European Screening Trial Research Articles

Impact of breast density on diagnostic accuracy in digital breast tomosynthesis versus digital mammography: results from a European screening trial

BackgroundThe diagnostic accuracy of digital breast tomosynthesis (DBT) and digital mammography (DM) in breast cancer screening may vary per breast density subgroup. The purpose of this study was to evaluate which women, based on automatically assessed breast density subgroups, have the greatest benefit of DBT compared with DM in the prospective Malmö Breast Tomosynthesis Screening Trial.Materials and methodsThe prospective European, Malmö Breast Tomosynthesis Screening Trial (n = 14,848, Jan. 27, 2010–Feb. 13, 2015) compared one-view DBT and two-view DM, with consensus meeting before recall. Breast density was assessed in this secondary analysis with the automatic software Laboratory for Individualized Breast Radiodensity Assessment. DBT and DM’s diagnostic accuracies were compared by breast density quintiles of breast percent density (PD) and absolute dense area (DA) with confidence intervals (CI) and McNemar’s test. The association between breast density and cancer detection was analyzed with logistic regression, adjusted for ages < 55 and ≥ 55 years and previous screening participation.ResultsIn total, 14,730 women (median age: 58 years; inter-quartile range = 16) were included in the analysis. Sensitivity was higher and specificity lower for DBT compared with DM for all density subgroups. The highest breast PD quintile showed the largest difference in sensitivity and specificity at 81.1% (95% CI 65.8–90.5) versus 43.2% (95% CI 28.7–59.1), p < .001 and 95.5% (95% CI 94.7–96.2) versus 97.2% (95% CI 96.6–97.8), p < 0.001, respectively. Breast PD quintile was also positively associated with cancer detected via DBT at odds ratio 1.24 (95% CI 1.09–1.42, p = 0.001).ConclusionWomen with the highest breast density had the greatest benefit from digital breast tomosynthesis compared with digital mammography with increased sensitivity at the cost of slightly lower specificity. These results may influence digital breast tomosynthesis’s use in an individualized screening program stratified by, for instance, breast density.Trial registration. Trial registration at https://www.ClinicalTrials.gov: NCT01091545, registered March 24, 2010.

Update on screening for lung cancer.

As the leading cause of cancer related death world wide, lung cancer is responsible for an enormous amount of suffering and disability. Detection of disease when it is surgically curable is associated with far greater odds of cure, and therefore it is a disease for which mass screening of high-risk populations has significant potential benefit. Starting in 2011, with the publication of the National Lung Screening Trial from United States (U.S.), mass screening programs have emerged throughout the U.S., as well as in other countries. More recently, large European screening trials have confirmed the potential mortality benefit of lung cancer screening. This invited non-systematic review paper covers the trial that data justify mass-screening, for lung cancer and proposes strategies for maximizing benefits and minimizing harms in the context of a mass public health lung cancer screening program.

Could Differences in Treatment Between Trial Arms Explain the Reduction in Prostate Cancer Mortality in the European Randomized Study of Screening for Prostate Cancer?

BackgroundDifferential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). ObjectiveTo quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA). Design, setting, and participantsA total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55–69yr) at 16yr of follow-up. Outcome measurements and statistical analysisThe outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths. Results and limitationsThe difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from −3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] −0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar—0.01% (95% CI −0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available. ConclusionsUse of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms. Patient summaryThis study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm.

EUPS-argues that lung cancer screening should be implemented in 18 months.

The European Position Statement (EUPS) expert group comprised of individuals who have been actively involved in the planning and execution of all the low dose CT (LDCT) randomised controlled European screening trials. They have argued that as lung cancer screening with LDCT saves lives, planning for implementation needs to be started by the national health organisations throughout Europe. The EUPS examined the current evidence which supports the planning for the implementation of lung cancer screening, as well as areas which require further work. One of the major areas the EUPS focused on was the management of prevalent lung nodules in CT-screening programmes, lung nodules at incident screening (newly detected) and CT-detected lung nodules in clinical practice should be managed with different protocols, due to different pre-test lung cancer probability. The EUPS provides nine recommendations and a "Call to Action" for implementation, which is naturally dependent on the outcome of the NELSON trial. Clearly, the issue is how Europe can take this forward as part of the political agenda of individual countries, as well as that of the EU Commission. An EU policy document has been developed, which focuses on the key steps in the implementation of cost effective lung cancer screening inEurope.

