Population-based Service Screening Research Articles

Assessing overdiagnosis of fecal immunological test screening for colorectal cancer with a digital twin approach

Evaluating the magnitude of overdiagnosis associated with stool-based service screening for colorectal cancer (CRC) beyond a randomized controlled trial is often intractable and understudied. We aim to estimate the proportion of overdiagnosis in population-based service screening programs for CRC with the fecal immunochemical test (FIT). The natural process of overdiagnosis-embedded disease was first built up to learn transition parameters that quantify the pathway of non-progressive and progressive screen-detected cases calibrated with sensitivity, while also taking competing mortality into account. The Markov algorithms were then developed for estimating these transition parameters based on Taiwan FIT service CRC screening data on 5,417,699 residents aged 50–69 years from 2004 to 2014. Following the digital twin design with the parallel universe structure for emulating the randomized controlled trial, the screened twin, mirroring the control group without screening, was virtually recreated by the application of the above-mentioned trained parameters to predict CRC cases containing overdiagnosis. The ratio of the predicted CRCs derived from the screened twin to the observed CRCs of the control group minus 1 was imputed to measure the extent of overdiagnosis. The extent of overdiagnosis for invasive CRCs resulting from FIT screening is 4.16% (95% CI: 2.61–5.78%). The corresponding figure is increased to 9.90% (95% CI: 8.41–11.42%) for including high grade dysplasia (HGD) and further inflated to 15.83% (95% CI: 15.23–16.46%) when the removal adenoma is considered. The modest proportion of overdiagnosis modelled by the digital twin method, dispensing with the randomized controlled trial design, suggests the harm done to population-based FIT service screening is negligible.

Breast cancers originating from the terminal ductal lobular units: In situ and invasive acinar adenocarcinoma of the breast, AAB

PurposeTo use mammographic tumour features (imaging biomarkers) to identify and investigate breast cancers originating from the terminal ductal lobular units (TDLUs) of the breast in order to overcome the confusion arising from the current histopathology terminology, which calls cancers arising from the TDLUs either “ductal” or “lobular”. MethodProspectively collected data from a randomized controlled mammography screening trial with more than four decades of follow up, and data from the subsequent population-based service screening program in Dalarna County, Sweden, provided the database necessary for studying nonpalpable, primarily screen-detected breast cancer cases in their earliest detectable phases. Large format thick (subgross) and thin section histopathologic images of breast cancers originating from the TDLUs were correlated with their mammographic tumour features (imaging biomarkers) and long-term patient outcome. ResultsThis systematic correlation indicates that imaging biomarkers can reliably determine the site of origin of breast cancers arising from the terminal ductal lobular units (TDLUs). This breast cancer subgroup has four specific mammographic tumour features: the in situ carcinomas developing from the TDLUs appear as powdery or crushed stone-like calcifications, while the invasive carcinomas appear as stellate/spiculated or circular/oval shaped tumour masses. These features are easily identified with breast imaging, either alone or in combination, unifocal or multifocal. We propose calling breast cancers of TDLU origin acinar adenocarcinoma of the breast (AAB). ConclusionsThe era of early detection necessitates rectifying the current, confusing histopathological nomenclature to one that is based on the anatomical site of origin of breast cancers. Invasive cancers originating from the TDLUs are either stellate/spiculated or circular, irrespective of the complex WHO histopathologic terminology. The mortality reduction accomplished by participation in mammography screening is mostly accomplished by identifying and treating the AABs in their non-palpable, early phase. AABs detected when < 15 mm diameter with no associated carcinoma originating from the major lactiferous ducts (ductal adenocarcinoma of the breast, DAB) have a good to excellent long-term outcome, irrespective of the current terminology, which tends to lead to overtreatment of these early invasive tumours. The conventionally used prognostic factors, including immunohistochemical biomarkers, fail to identify those 1–14 mm invasive AABs tumours that are eventually fatal. This identification can be made preoperatively by including the characteristic mammographic tumour features, imaging biomarkers, in primary diagnosis, treatment planning, and predicting long-term patient outcome. Forthcoming articles will address breast malignancies originating from structures of the breast other than the TDLUs.

Effectiveness of Population-Based Service Screening with Mammography for Women Aged 70-74 Years in Sweden.

