Overcoming barriers: Modelling the effect of potential future changes of organized breast cancer screening in Italy.

OBJECTIVES: Organized breast cancer screening may not achieve its full potential due to organizational and cultural barriers. In Italy, two identified barriers were low attendance in Southern Italy and, in Italy as a whole, underscreening and overscreening in parts of the eligible population. The objective of this study was to identify potential changes to overcome these barriers and to quantify their costs and effects. METHODS: To assess the impact of potential measures to improve breast cancer screening in Italy, we performed an evaluation of costs and effects for increasing adherence for Southern Italy and harmonizing screening intervals (biennial screening) for the whole of Italy, using an online tool (EU-TOPIA evaluation tool) based on the MIcrosimulation SCreening ANalysis (MISCAN) model. RESULTS: Increasing adherence in Southern Italy through investing in mobile screening units has an acceptable cost-effectiveness ratio of €9531 per quality-adjusted life year gained. Harmonizing the screening interval by investing in measures to reduce opportunistic screening and simultaneously investing in mobile screening units to reduce underscreening is predicted to gain 1% fewer life-years, while saving 19% of total screening costs compared to the current situation. CONCLUSIONS: Increasing adherence in Southern Italy and harmonizing the screening interval could result in substantial improvements at acceptable costs, or in the same benefits at lower costs. This example illustrates a systematic approach that can be easily applied to other European countries, as the online tools can be used by stakeholders to quantify effects and costs of a broad range of specific barriers, and ways to overcome them.

Extending Age Ranges in Breast Cancer Screening in Four European Countries: Model Estimations of Harm-to-Benefit Ratios.

The main benefit of breast cancer (BC) screening is a reduction in mortality from BC. However, screening also causes harms such as overdiagnosis and false-positive results. The balance between benefits and harms varies by age. This study aims to assess how harm-to-benefit ratios of BC screening vary by age in the Netherlands, Finland, Italy and Slovenia. Using microsimulation models, we simulated biennial screening with 100% attendance at varying ages for cohorts of women followed over a lifetime. The number of overdiagnoses, false-positive diagnoses, BC deaths averted and life-years gained (LYG) were calculated per 1000 women. We compared four strategies (50-69, 45-69, 45-74 and 50-74) by calculating four harm-to-benefit ratios, respectively. Compared to the reference strategy 50-69, screening women at 45-74 or 50-74 years would be less beneficial in any of the four countries than screening women at 45-69, which would result in relatively fewer overdiagnoses per death averted or LYG. At the same time, false-positive results per death averted would increase substantially. Adapting the age range of BC screening is an option to improve harm-to-benefit ratios in all four countries. Prioritization of considered harms and benefits affects the interpretation of results.

The EU-TOPIA evaluation tool: An online modelling-based tool for informing breast, cervical, and colorectal cancer screening decisions in Europe.

BACKGROUND: Aiming to support European countries in improving their breast, cervical, and colorectal cancer (CRC) screening programmes, the EU-TOPIA consortium has developed an online user-friendly tool (the EU-TOPIA evaluation tool; https://miscan.eu-topia.org) based on the Microsimulation Screening Analysis (MISCAN) model. METHODS: We designed an online platform that allows stakeholders to use their country-specific data (demographic, epidemiological, and cancer screening information) to quantify future harms and benefits of different cancer screening scenarios in their country. Current cancer screening programmes and impacts of potential changes in screening protocols (such as extending target ages or increasing screening attendance) can be simulated. Results are scaled to the country-specific population. To illustrate the tool, we used the tool to simulate two different CRC screening scenarios in the Netherlands: biennial fecal immunochemical testing (FIT) in ages 55-75 and colonoscopy every ten years in ages 55-75. Data from the Dutch screening programme was used to inform both scenarios. RESULTS: A total of 482,700 CRC cases and 178,000 CRC deaths were estimated in the Netherlands with FIT screening (for individuals aged 40-100 years, 2018-2050), with 47.3 million FITs performed (1.92 million positives of which 1.64 million adhered to diagnostic colonoscopy). With colonoscopy screening, CRC incidence and mortality were, respectively, up to 17% and 14% lower than in the current FIT screening programme, requiring, however, a colonoscopy demand that was 7-fold higher. CONCLUSIONS: Our study presents an essential online tool for stakeholders and medical societies to quantify estimates of benefits and harms of early cancer detection in Europe.