Mortality, survival and incidence rates in the ITALUNG randomised lung cancer screening trial

BackgroundITALUNG is contributing to the European evaluation of low-dose CT (LDCT) screening for lung cancer (LC).MethodsEligible subjects aged 55–69 years, smokers or ex-smokers (at least 20 pack-years in the last...

What explains the differences between centres in the European screening trial? A simulation study

BackgroundThe European Randomised study of Screening for Prostate Cancer (ERSPC) is a multicentre, randomised screening trial on men aged 55–69 years at baseline without known prostate cancer (PrCa) at randomisation to an intervention arm invited to screening or to a control arm. The ERSPC has shown a significant 21% reduction in PrCa mortality at 13 years of follow-up. The effect of screening appears to vary across centres, for which several explanations are possible. We set to assess if the apparent differences in PrCa mortality reduction between the centres can be explained by differences in screening protocols. MethodsWe examined the centre differences by developing a simulation model and estimated how alternative screening protocols would have affected PrCa mortality. ResultsOur results showed outcomes similar to those observed, when the results by centres were reproduced by simulating the screening regimens with PSA threshold of 3 versus 4ng/ml, or screening interval of two versus four years. The findings suggest that the differences are only marginally attributable to the different screening protocols. ConclusionThe small screening impact in Finland was not explained by the differences in the screening protocols. A possible reason for it was the contamination of and the unexpectedly low PrCa mortality in the Finnish control arm.

Impact of cause of death adjudication on the results of the European prostate cancer screening trial

Background:The European Randomised Study of Prostate Cancer Screening has shown a 21% relative reduction in prostate cancer mortality at 13 years. The causes of death can be misattributed, particularly in elderly men with multiple comorbidities, and therefore accurate assessment of the underlying cause of death is crucial for valid results. To address potential unreliability of end-point assessment, and its possible impact on mortality results, we analysed the study outcome adjudication data in six countries.Methods:Latent class statistical models were formulated to compare the accuracy of individual adjudicators, and to assess whether accuracy differed between the trial arms. We used the model to assess whether correcting for adjudication inaccuracies might modify the study results.Results:There was some heterogeneity in adjudication accuracy of causes of death, but no consistent differential accuracy by trial arm. Correcting the estimated screening effect for misclassification did not alter the estimated mortality effect of screening.Conclusions:Our findings were consistent with earlier reports on the European screening trial. Observer variation, while demonstrably present, is unlikely to have materially biased the main study results. A bias in assigning causes of death that might have explained the mortality reduction by screening can be effectively ruled out.

Bag-of-frequencies: a descriptor of pulmonary nodules in computed tomography images.

We present a novel descriptor for the characterization of pulmonary nodules in computed tomography (CT) images. The descriptor encodes information on nodule morphology and has scale-invariant and rotation-invariant properties. Information on nodule morphology is captured by sampling intensity profiles along circular patterns on spherical surfaces centered on the nodule, in a multi-scale fashion. Each intensity profile is interpreted as a periodic signal, where the Fourier transform is applied, obtaining a spectrum. A library of spectra is created and labeled via unsupervised clustering, obtaining a Bag-of-Frequencies, which is used to assign each spectra a label. The descriptor is obtained as the histogram of labels along all the spheres. Additional contributions are a technique to estimate the nodule size, based on the sampling strategy, as well as a technique to choose the most informative plane to cut a 2-D view of the nodule in the 3-D image. We evaluate the descriptor on several nodule morphology classification problems, namely discrimination of nodules versus vascular structures and characterization of spiculation. We validate the descriptor on data from European screening trials NELSON and DLCST and we compare it with state-of-the-art approaches for 3-D shape description in medical imaging and computer vision, namely SPHARM and 3-D SIFT, outperforming them in all the considered experiments.

Screening for lung cancer

The purpose of this review is to provide an update on the current data about low-dose computed tomography (LD-CT) lung cancer screening. The National Lung Screening Trial (NLST) was the first study that provided statistical evidence that LD-CT screening for lung cancer significantly reduces lung cancer mortality by 20%. Three statistically underpowered European trials could not confirm the positive effect of LD-CT screening on lung cancer mortality. Major obstacles in lung cancer screening are overdiagnosis and the large number of false-positive results. In the NLST, more than 24% of the screens were positive, most of which (96.4%) proved to be benign in nature. Optimized protocols for the workup of detected nodules may help to reduce the number of false-positive screens. Currently, the NLST is the only sufficiently powered trial to report a lower mortality rate with LD-CT screening. Long-term follow-up data are still anticipated on the European screening trials. Furthermore, data on the extent of the potential dangers of LD-CT screening, such as overdiagnosis, false-positive results, and the effect of cumulative radiation dose, have yet to be investigated thoroughly.