Consensus has been reached on the effectiveness of inviting women aged 50 to 69 years to mammography screening, but for older women, the evidence is scarce. The aim of this study was to estimate the marginal effectiveness of inviting women to mammography screening with an upper age limit of 74 years versus stopping at age 69 using data from the Swedish service-screening program. A cohort design was used to compare the breast cancer mortality in the period 1986 to 2012 between geographic areas and periods where women were invited to screening up to the age of 74 years (study group) with those where women were invited up to age 69 (control group). The study group and the control group were compared using the incidence-based breast cancer mortality rate ratio where only breast cancer deaths in cases diagnosed at 70 to 74 years of age were counted. After 20 years of follow-up, there were 1,040 and 1,173 breast cancer deaths in the study and the control group, respectively. The breast cancer mortality rate ratio for women invited up to age 74 versus women invited up to age 69 was 0.80 [95% confidence interval (CI): 0.75-0.85] after bias adjustments. The corresponding rate ratio for participating women was 0.73 (95% CI: 0.66-0.81). Continuing to screen women up to 74 years of age is effective compared with stopping screening at 69 years. This large long-term study will add to the knowledge of the effect of mammography screening for women 70 to 74 years.

Quantitative Models for Modeling Overdetection in Population-Based Screening for Colorectal Cancer

Background: Overdetection resulting from population-based cancer screening has been debatable over the past decade. However, a systematic approach for quantitative estimation of overdetection has been barely addressed. Contextually, mass screening for breast cancer and prostate cancer has been well documented, but colorectal cancer (CRC) has been scarcely highlighted. Aim: The aim of this study is to develop a systematic approach for quantitative estimation of overdetection and elucidating the mechanism of overdetection in population-based colorectal cancer screening. Methods: The graphic method was first proposed by comparing cumulative incidence curves of advanced and nonadvanced cancers. Then, the modeling approaches used for quantitative methods were developed. We proposed the standardized overdetection ratio (SOR), the index including expected and observed which are simulated by a 3-state Markov model (normal, preclinical detectable phase, clinical phase) based on screened group and control group, respectively. Moreover, we developed the 5-state Markov model in conjunction with SOR to quantify the extent of overdetection. Two randomized controlled trials on guaiac–fecal occult blood test (gFOBT) in U.K. and Denmark and population-based service screening using fecal immunochemical test (FIT) in Taiwan were applied to assess the proposed methods to quantify overdetection in population-based cancer screening. Results: Using the graphic method, the average of overdetection was 31.1% and 24.9% for the UK trial and the Denmark trial, respectively. However, the estimated proportion of overdetection may be biased because the graphic method did not take the natural history of adenoma and high awareness in the routine clinical practice into account. According to the proposed 3-state Markov model, the overdetection of CRC was 9% with gFOBT based on the 2 randomized controlled trials in Europe and 7% with FIT based on a nationwide screening program in Taiwan. The estimated overdetection by the 5-state Markov model were 6.1% and 9.2% for the U.K. and Denmark trial, respectively. Moreover, the main pathway for overdetection in population-based CRC screening is from nonadvanced in the preclinical phase to advanced in the preclinical phase which is supported by the evidence that SOR decreases from 1.29 to 1.16 and 1.16 to 0.97 for the U.K. and Denmark trial, respectively. Conclusion: This study developed the graphic method and the disease natural progression model for quantitative assessment of overdetection in colorectal cancer. The index, SOR, was proposed not only to assess the extent of overdetection but also to elucidate the mechanism to know how overdetection affects the progression of colorectal cancer from the preclinical phase to the clinical phase with information of cancer stage.

Effectiveness of fecal immunochemical testing in reducing colorectal cancer mortality from the One Million Taiwanese Screening Program.

BACKGROUNDThe effectiveness of fecal immunochemical testing (FIT) in reducing colorectal cancer (CRC) mortality has not yet been fully assessed in a large, population-based service screening program.METHODSA prospective cohort study of the follow-up of approximately 5 million Taiwanese from 2004 to 2009 was conducted to compare CRC mortality for an exposed (screened) group and an unexposed (unscreened) group in a population-based CRC screening service targeting community residents of Taiwan who were 50 to 69 years old. Given clinical capacity, this nationwide screening program was first rolled out in 2004. In all, 1,160,895 eligible subjects who were 50 to 69 years old (ie, 21.4% of the 5,417,699 subjects of the underlying population) participated in the biennial nationwide screening program by 2009.RESULTSThe actual effectiveness in reducing CRC mortality attributed to the FIT screening was 62% (relative rate for the screened group vs the unscreened group, 0.38; 95% confidence interval, 0.35-0.42) with a maximum follow-up of 6 years. The 21.4% coverage of the population receiving FIT led to a significant 10% reduction in CRC mortality (relative rate, 0.90; 95% confidence interval, 0.84-0.95) after adjustments for a self-selection bias.CONCLUSIONSThis large, prospective Taiwanese cohort undergoing population-based FIT screening for CRC had the statistical power to demonstrate a significant CRC mortality reduction, although the follow-up time was short. Although such findings are informative for health decision makers, continued follow-up of this large cohort will be required to estimate the long-term impact of FIT screening if the covered population is expanded. Cancer 2015;121:3221–3229. © 2015 American Cancer Society.A significant reduction in colorectal cancer mortality resulting from fecal immunochemical testing is demonstrated by a large, population-based, nationwide service screening program with a maximum follow-up of 6 years. Although long-term follow-up of this nationwide service screening program is required, these findings are useful for convincing health decision makers that the continuous promotion of such a nationwide screening program is worthwhile.

