test result contributed to a delayed decision to seek help. CONCLUSION: Screening participants need to be informed of the limitations of screening and the ongoing risk of developing colorectal cancer even when in receipt of a negative result: the importance of minimizing delay in seeking medical advice for colorectal symptoms should be emphasized.

The efficacy of prostate-specific antigen screening: Impact of key components in the ERSPC and PLCO trials.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The US Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates. METHODS: The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials. RESULTS: Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0. CONCLUSIONS: The observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results. Cancer 2018;124:1197-206. © 2017 American Cancer Society.

Reconciling the Effects of Screening on Prostate Cancer Mortality in the ERSPC and PLCO Trials.

BACKGROUND: The ERSPC (European Randomized Study of Screening for Prostate Cancer) found that screening reduced prostate cancer mortality, but the PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) found no reduction. OBJECTIVE: To evaluate whether effects of screening on prostate cancer mortality relative to no screening differed between the ERSPC and PLCO. DESIGN: Cox regression of prostate cancer death in each trial group, adjusted for age and trial. Extended analyses accounted for increased incidence due to screening and diagnostic work-up in each group via mean lead times (MLTs), which were estimated empirically and using analytic or microsimulation models. SETTING: Randomized controlled trials in Europe and the United States. PARTICIPANTS: Men aged 55 to 69 (ERSPC) or 55 to 74 (PLCO) years at randomization. INTERVENTION: Prostate cancer screening. MEASUREMENTS: Prostate cancer incidence and survival from randomization; prostate cancer incidence in the United States before screening began. RESULTS: Estimated MLTs were similar in the ERSPC and PLCO intervention groups but were longer in the PLCO control group than the ERSPC control group. Extended analyses found no evidence that effects of screening differed between trials (P = 0.37 to 0.47 [range across MLT estimation approaches]) but strong evidence that benefit increased with MLT (P = 0.0027 to 0.0032). Screening was estimated to confer a 7% to 9% reduction in the risk for prostate cancer death per year of MLT. This translated into estimates of 25% to 31% and 27% to 32% lower risk for prostate cancer death with screening as performed in the ERSPC and PLCO intervention groups, respectively, compared with no screening. LIMITATION: The MLT is a simple metric of screening and diagnostic work-up. CONCLUSION: After differences in implementation and settings are accounted for, the ERSPC and PLCO provide compatible evidence that screening reduces prostate cancer mortality. PRIMARY FUNDING SOURCE: National Cancer Institute.

Design-corrected variation by centre in mortality reduction in the ERSPC randomised prostate cancer screening trial.

Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years' follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.

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.

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

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

Absolute Effect of Prostate Cancer Screening: Balance of Benefits and Harms by Center within the European Randomized Study of Prostate Cancer Screening.

PURPOSE: The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening (ERSPC). EXPERIMENTAL DESIGN: We analyzed the absolute mortality reduction expressed as number needed to invite (NNI = 1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO = 1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. RESULTS: Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI, 200-7,000 and NNO, 16-69. Extent of overdiagnosis and mortality reduction was closely associated [correlation coefficient, r = 0.76; weighted linear regression coefficient, ß = 33; 95% confidence interval (CI), 5-62; R(2) = 0.72]. For an averted prostate cancer death at 13 years of follow-up, 12 to 36 excess cases had to be detected in various centers. CONCLUSIONS: The differences between the ERSPC centers likely reflect variations in prostate cancer incidence and mortality, as well as in screening protocol and performance. The strong interrelation between the benefits and harms suggests that efforts to maximize the mortality effect are bound to increase overdiagnosis and might be improved by focusing on high-risk populations. The optimal balance between screening intensity and risk of overdiagnosis remains unclear.

Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial.

