Prostate-cancer mortality at 11 years of follow-up.

BACKGROUND: Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS: The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS: After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS: Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

Quality-of-life effects of prostate-specific antigen screening.

BACKGROUND: After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. METHODS: On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. RESULTS: Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). CONCLUSIONS: The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.).

Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study.

BACKGROUND: Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening. METHODS: Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases-2D only and integrated 2D and 3D mammography-yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar's test. FINDINGS: 7292 women were screened (median age 58 years [IQR 54-63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p<0.0001). Cancer detection rates were 5.3 cancers per 1000 screens (95% CI 3.8-7.3) for 2D only, and 8.1 cancers per 1000 screens (6.2-10.4) for integrated 2D and 3D screening. The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2.7 cancers per 1000 screens (1.7-4.2). 395 screens (5.5%; 95% CI 5.0-6.0) resulted in false positive recalls: 181 at both screen reads, and 141 with 2D only versus 73 with integrated 2D and 3D screening (p<0.0001). We estimated that conditional recall (positive integrated 2D and 3D mammography as a condition to recall) could have reduced false positive recalls by 17.2% (95% CI 13.6-21.3) without missing any of the cancers detected in the study population. INTERPRETATION: Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening. FUNDING: National Breast Cancer Foundation, Australia; National Health and Medical Research Council, Australia; Hologic, USA; Technologic, Italy.

Accuracy of tumour size assessment in the preoperative staging of breast cancer: comparison of digital mammography, tomosynthesis, ultrasound and MRI.

PURPOSE: Accurate measurement of breast tumour size is fundamental for treatment planning. We compared the accuracy of digital mammography (DM), digital breast tomosynthesis (DBT), ultrasound (US) and magnetic resonance imaging (MRI) for the preoperative evaluation of breast cancer size. MATERIALS AND METHODS: We retrospectively reviewed 149 breast cancers in 110 patients who underwent DM, DBT, US and MRI between January 2010 and December 2011, before definitive surgery. The lesions were measured by two radiologists, without knowledge of the final histological examination, considered the gold standard. For each imaging modality, the maximum tumour size was measured to the nearest millimetre; the measurements were considered concordant if they were within ± 5 mm. Pearson's correlation coefficient was calculated for each imaging modality. RESULTS: The median pathological tumour size was 22.3 mm. MRI and DBT had a level of concordance with pathology of 70% and 66%, respectively, which was higher than that of DM (54%). DBT and MRI measurements had a better correlation with pathological tumour size (R:0.89 and R:0.92, respectively) compared to DM (R:0.83) and US (R:0.77). CONCLUSIONS: DBT and MRI are superior to DM and US in the preoperative assessment of breast tumour size. DBT seems to improve the accuracy of DM, although MRI remains the most accurate imaging modality for breast cancer extension.

Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA).

As the mean age of the global population increases, breast cancer in older individuals will be increasingly encountered in clinical practice. Management decisions should not be based on age alone. Establishing recommendations for management of older individuals with breast cancer is challenging because of very limited level 1 evidence in this heterogeneous population. In 2007, the International Society of Geriatric Oncology (SIOG) created a task force to provide evidence-based recommendations for the management of breast cancer in elderly individuals. In 2010, a multidisciplinary SIOG and European Society of Breast Cancer Specialists (EUSOMA) task force gathered to expand and update the 2007 recommendations. The recommendations were expanded to include geriatric assessment, competing causes of mortality, ductal carcinoma in situ, drug safety and compliance, patient preferences, barriers to treatment, and male breast cancer. Recommendations were updated for screening, primary endocrine therapy, surgery, radiotherapy, neoadjuvant and adjuvant systemic therapy, and metastatic breast cancer.

Screening and prostate-cancer mortality in a randomized European study.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

Prospective study of breast tomosynthesis as a triage to assessment in screening.