Disability-Adjusted Life Years Averted Versus Quality-Adjusted Life Years Gained: A Model Analysis for Breast Cancer Screening.

OBJECTIVES: To quantify the impact of mammography-based screening on the quality of life, disability-adjusted life years (DALYs) averted or quality-adjusted life years (QALYs) gained can be used. We aimed to assess whether the use of DALYs averted or QALYs gained will lead to different cost-effective screening strategies. METHODS: Using the microsimulation model MISCAN, we simulated different breast cancer screening strategies varying in starting age (starting at 45, 47, and 50 years), stopping age (stopping at 69, 72, and 74 years), and frequency (annual [A], biennial [B], combination of both [A + B], and triennial [T]). In total, we defined 24 different breast cancer screening strategies, including no screening as a reference strategy. We calculated incremental cost-effectiveness ratios (ICERs) and compared which strategies were on the efficiency frontiers for DALYs and QALYs. RESULTS: Breast cancer screening averted between 46.00 and 105.58 DALYs and gained between 28.69 and 64.50 QALYs per 1000 women. For DALYs there were 5 strategies on the efficiency frontier (T50-69, T50-74, T45-74, B45-74, and A45-74). The same strategies plus one (B45-72) were on the efficiency frontier for QALYs. CONCLUSIONS: Using DALYs averted instead of QALYs gained to assess the effects on quality of life from breast cancer screening in the Dutch population yields differences in ICERs, but almost the same strategies were on the efficiency frontiers. Whether the choice in outcome measure leads to a difference in optimal policy depends on the cost-effectiveness threshold.

Development and Validation of Three Regional Microsimulation Models for Predicting Colorectal Cancer Screening Benefits in Europe.

Background. Validated microsimulation models have been shown to be useful tools in providing support for colorectal cancer (CRC) screening decisions. Aiming to assist European countries in reducing CRC mortality, we developed and validated three regional models for evaluating CRC screening in Europe. Methods. Microsimulation Screening Analysis-Colon (MISCAN-Colon) model versions for Italy, Slovenia, and Finland were quantified using data from different national institutions. These models were validated against the best available evidence for the effectiveness of screening from their region (when available): the Screening for COlon REctum (SCORE) trial and the Florentine fecal immunochemical test (FIT) screening study for Italy; the Norwegian Colorectal Cancer Prevention (NORCCAP) trial and the guaiac fecal occult blood test (gFOBT) Finnish population-based study for Finland. When published evidence was not available (Slovenia), the model was validated using cancer registry data. Results. Our three models reproduced age-specific CRC incidence rates and stage distributions in the prescreening period. Moreover, the Italian and Finnish models replicated CRC mortality reductions (reasonably) well against the best available evidence. CRC mortality reductions were predicted slightly larger than those observed (except for the Florentine FIT study), but consistently within the corresponding 95% confidence intervals. Conclusions. Our findings corroborate the MISCAN-Colon reliability in supporting decision making on CRC screening. Furthermore, our study provides the model structure for an additional tool (EU-TOPIA CRC evaluation tool: http://miscan.eu-topia.org) that aims to help policymakers and researchers monitoring or improving CRC screening in Europe.

The potential of breast cancer screening in Europe.