BACKGROUND: Age-specific effects of mammographic screening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, which compared the effect of invitation to annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no significant difference in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up. METHODS: Women aged 39-41 from 23 UK NHS Breast Screening Programme units years were randomly assigned by individual randomisation (1:2) to either an intervention group offered annual screening by mammography up to and including the calendar year of their 48th birthday or to a control group receiving usual medical care (invited for screening at age 50 years and every 3 years thereafter). Both groups were stratified by general practice. We compared breast cancer incidence and mortality by time since randomisation. Analyses included all women randomly assigned who could be traced with the National Health Service Central Register and who had not died or emigrated before entry. The primary outcome measures were mortality from breast cancer (defined as deaths with breast cancer coded as the underlying cause of death) and breast cancer incidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of the mortality effect, we analysed the results in different follow-up periods. This trial is registered, number ISRCTN24647151. FINDINGS: Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants were randomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical care were included in this analysis. After a median follow-up of 17 years (IQR 16·8-18·8), the rate ratio (RR) for breast cancer mortality was 0·88 (95% CI 0·74-1·04) from tumours diagnosed during the intervention phase. A significant reduction in breast cancer mortality was noted in the intervention group compared with the control group in the first 10 years after diagnosis (RR 0·75, 0·58-0·97) but not thereafter (RR 1·02, 0·80-1·30) from tumours diagnosed during the intervention phase. The overall breast cancer incidence during 17 year follow-up was similar between the intervention group and the control group (RR 0·98, 0·93-1·04). INTERPRETATION: Our results support an early reduction in mortality from breast cancer with annual mammography screening in women aged 40-49 years. Further data are needed to fully understand long-term effects. Cumulative incidence figures suggest at worst a small amount of overdiagnosis. FUNDING: National Institute for Health Research Health Technology Assessment programme and the American Cancer Society. Past funding was received from the Medical Research Council, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute.

Case-control Studies on the Effectiveness of Breast Cancer Screening: Insights from the UK Age Trial.

BACKGROUND: Ongoing breast cancer screening programs can only be evaluated using observational study designs. Most studies have observed a reduction in breast cancer mortality, but design differences appear to have resulted in different estimates. Direct comparison of case-control and trial analyses gives more insight into this variation. Here, we performed case-control analyses within the randomized UK Age Trial. METHODS: The Age Trial assessed the effect of screening on breast cancer mortality in women ages 40-49 years. In our approach, case subjects were defined as breast cancer deaths between trial entry (1991-1997) and 2004. Women were ages 39-41 years at entry. For every case subject, five control subjects were selected. All case subjects were included in analyses of screening invitation (356 case subjects, 1,780 controls), whereas analyses of attendance were restricted to women invited to screening (105 case subjects, 525 age-matched controls). Odds ratios (OR) were estimated with conditional logistic regression. We used and compared two methods to correct for self-selection bias. RESULTS: Screening invitation resulted in a breast cancer mortality reduction of 17% (95% confidence interval [CI]: -36%, +6%), similar to trial results. Different exposure definitions and self-selection adjustments influenced the observed breast cancer mortality reduction. Depending on the method, "ever screened" appeared to be associated with a small reduction (OR: 0.86, 95% CI: 0.40, 1.89) or no reduction (OR: 1.02, 95% CI: 0.48, 2.14) using the two methods of correction. Recent attendance resulted in an adjusted mortality reduction of 36% (95% CI: -69%, +31%) or 45% (95% CI: -71%, +5%). CONCLUSIONS: Observational studies, and particularly case-control studies, are an important monitoring tool for breast cancer screening programs. The focus should be on diminishing bias in observational studies and gaining a better understanding of the influence of study design on estimates of mortality reduction.

Metastatic Prostate Cancer Incidence and Prostate-specific Antigen Testing: New Insights from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality. DESIGN, SETTING, AND PARTICIPANTS: Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. RESULTS AND LIMITATIONS: In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. CONCLUSIONS: The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. PATIENT SUMMARY: The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

Colonoscopic factors associated with adenoma detection in a national colorectal cancer screening program.