There is limited evidence on the role of 3D mammography with tomosynthesis in breast screening, although early studies suggest that it may improve specificity. We prospectively evaluated the effect of integrating 3D mammography as a triage to assessment in 158 consecutive recalls to assessment (recalled in standard 2D-mammographic screening) in asymptomatic subjects. Radiologists provided 3D mammography-based opinion as to whether recall/assessment was warranted or unnecessary, and all subjects proceeded to assessment. 3D triage was positive (confirmed the need for assessment) in all 21 subjects with breast cancer (there were no false negatives), and would have avoided recall in 102 of 137 (74.4%) subjects with a negative/benign final outcome in whom 3D triage did not recommend recall. Proportion of true negative 3D triage (as a proxy for potential reduction in recalls) was slightly higher in dense than non-dense breasts, did not differ across age-groups, but was significantly associated with the type of lesion seen on imaging (being highest for distortions, asymmetric densities, and lesions with ill-defined margins). While the simulation design may have over-estimated the potential for 3D mammography triage to reduce recalls, this study clearly demonstrates its capability to improve breast screening specificity and to reduce recall rates. Future studies of 3D mammography should further assess its role as a recall-reducing strategy in screening practice and should include formal cost-analysis.

Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla.

OBJECTIVE: Systematic evidence synthesis of ultrasound-guided needle biopsy (UNB) of axillary nodes in breast cancer. SUMMARY BACKGROUND DATA: Women affected by invasive breast cancer undergo initial staging with sentinel node biopsy, generally progressing to axillary node dissection (AND) if metastases are found. Preoperative UNB can potentially identify and triage women with node metastases directly to AND. METHODS: Review and meta-analysis of studies reporting UNB accuracy: we estimated sensitivity, specificity, and PPV, using bivariate random-effects models and examined the effect of covariates; we calculated UNB utility (effect on axillary surgery). RESULTS: Thirty-one studies provided 2874 UNB data from 6166 subjects (median proportion with metastatic nodes 47.2%; IQR 39.5%, 61.2%). Modeled estimates for UNB were: sensitivity 79.6% (95% confidence intervals [CI] 74.1-84.2), specificity 98.3% (95%CI 97.2-99.0), PPV 97.1% (95%CI 95.2-98.3); median UNB insufficiency was 4.1% (IQR0%-10.9%). UNB sensitivity increased with increasing ultrasound sensitivity, and was higher in studies performing UNB for "suspicious" than for "visible" nodes. Specificity was higher in studies of consecutive (vs. selected) subjects, in studies reporting ultrasound data, and in more recent studies. Median proportion of women triaged directly to AND (attributed to UNB) was 19.8% (IQR11.6%-28.1%) or 17.7% (IQR11.6%-27.1%) if restricted to clinically node-negative series. Median proportion of women with metastatic axillary nodes potentially triaged to AND was 55.2% (IQR41.8%-68.2%) and was higher (65.6%; IQR48.9%-69.7%) in the subgroup of studies with median tumor size ≥21 mm. CONCLUSIONS: Preoperative UNB of the axilla is accurate for initial staging of women with invasive breast cancer. Meta-analysis indicates that UNB provides better utility in women with average or higher underlying risk of node metastases.

Ductal carcinoma in situ at core-needle biopsy: meta-analysis of underestimation and predictors of invasive breast cancer.

PURPOSE: To perform a meta-analysis to report pooled estimates for underestimation of invasive breast cancer (where core-needle biopsy [CNB] shows ductal carcinoma in situ [DCIS] and excision histologic examination shows invasive breast cancer) and to identify preoperative variables that predict invasive breast cancer. MATERIALS AND METHODS: Studies were identified by searching MEDLINE and were included if they provided data on DCIS underestimates (overall and according to preoperative variables). Study-specific and pooled percentages for DCIS underestimates were calculated. By using meta-regression (random effects logistic modeling) the association between each study-level preoperative variable and understaged invasive breast cancer was investigated. RESULTS: Fifty-two studies that included 7350 cases of DCIS with findings at excision histologic examination as the reference standard met the eligibility criteria and were included. There were 1736 underestimates (invasive breast cancer at excision); the random-effects pooled estimate was 25.9% (95% confidence interval: 22.5%, 29.5%). Preoperative variables that showed significant univariate association with higher underestimation included the use of a 14-gauge automated device (vs 11-gauge vacuum-assisted biopsy, P = .006), high-grade lesion at CNB (vs non-high grade lesion, P < .001), lesion size larger than 20 mm at imaging (vs lesions ≤ 20 mm, P < .001), Breast Imaging Reporting and Data System (BI-RADS) score of 4 or 5 (vs BI-RADS score of 3, P for trend = .005), mammographic mass (vs calcification only, P < .001), and palpability (P < .001). CONCLUSION: About one in four DCIS diagnoses at CNB represent understaged invasive breast cancer. Preoperative variables significantly associated with understaging include biopsy device and guidance method, size, grade, mammographic features, and palpability.