Currently, all European countries offer some form of breast cancer screening. Nevertheless, disparities exist in the status of implementation, attendance and the extent of opportunistic screening. As a result, breast cancer screening has not yet reached its full potential. We examined how many breast cancer deaths could be prevented if all European countries would biennially screen all women aged 50 to 69 for breast cancer. We calculated the number of breast cancer deaths already prevented due to screening as well as the number of breast cancer deaths which could be additionally prevented if the total examination coverage (organised plus opportunistic) would reach 100%. The calculations are based on total examination coverage in women aged 50 to 69, the annual number of breast cancer deaths for women aged 50 to 74 and the maximal possible mortality reduction from breast cancer, assuming similar effectiveness of organised and opportunistic screening. The total examination coverage ranged from 49% (East), 62% (West), 64% (North) to 69% (South). Yearly 21 680 breast cancer deaths have already been prevented due to mammography screening. If all countries would reach 100% examination coverage, 12 434 additional breast cancer deaths could be prevented annually, with the biggest potential in Eastern Europe. With maximum coverage, 23% of their breast cancer deaths could be additionally prevented, while in Western Europe it could be 21%, in Southern Europe 15% and in Northern Europe 9%. Our study illustrates that by further optimising screening coverage, the number of breast cancer deaths in Europe can be lowered substantially.

Effect of organised cervical cancer screening on cervical cancer mortality in Europe: a systematic review.

BACKGROUND: Organised cervical cancer (CC) screening programmes are delivered in many different ways across the European Union and its regions. Our aim was to systematically review the impact of these programs on CC mortality. METHODS: Two independent reviewers identified all eligible studies investigating the effect of organised screening on CC mortality in Europe. Six databases including Embase, Medline and Web of Science were searched (March 2018) with predefined inclusion and exclusion criteria. Only original studies with at least five years of follow-up were considered. Validated tools were used to assess the risk of bias of the included studies. RESULTS: Ten observational studies were included: seven cohort and three case-control studies. No randomised controlled trials were found, and there were no eligible studies from the eastern and southern part of Europe. Among the eligible studies, seven were conducted in the twentieth century; they scored lower on the risk of bias assessment. CC mortality reduction for women attending organised screening vs. non-attenders ranged from 41% to 92% in seven studies. Reductions were similar in Western (45-92%) and Northern (41-87%) Europe and were higher in the three more recent studies (66-92%). For invited vs. non-invited women, this reduction ranged from 17% to 79% in five studies. CONCLUSION: Although data were lacking in Southern and Eastern Europe and the effect size varied between countries and studies, this systematic review provides evidence that organised CC screening reduces CC mortality in those parts of Europe where CC screening was implemented and monitored.

Evidence for reducing cancer-specific mortality due to screening for breast cancer in Europe: A systematic review.

BACKGROUND: The aim of this study was to quantify the impact of organised mammography screening on breast cancer mortality across European regions. Therefore, a systematic review was performed including different types of studies from all European regions and stringently used clearly defined quality appraisal to summarise the best evidence. METHODS: Six databases were searched including Embase, Medline and Web of Science from inception to March 2018. To identify all eligible studies which assessed the effect of organised screening on breast cancer mortality, two reviewers independently applied predefined inclusion and exclusion criteria. Original studies in English with a minimum follow-up of five years that were randomised controlled trials (RCTs) or observational studies were included. The Cochrane risk of bias instrument and the Newcastle-Ottawa Scale were used to assess the risk of bias. RESULTS: Of the 5015 references initially retrieved, 60 were included in the final analysis. Those comprised 36 cohort studies, 17 case-control studies and 7 RCTs. None were from Eastern Europe. The quality of the included studies varied: Nineteen of these studies were of very good or good quality. Of those, the reduction in breast cancer mortality in attenders versus non-attenders ranged between 33% and 43% (Northern Europe), 43%-45% (Southern Europe) and 12%-58% (Western Europe). The estimates ranged between 4% and 31% in invited versus non-invited. CONCLUSION: This systematic review provides evidence that organised screening reduces breast cancer mortality in all European regions where screening was implemented and monitored, while quantification is still lacking for Eastern Europe. The wide range of estimates indicates large differences in the evaluation designs between studies, rather than in the effectiveness of screening.