Lungenkrebsscreening aktuell - Wo stehen wir 2013?

Lung cancer is one of the leading causes of death in Europe and the USA. A relatively good prognosis is limited to those patients in whom the tumor is detected at an early stage. As clinical symptoms of lung cancer are a late finding in the natural course of the disease, most of the patients are diagnosed at an advanced tumor stage when palliative care remains the only therapeutic option. For this reason, early diagnosis of lung cancer might save lives. The National Lung Screening Trial (NLST), in the U. S. A., provided evidence that screening with low-dose CT (LD-CT) is able to reduce lung cancer mortality by 20.0 %. The encouraging results of the NLST, however, could not be confirmed by the preliminary results of ongoing European trials. Even if the European trials are able to confirm a reduction in lung cancer mortality by LD-CT, a number of important questions must be answered before the implementation of nationwide screening programs. First of all, the population that might benefit from CT lung cancer screening has to be defined precisely. Furthermore, guidelines have to be established about how to manage screening participants with detected lung nodules, as the vast majority of these pulmonary nodules will prove to be benign. This review article summarizes the results of the NLST and the initial data from the European screening trials, and will discuss some of the major open questions in lung cancer screening with CT.

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Efficacy versus effectiveness study design within the European screening trial for prostate cancer: consequences for cancer incidence, overall mortality and cancer-specific mortality

To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC). Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC-specific mortality. In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%). Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a 'healthy screenee bias'. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced.

Infectious Complications and Hospital Admissions After Prostate Biopsy in a European Randomized Trial

BackgroundThe complications of prostate needle biopsy (PNB) are important when considering the benefits and harms of prostate cancer screening. Studies from the United States and Canada have recently reported increasing numbers of hospitalizations for infectious complications after PNB. ObjectiveExamine the risk of infectious complications and hospital admissions after PNB in a European screening trial. Design, setting, and participantsFrom 1993 to 2011, 10 474 PNBs were performed in the European Randomized Study of Screening for Prostate Cancer (Rotterdam section). Prophylaxis originally consisted of trimethoprim-sulfamethoxazole. Beginning in 2008, it was changed to ciprofloxacin. MeasurementsFebrile complications and hospital admissions were assessed by questionnaires 2 wk after PNB. Logistic regression was used to identify risk factors for biopsy-related fever and hospital admission. Results and limitationsFever and hospital admission were reported on 392 of 9241 questionnaires (4.2%) and 78 of 9198 questionnaires (0.8%), respectively. Although most fevers were managed on an outpatient basis, 81% of hospital admissions were for infection. Of the 56 available blood cultures, 34 were positive with Escherichia coli as the predominant organism. On multivariable analysis, prostate enlargement and diabetes were significantly associated with an increased risk of fever after PNB, whereas later year of biopsy was the only factor significantly associated with an increased risk of hospital admission. ConclusionsIn a European screening trial, <5% PNBs resulted in febrile complications. Significant risk factors included diabetes and prostatic enlargement. Although most fevers were managed on an outpatient basis, infection remained the leading cause of hospital admission after PNB. Consistent with prior international reports, the frequency of hospital admissions after PNB significantly increased over time. Nevertheless, the absolute frequency of hospital admissions related to PNB was low and should not dissuade healthy men who would benefit from early prostate cancer diagnosis from undergoing biopsy when clinically indicated.

Is screening for prostate cancer with prostate specific antigen an appropriate public health measure?

Screening and treatment for prostate cancer is controversial. In the absence of randomized trials, several prominent medical organizations in the United States and Europe have formulated policies that range from enthusiastic support to significant skepticism concerning the efficacy of screening and subsequent treatment for prostate cancer. Sharp rises in the incidence of prostate cancer have occurred whenever PSA testing has been introduced on a wide scale. Unfortunately, it is unclear whether declines in prostate cancer mortality can be attributed to PSA testing. Other explanations include the early use of anti-androgen therapy or changes in environmental factors such as diet. Repeated testing for serum PSA has produced significant shifts in the types of cases being identified and has raised the possibility of significant over-diagnosis of this disease. The European screening trial and the PLCO trial in the US will hopefully provide some insights into the value of population-based testing.