Accuracy of a preoperative model for predicting invasive breast cancer in women with ductal carcinoma-in-situ on vacuum-assisted core needle biopsy.

BACKGROUND: Core needle biopsy (CNB) diagnoses of ductal carcinoma-in-situ (DCIS) may represent understaged invasive breast cancer (IBC). We aimed to develop a model that helps identify preoperatively women with IBC after a CNB diagnosis of DCIS. METHODS: Retrospective study of all women with DCIS on vacuum-assisted CNB of microcalcifications (1999-2008), with prospective classification of imaging variables independently by two radiologists. Variables included lesion size and level of suspicion on imaging, morphology and distribution of microcalcifications, DCIS nuclear grade on CNB, number of cores, and age. Multivariate logistic regression models of the probability of IBC were developed; the accuracy of these models was examined for each radiologist. RESULTS: Excision histology showed IBC in 77 (17.4%) of 442 subjects with DCIS on CNB. Lesion size on imaging yielded the best model fit and highest accuracy, and had the highest agreement between radiologists. Addition of grade to a model which included size improved model fit (P < 0.0001). However, model fit and accuracy were not improved by inclusion of any other variables. A model based on size and grade had similar areas under the receiver operating characteristic curve (accuracy of 74%) for each radiologist. Modeled sensitivity, specificity, and predictive values for different combinations of size and grade thresholds are reported. If the imaging lesion is >50 mm and the CNB grade is high, the model's positive predictive value is ≥50%. CONCLUSIONS: A model based on imaging size of microcalcifications and CNB nuclear grade can identify women at high risk of having IBC with moderate accuracy and may be used to guide informed preoperative discussion in women with newly diagnosed DCIS on CNB.

The evolving role of new imaging methods in breast screening.

The potential to avert breast cancer deaths through screening means that efforts continue to identify methods which may enhance early detection. While the role of most new imaging technologies remains in adjunct screening or in the work-up of mammography-detected abnormalities, some of the new breast imaging tests (such as MRI) have roles in screening groups of women defined by increased cancer risk. This paper highlights the evidence and the current role of new breast imaging technologies in screening, focusing on those that have broader application in population screening, including digital mammography, breast ultrasound in women with dense breasts, and computer-aided detection. It highlights that evidence on new imaging in screening comes mostly from non-randomised studies that have quantified test detection capability as adjunct to mammography, or have compared measures of screening performance for new technologies with that of conventional mammography. Two RCTs have provided high-quality evidence on the equivalence of digital and conventional mammography and on outcomes of screen-reading complemented by CAD. Many of these imaging technologies enhance cancer detection but also increase recall and false positives in screening.

Is conventional urinary cytology still reliable for diagnosis of primary bladder carcinoma? Accuracy based on data linkage of a consecutive clinical series and cancer registry.