BACKGROUND AND STUDY AIMS: Adenoma detection is a key objective of colonoscopy, particularly in the context of colorectal cancer screening. The aim of this observational study was to identify the technical colonoscopy factors associated with adenoma detection. PATIENTS AND METHODS: The study analyzed data from the English Bowel Cancer Screening Programme. The indication for all colonoscopies was a positive fecal occult blood test. The relationships between the following colonoscopy factors and adenoma detection (one or more adenomas, advanced adenomas, right-sided adenomas, and total number of adenomas) were examined in multivariable analyses: bowel preparation quality, cecal intubation, withdrawal time, rectal retroversion, colonoscopist experience, antispasmodic use, sedation use, and start time of procedure. The following patient factors were controlled for: age, sex, body mass index, smoking, alcohol, deprivation, and geographical location. RESULTS: A total of 31088 colonoscopies were analyzed. The following technical factors increased the relative risk of adenoma detection (P < 0.001 in multivariable analysis unless otherwise stated): cecal intubation, increased withdrawal time, higher quality bowel preparation, intravenous antispasmodic use, earlier procedure start time within a session (P = 0.018), and greater colonoscopist experience. Detection of advanced and right-sided adenomas also increased with these factors. Adenoma detection did not differ between sedated and unsedated colonoscopy (P = 0.143). CONCLUSION: This study demonstrated important associations between colonoscopy practice and adenoma detection. Use of intravenous antispasmodic was associated with increased adenoma detection. The effect of the start time of colonoscopy suggests that endoscopist fatigue may have a deleterious impact on adenoma detection.

Prostate-specific antigen-based prostate cancer screening: reduction of prostate cancer mortality after correction for nonattendance and contamination in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Large randomized screening trials provide an estimation of the effect of screening at a population-based level. The effect of screening for individuals, however, is diluted by nonattendance and contamination in the trial arms. OBJECTIVE: To determine the prostate cancer (PCa) mortality reduction from screening after adjustment for nonattendance and contamination. DESIGN, SETTING, AND PARTICIPANTS: A total of 34,833 men in the core age group, 55-69 yr, were randomized to a screening or control arm in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). Prostate-specific antigen (PSA) testing was offered to all men in the screening arm at 4-yr intervals. A prostate biopsy was offered to men with an elevated PSA. The primary end point was PCa-specific mortality. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Nonattendance was defined as nonparticipation in the screening arm. Contamination in the control arm was defined as receiving asymptomatic PSA testing or a prostate biopsy in the absence of symptoms. Relative risks (RRs) were calculated with an intention to screen (ITS) analysis and after correction for nonattendance and contamination using a method that preserves the benefits obtained by randomization. RESULTS AND LIMITATIONS: The ITS analysis resulted in an RR of 0.68 (95% confidence interval [CI], 0.53-0.89) in favor of screening at a median follow-up of 13 yr. Correction for both nonattendance and contamination resulted in an RR of 0.49 (95% CI, 0.27-0.87) in favor of screening. CONCLUSIONS: PCa screening as conducted in the Rotterdam section of the ERSPC can reduce the risk of dying from PCa up to 51% for an individual man choosing to be screened repeatedly compared with a man who was not screened. This benefit of screening should be balanced against the harms of overdiagnosis and subsequent overtreatment. TRIAL REGISTRATION: ISRCTN49127736.

Screening and primary prevention of colorectal cancer: a review of sex-specific and site-specific differences.