A Stochastic Model for Calibrating the Survival Benefit of Screen-Detected Cancers

Comparison of the survival of clinically detected and screen-detected cancer cases from either population-based service screening programs or opportunistic screening is often distorted by both lead-time and length biases. Both are correlated with each other and are also affected by measurement errors and tumor attributes such as regional lymph node spread. We propose a general stochastic approach to calibrate the survival benefit of screen-detected cancers related to both biases, measurement errors, and tumor attributes. We apply our proposed method to breast cancer screening data from one arm of the Swedish Two-County trial in the trial period together with the subsequent service screening for the same cohort. When there is no calibration, the results—assuming a constant (exponentially distributed) post-lead-time hazard rate (i.e., a homogeneous stochastic process)—show a 57% reduction in breast cancer death over 25 years. After correction, the reduction was 30%, with approximately 12% of the overestimation being due to lead-time bias and 15% due to length bias. The additional impacts of measurement errors (sensitivity and specificity) depend on the type of the proposed model and follow-up time. The corresponding analysis when the Weibull distribution was applied—relaxing the assumption of a constant hazard rate—yielded similar findings and lacked statistical significance compared with the exponential model. The proposed calibration approach allows the benefit of a service cancer screening program to be fairly evaluated. This article has supplementary materials online.

Overdiagnosis in the population-based service screening programme with mammography for women aged 40 to 49 years in Sweden

To estimate the level of overdiagnosis of all breast cancers and of invasive breast cancers in women aged 40-49 invited to the subsequent screening rounds in the Swedish service-screening programme 1986-2005. To estimate the level of overdiagnosis in subsequent screening, the rate ratios (RR) of the breast cancer incidence in the study group (women in areas with screening in ages 40-49) and the control group (women in areas with no screening in ages 40-49) were calculated for all breast cancers and for invasive breast cancers. The RR estimates were adjusted for the prescreening difference in incidence between study and control group and for lead time. The prescreening incidence rate ratio was estimated at 0.92 (95% confidence interval [CI]: 0.88-0.97). The number of breast cancer cases and person-years were 6047 and 3.8 million, and 7790 and 5.2 million, in the study group and control group respectively during the study period. The RR estimate for all cancers was 1.01 (95% CI: 0.94-1.08) when adjusted for prescreening difference and a lead time of 1.2 years. The corresponding estimate for invasive breast cancers was 0.95 (95% CI: 0.88-1.02). We found no significant overdiagnosis for women aged 40-49 in the Swedish service screening programme with mammography.

Controversies in mammography screening: let us not ignore science in this never-ending debate

There has been an ongoing debate on mortality reduction from mammography screening since the randomized control trials in the 1970s and 1980s which showed a mortality reduction of about 25%. In addition to the mortality reduction, the debates have been focusing on screening of women below 50 years of age and over-diagnosis. Randomized control trials (RCTs) are the gold standard for investigations of new therapies and diagnostic interventions. The design of a RCT is challenging, and some of the mammographic RCTs had, without doubt, limitations. RCTs are comparing the outcome of women invited to intervention (mammography screening) versus a control group. However, many women invited do not attend (‘nonattenders’) and many women in the ‘control group’ have a mammographic examination outside the program. No correction is made for this bias in the RCTs. Results from the Swedish RCTs have been of utmost importance, and are the scientific rationale for implementing mammographic service screening. The recently published results from the Swedish ‘Two-County Trial’ with a follow-up of three decades has confirmed that a highly significant reduction in breast cancer mortality of 30% in women invited to screening has persisted throughout the long follow-up period (1). The Nordic countries have today nationwide populationbased screening programs. An overview of service screening from 13 Swedish counties reported a substantial reduction in breast cancer mortality between 40% and 45% (2). The Icelandic mammography screening, the oldest populationbased program worldwide, showed a 35–40% reduction in breast cancer mortality based on a case-control study (3). A similar mortality reduction was reported in the Copenhagen screening for women actually participating in the mammography program (4). The Danish screening program has recently become nationwide. The smaller impact on mortality rate reported in the Finnish program has been explained by the younger age group targeted in Finland (5). It should be noted that a remarkably high mortality reduction of more than 70% after correction for selfselection bias has recently been reported (6). Evaluation of the Norwegian Breast Cancer Screening Program (NBCSP) has just started, and the results are expected within one to two years. Another controversy has been mammography screening for women aged 40–49 years. Most of the RCTs were not designed to evaluate the impact on this age group. However, several studies have clearly indicated that screening would be of benefit for women below 50 years of age. A recent publication from Sweden on the effectiveness of population-based service screening for women aged 40– 49 years showed a reduction in breast cancer mortality of 29% in the age group 40–49 years and 37% in the age group 45–49 years for the women who actually attended the mammographic screening program (7). In 2009 the US Preventive Services Task Force (USPSTF) declared that routine screening mammography in women aged 40–49 years should not be recommended (8). This statement has been heavily criticized as it is not supported by science. The age of 50 years is nothing but an arbitrary threshold without biological or scientific importance and has been arbitrarily chosen as a surrogate for menopause (9). Over-diagnosis, defined as a cancer diagnosed at mammography which would never have presented in the women’s lifetime in the absence of screening is another controversy. Over-diagnosis exists, but the question is how big the problem is: 1%, 10%, 25%, or even higher (10–12). The reason is that presently there is no way to determine which cases of DCIS (and perhaps even small low-grade invasive cancers) that will progress to lethal cancers. Spontaneous regression, on the other hand, is obviously a very rare phenomenon (12). Headlines in newspapers and medical journals over the last years on a minor effect of mammographic screening on mortality and a substantial over-diagnosis rate are beginning to disturb our belief. A register-based study on the NBCSP published in New England Journal of Medicine concluded that mammography screening accounted for only one-third of the moderate reduction in breast cancer mortality (13). Another recent publication compared results from Sweden and Norway, and concluded that screening did not play ‘a direct part’ in the reduction of breast cancer mortality (14). Over-diagnosis up to 50% has been postulated (11). If so, the question of course would be whether ‘mammographic screening is justifiable considering its substantial over-diagnosis rate and minor effect on mortality’ (10). The flaws in these estimations have been summarized in an overview on over-diagnosis in mammography screening (12). Regarding the recently reported minor effect on mortality and the high over-diagnosis rate in the NBCSP (10, 11, 13, 14), it is important to be aware that these publications are register-based research without access to individualized data. Register-based studies have several limitations (which is also the case for case-control studies!). For