OBJECTIVE: Reported urine cytology accuracy, particular sensitivity, is highly variable. We evaluated the accuracy of urinary cytology for primary bladder cancer using population data linkage to provide valid estimates. STUDY DESIGN: Consecutive cytology tests processed through a major service between January 2000 and December 2004 were linked to a regional population cancer registry (allowing outcome ascertainment). Sensitivity and specificity were calculated using different thresholds, based on standardized reporting categories (C1 = negative, C2 = reactive, C3 = atypical, C4 = suspicious, C5 = malignant, Cx = inadequate). RESULTS: Cancer registry matching of 2,594 tests revealed 130 incident bladder cancers, of which 97 occurred within 12 months of cytology and were included in calculating accuracy. Sensitivity (C3-C5 considered positive) ranged between 40.2 and 42.3%, and specificity was 93.7-94.1%. If C3 results are counted as negative, sensitivity estimates reduced to 24.7-26.0%. The positive predictive value of a C3, C4 or C5 report was 11.7, 39.2, and 66.6%, respectively. High tumor grade was associated with significantly higher sensitivity compared to low and intermediate grades combined (p = 0.02). CONCLUSION: Urine cytology is highly specific but has intermediate sensitivity, indicating that it has a role in adjunct diagnosis, but not in screening for primary bladder cancer. C3 results should be considered 'positive' and further investigated, and all positive results should prompt further intervention.

Influence of seasonal variations in ambient temperatures on performance of immunochemical faecal occult blood test for colorectal cancer screening: observational study from the Florence district.

BACKGROUND: Faecal occult blood testing (FOBT) in population screening has proved to be effective in reducing mortality from colorectal cancer. In Italy a latex agglutination FOBT has been adopted for a single-sample screening programme. The aim of this study was to examine the performance of FOBTs in the Florence screening programme over several seasons to evaluate the impact of variations in ambient temperature on the performance of the screening test. METHODS: Measured haemoglobin (Hb) concentrations were aggregated into seasons with their average ambient temperature (AAT). Using logistic regression, the AAT over the period preceding the test measurement was analysed. This period included the time between faecal sampling and return of the test sample (mean 7days) and the time in the laboratory refrigerator before analysis (mean 4days). The AAT from days 5-11 before analysis of the test sample was considered a determinant of test positivity. The Kruskal-Wallis rank test was used to evaluate the significance of seasonal and/or AAT-related differences in Hb concentration. A logistic regression model adjusted for sex, age, season and screening episode (first or repeated examination) was constructed. RESULTS: 199 654 FOBT results were examined. Mean FOBT seasonal Hb concentrations (ng/ml) were: spring 27.6 (95% CI 26.2 to 29.1); summer 25.2 (95% CI 23.1 to 27.3); autumn 29.2 (95% CI 27.7 to 30.6); winter 29.5 (95% CI 27.9 to 31.1). Logistic regression showed that there was a 17% lower probability of the FOBT being positive in summer than in winter. The results of the logistic regression showed that an increase in temperature of 1°C produced a 0.7% reduction in probability of a FOBT being positive. In the summer the probability of detecting a cancer or an advanced adenoma was about 13% lower than in the winter. CONCLUSIONS: This study showed that there is a significant fall in Hb concentration at higher ambient temperatures. These results will have important implications for the organisation of immunochemical FOBT-based screening programmes, particularly in countries with high ambient temperatures.

The effect of study arm on prostate cancer treatment in the large screening trial ERSPC.

Prostate cancer (PC) mortality is the most valid end-point in screening trials, but could be influenced by the choice of initial treatment if treatment has an effect on mortality. In this study, PC treatment was compared between the screening and control arms in a screening trial. Data were collected from the European Randomized Study of Screening for Prostate Cancer (ERSPC). The characteristics and initial treatment of PC cases detected in the screening and the control arm were compared. Polytomous logistic regression analysis was used to assess the influence of study arm on treatment, adjusting for potential confounders and with statistical imputation of missing values. A total of 8,389 PC cases were detected, 5,422 in the screening arm and 3,145 in the control arm. Polytomous regression showed that trial arm was associated with treatment choice after correction for missing values, especially in men with high-risk PC. A control subject with high-risk PC was more likely than a screen subject to receive radiotherapy (OR: 1.43, 95% CI: 1.01-2.05, p = 0.047), expectant management (OR: 2.92, 95% CI: 1.33-6.42, p = 0.007) or hormonal treatment (OR: 1.77, 95% CI: 1.07-2.94, p = 0.026) instead of radical prostatectomy. However, trial arm had only a minor role in treatment choice compared to other variables. In conclusion, a small effect of trial arm on treatment choice was seen, particularly in men with high-risk PC. Therefore, differences in treatment between arms are unlikely to play a major role in the interpretation of the results of the ERSPC.