BACKGROUND: Colorectal cancer (CRC) is the second commonest cancer in England. Incidence rates for colorectal adenomas and advanced colorectal neoplasia are higher in men than in women of all age groups. The male-to-female ratio for CRC incidence rates differs for different parts of the large bowel. OBJECTIVE: To summarize the current evidence on colorectal screening and prevention, focussing on potential differences in benefits between sexes and colorectal sites. METHODS (I): , We reviewed the evidence from randomized controlled trials (RCTs) of the impact of different screening approaches on CRC incidence and mortality, overall, for each sex separately, and for subsites of the large bowel. (ii) We reviewed studies comparing detection parameters for faecal immunochemical tests for haemoglobin (FIT) with guaiac FOBt (gFOBt). (iii) The role of aspirin in CRC prevention in the general population was reviewed using evidence from RCTs, with specific emphasis on the differences observed between sexes and lesion site. RESULTS: (i) Our intention-to-treat random-effects meta-analysis showed that once-only flexible sigmoidoscopy (FS) screening performed on average-risk individuals aged 55 + decreased CRC incidence by 18% and mortality by 28%, but sex-specific results were lacking. (ii) Modern quantitative FIT were superior to qualitative gFOBt in average-risk population screening in their ability to discriminate between individuals with and without colorectal neoplasia. Some recent FIT studies suggest varying operating characteristics in men and women. (iii) Evidence of an effect of aspirin on the incidence of CRC (in particular, proximal disease) in both sexes aged 40 and over at average-risk of CRC is emerging. CONCLUSIONS: We encourage researchers of CRC screening and prevention to publish their results by sex where possible. Pilot studies should be undertaken before implementation of quantitative FIT in a national screening programme to establish the appropriate threshold. Finally, individual risk assessment for CRC and non-CRC events, will be necessary to make an informed decision on whether a patient should receive aspirin chemoprevention.

Excess all-cause mortality in the evaluation of a screening trial to account for selective participation.

OBJECTIVE: In addition to disease-specific mortality, a randomized controlled cancer screening trial may be evaluated in terms of excess mortality, in which case no patient-specific information on causes of death is needed. We studied the effect of not accounting for attendance on the calculated excess mortality in a prostate cancer screening trial. METHODS: The numerator of the excess mortality rate related to prostate cancer diagnoses in each study arm equals the excess number of deaths observed in the cancer patients. The estimation of the expected number of deaths in the absence of the prostate cancer diagnoses has to account for the self-selection of those participating in the trial, particularly if the proportion of non-participants is substantial. SETTING: The European prostate cancer screening trial (ERSPC). RESULTS: In the screening arm, non-attendees had roughly twice the mortality rate of attendees. Approximately twice as many cancers were detected in the screening arm compared with the control arm, primarily in attendees. Unless attendance is properly accounted for, the expected mortality of prostate cancer patients in the screening arm is overestimated by 0.9-3.6 deaths per 1000 person-years. CONCLUSIONS: Attendees have a lower all-cause mortality rate (are healthier) and a higher probability of a prostate cancer diagnosis than non-attendees and the men randomized to the control arm. If attendance is not accounted for, the excess mortality and the between-arm excess mortality rate ratio are underestimated and screening is considered more effective than it actually is. These effects may be sizeable, notably if non-attendance is common. Correcting for attendance status is important in the calculation of the excess mortality rate in prostate cancer patients that can be used in conjunction with a disease-specific mortality analysis in a randomized controlled cancer screening trial.

Impacts of a population-based prostate cancer screening programme on excess total mortality rates in men with prostate cancer: a randomized controlled trial.

OBJECTIVES: To assess the effect of screening in terms of excess mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). METHODS: A total of 141,578 men aged 55­69 were randomized to systematic screening or usual care in ERSPC sections in Finland, Italy, the Netherlands and Sweden. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC)patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a diagnosis with PC adjusted for study centre,study arm and study attendance. The excess mortality rates were compared between the two study arms. RESULTS: The PC incidence was 9.25 per 1000 person-years in the intervention arm and 5.49 per 1000 person-years in the control arm, relative risk (RR) 1.69 (95% confidence interval [CI]1.62­1.76). The excess mortality among men with PC was 0.29 per 1000 person-years in the intervention arm and 0.37 per 1000 person-years in the control arm; the RR for excess mortality was 0.77 (95% CI 0.55­1.08). The absolute risk reduction in the excess mortality was 0.08 per 1000 person-years. The overall mortality was not significantly different between the intervention and the control arms of the study: RR 0.99 (95% CI 0.96­1.01). CONCLUSIONS: Although the reduction in excess mortality was not statistically significant, the between arm reduction in excess mortality rate was in line with the previously reported 20% reduction in the disease-specific mortality. This finding indicates that the reduction in PC mortality in the ERSPC trial cannot be due to a bias in cause of death adjudication.