Oncologic Imaging: A Guiding Hand of Personalized Cancer Care

Our discipline is in a remarkably strong position to guide and advance the practice of medicine in the 21st century.

Computer-aided System of Evaluation for Population-based All-in-One Service Screening (CASE-PASS): From Study Design to Outcome Analysis with Bias Adjustment

Population-based routine service screening has gained popularity following an era of randomized controlled trials. The evaluation of these service screening programs is subject to study design, data availability, and the precise data analysis for adjusting bias. We developed a computer-aided system that allows the evaluation of population-based service screening to unify these aspects and facilitate and guide the program assessor to efficiently perform an evaluation. This system underpins two experimental designs: the posttest-only non-equivalent design and the one-group pretest-posttest design and demonstrates the type of data required at both the population and individual levels. Three major analyses were developed that included a cumulative mortality analysis, survival analysis with lead-time adjustment, and self-selection bias adjustment. We used SAS AF software to develop a graphic interface system with a pull-down menu style. We demonstrate the application of this system with data obtained from a Swedish population-based service screen and a population-based randomized controlled trial for the screening of breast, colorectal, and prostate cancer, and one service screening program for cervical cancer with Pap smears. The system provided automated descriptive results based on the various sources of available data and cumulative mortality curves corresponding to the study designs. The comparison of cumulative survival between clinically and screen-detected cases without a lead-time adjustment are also demonstrated. The intention-to-treat and noncompliance analysis with self-selection bias adjustments are also shown to assess the effectiveness of the population-based service screening program. Model validation was composed of a comparison between our adjusted self-selection bias estimates and the empirical results on effectiveness reported in the literature. We demonstrate a computer-aided system allowing the evaluation of population-based service screening programs with an adjustment for self-selection and lead-time bias. This is achieved by providing a tutorial guide from the study design to the data analysis, with bias adjustment.

Service Screening with Mammography in Sweden: Evaluation of Effects of Screening on Breast Cancer Mortality in Age Group 40-49 Years

The aim of the study was to develop a model for estimating the effect of the nation-wide service screening program with mammography on breast cancer mortality in Sweden. In 1997, the introduction of population-based service screening had been completed in all 26 counties. In approximately half of the counties suitable for evaluation, the lower age limit for invitation was 40 years (study population) and in the other half the age limit was 50 years (control population). The numbers of females aged 40-49 years for the two populations were 202 152 and 237 279, respectively (1988). The study and control populations were compared for the period 1986-1996 with regard to refined breast cancer mortality. To adjust for geographical differences, the period 1976-1986 was used as reference. With a mean follow-up time of 8 years, the estimated relative risk of breast cancer death in relation to invitation to service screening among women aged 40-49 years at breast cancer diagnosis was 0.91 (95% confidence interval 0.72-1.15). These findings were compatible with those presented in the previous overview of the Swedish randomized studies.