Design-related bias in estimates of accuracy when comparing imaging tests: examples from breast imaging research.

This work highlights concepts on the potential for designrelated factors to bias estimates of test accuracy in comparative imaging research. We chose two design factors, selection of eligible subjects and the reference standard, to examine the effect of design limitations on estimates of accuracy. Estimates of sensitivity in a study of the comparative accuracy of mammography and ultrasound differed according to how subjects were selected. Comparison of a new imaging test with an existing test should distinguish whether the new test is to be used as a replacement for, or as an adjunct to, the conventional test, to guide the method for subject selection. Quality of the reference standard, examined in a meta-analysis of preoperative breast MRI, varied across studies and was associated with estimates of incremental accuracy. Potential solutions to deal with the reference standard are outlined where an ideal reference standard may not be available in all subjects. These examples of breast imaging research demonstrate that design-related bias, when comparing a new imaging test with a conventional imaging test, may bias accuracy in a direction that favours the new test by overestimating the accuracy of the new test or by underestimating that of the conventional test.

Interval cancers in breast cancer screening: comparison of stage and biological characteristics with screen-detected cancers or incident cancers in the absence of screening.

AIMS AND BACKGROUND: To analyze stage distribution and biological features of interval cancers observed in Verona mammography screening compared to screen-detected cancers and "clinical" cancers occurring in the absence of screening, as provided by the Veneto Cancer Registry. METHODS AND STUDY DESIGN: Screen-detected cancers were identified in the screening archives. Interval cancers and clinical cancers (occurring in women never screened or not yet invited) were identified through the local cancer registry. Studied variables were age, stage, pathological pT and pN category, histological grading, estrogen and progesterone receptor status, and proliferation index (Ki67). RESULTS: We compared 95 interval cancers, 761 screen-detected cancers, and 1873 clinical cancer cases. Interval cancers had more aggressive features than screen-detected cancers, the difference being statistically significant for pT (P=106), pN (P = 0.0003), grading (P = 0.007), estrogen receptors (P = 0.0006), and progesterone receptors (P = 0.00005), but not for Ki67 (P = 0.18). The features of interval cancers were not more aggressive than those of clinical cancers for pT (P = 0.84), pN (P = 0.33), grading (P = 0.61), estrogen receptors (P = 0.48), and progesterone receptors (P = 0.69), and were better for Ki67 (P = 0.02). In contrast, screen-detected cancers showed significantly better features than clinical cancers, for all studied variables: pT (P = 10(-6)), pN (P = 10(-6)), grading (P = 10(-6)), estrogen receptors (P = 10(-5)), progesterone receptors (P = 10(-6)), and Ki67 (P = 10(-6)). CONCLUSIONS: Our findings are consistent with the length biased sampling hypothesis of interval cancers having a faster growth rate and a less favorable presentation than screen-detected cancers. Compared to clinical cancers, interval cancers had similar features, whereas screen-detected cancers had definitely more favorable features. This finding suggests, rather than a faster growth rate for interval cancers, a slower growth rate for screen-detected cancers, which, together with diagnostic anticipation, may explain a certain degree of overdiagnosis.

Risk of CIN2 in women with a pap test without endocervical cells vs. those with a negative pap test with endocervical cells: a cohort study with 4.5 years of follow-up.

OBJECTIVE: To measure the risk of cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in the 4.5 years following a negative Pap smear with adequate endocervical cells (ECC) (+) or absent/scarce ECC (-). STUDY DESIGN: A prospective, nonconcurrent study of the archives of 11 Italian population-based screening programs was conducted. Only 25-50-year-old women with a first negative Pap test were included. RESULTS: Women were classified as ECC+ or ECC- and followed for 4.5 years. The endpoint was the occurrence of a CIN2+ histologic diagnosis. Eligible subjects with negative Pap tests ECC+ and ECC- numbered 469,694 and 20,596, respectively. At least 1 subsequent test was available during follow-up for 335,763 and 11,972 subjects, and 691 and 13 CIN2+ lesions were observed, respectively. The risk of CIN2+ was 2.06 and 1.09 per 1,000 women over 4.5 years, and age-adjusted relative risk associated with ECC--was 0.55 (95% CI 0.28-1.06). CONCLUSION: Women with a negative Pap ECC--have a lower risk of CIN2+ than women with a negative Pap ECC+ and should repeat screening with frequency (3-5 years in Europe), independent of age.

Misclassification of breast cancer as cause of death in a service screening area.

OBJECTIVE: The aim of this study was to assess the misclassification of cause of death for breast cancer cases, and to evaluate the differential misclassification between cases detected in an organized screening program and cases found in current clinical practice. METHODS: All deaths occurring between 1999 and 2002 within breast cancer cases were linked to hospital discharge records. Death certificates and latest available hospital discharge notes were classified into various categories. We created a classification algorithm defining which combinations of categories (of death certificates and hospital discharge notes) suggested the probability of misclassification and the need for an in-depth diagnostic review. Questionable cases were reviewed by a team of experts in order to reach a consensus on cause of death. Based on our algorithmic classification and diagnostic review results, the agreement between original cause of death and that resulting from the assessment process was analyzed stratifying for every variable of interest. RESULTS: According to death certificates, breast cancer was the cause of death in 66.9% of subjects, and after assessment this figure changed to 65.7%. The misclassification rate was 4.3% and did not differ significantly between screen-detected (4.7%) and non-screen-detected (4.3%) cases. Higher misclassification rates in favor of false positivity (cause of death wrongly attributed to breast cancer in death certificates) was observed for subjects with multiple cancers (6.5% vs. 1.9%), with no admission in the year before death (4.6% vs. 2.4%) and with an unknown cancer stage (4.9% vs 2.4% or 2.3%). CONCLUSIONS: The cause of death misclassification rate is modest, causing a slight overestimate of deaths attributed to breast cancer, and is not affected by modality of diagnosis. The study confirmed the validity of using cause-specific mortality for service screening evaluation.

Technical aspects of breast MRI--do they affect outcomes?

In a systematic review of breast MRI for assessing ipsilateral breast cancer to detect additional lesions, technical details were extracted from publications to assess their effect on diagnostic performance. Where technical parameters were complete, we examined their effect on summary ROC models, and the TP:FP ratio and PPV, using random-effects logistic regression. A total of 2,801 breasts in 19 publications underwent statistical analysis for year of study, slice thickness, and repetitions after contrast-medium injection. None were associated with TP/FP ratio. Summary ROC analysis provided weak evidence (P = 0.09) of an association between diagnostic performance and time period, however no trend over time. Tesla strength was reported in 2,801 cases. Other key information was omitted including whether both breasts were examined for 1683 (60%), position of the patient in 1,375 (49%), and imaging planes used in 688 (25%). Contrast agent and dose were reported for 2,646 (95%) breasts. Reporting technique was inconsistently reported. Single radiology reports were found in 1,637 (58%) cases, double in 347 (12.4%), and in 960 (34%) knowledge of mammography or ultrasound findings was not stated. Slice thickness, number of sequences after contrast medium, and year of study did not show significant performance differences. Other technical information was deficient. There is an urgent need to improve the quality of reporting of breast MRI studies.

The overdiagnosis nightmare: a time for caution.

Overdiagnosis (and overtreatment) of cancers not bound to become symptomatic during lifetime is an unavoidable drawback of mammography screening. The magnitude of overdiagnosis has been estimated to be in the range of 5-10%, and thus acceptable in view of screening benefits as to reduced mortality. In a recent research article in BMC Women's Health, Jørgensen, Zahl and Gøtzsche suggest that overdiagnosis may be as high as 33%, based on their analysis of breast cancer incidence in screened and non-screened areas in Denmark. Here we consider how reliable such analyses can be, why it might have been useful to adjust comparisons between screened and non-screened areas for early detection lead time, and what further evidence might be needed to build on or confirm these results.