Impact of colorectal cancer screening on cancer-specific mortality in Europe: A systematic review.

BACKGROUND: Populations differ with respect to their cancer risk and screening preferences, which may influence the performance of colorectal cancer (CRC) screening programs. This review aims to systematically compare the mortality effect of CRC screening across European regions. METHODS: Six databases including Embase, Medline, Web of Science, PubMed publisher, Google Scholar and Cochrane Library were searched for relevant studies published before March 2018. Bibliographic searches were conducted to select studies assessing the effect of various screening tests (guaiac fecal occult blood test [gFOBT]; flexible sigmoidoscopy [FS]; fecal immunochemical test [FIT] and colonoscopy) on CRC mortality in Europe (PROSPERO protocol: CRD42016042433). Abstract reviewing, data extraction and risk of bias assessment were conducted independently by two reviewers. RESULTS: A total of 18 studies were included; of which, 11 were related to gFOBT, 4 to FS, 2 to FIT and 1 to colonoscopy; 8 were randomised clinical trials, and 10, observational studies, and an approximately equal number of studies represented Northern, Western and Southern European regions. Among individuals invited to screening, CRC mortality reductions varied from 8% to 16% for gFOBT and from 21% to 30% for FS. When studies with a high risk of bias were considered, ranges were more extensive. The estimated effectiveness of gFOBT and FS screening appeared similar across different European regions. CONCLUSIONS: CRC mortality impact of inviting individuals with similar adopted screening strategies (gFOBT or FS) may be consistent across several European settings.

Systematic reviews as a 'lens of evidence': Determinants of benefits and harms of breast cancer screening.

This systematic review, stimulated by inconsistency in secondary evidence, reports the benefits and harms of breast cancer (BC) screening and their determinants according to systematic reviews. A systematic search, which identified 9,976 abstracts, led to the inclusion of 58 reviews. BC mortality reduction with screening mammography was 15-25% in trials and 28-56% in observational studies in all age groups, and the risk of stage III+ cancers was reduced for women older than 49 years. Overdiagnosis due to mammography was 1-60% in trials and 1-12% in studies with a low risk of bias, and cumulative false-positive rates were lower with biennial than annual screening (3-17% vs 0.01-41%). There is no consistency in the reviews' conclusions about the magnitude of BC mortality reduction among women younger than 50 years or older than 69 years, or determinants of benefits and harms of mammography, including the type of mammography (digital vs screen-film), the number of views and the screening interval. Similarly, there was no solid evidence on determinants of benefits and harms or BC mortality reduction with screening by ultrasonography or clinical breast examination (sensitivity ranges, 54-84% and 47-69%, respectively), and strong evidence of unfavourable benefit-to-harm ratio with breast self-examination. The reviews' conclusions were not dependent on the quality of the reviews or publication date. Systematic reviews on mammography screening, mainly from high-income countries, systematically disagree on the interpretation of the benefit-to-harm ratio. Future reviews are unlikely to clarify the discrepancies unless new original studies are published.

Impact of gender on tumor stage and survival of upper urinary tract urothelial cancer : A population-based study.

BACKGROUND: The aim of this study was to analyze the impact of gender on tumor stage, overall and cancer-specific mortality of upper urinary tract urothelial cancer (UTUC) in a population-based, nationwide analysis. METHODS: All Austrian patients with UTUC diagnosed between 1983 and 2010 were included in this study. Overall mortality was estimated by the Kaplan-Meier method. Cancer-specific (UTUC) mortality was estimated by cumulative incidence with mortality due to other causes as a competing risk. The effect of age was adjusted in a descriptive as well as a statistical inferential way. RESULTS: This study included 2066 patients (men n = 1169, mean age 68.3 ±11.5 years, women n = 897, 72.6 ±10.4 years). Tumor stage distribution was as follows: pT1: men n = 411, women n = 268, pT2: men n = 263, women n = 187, pT3: men n = 382, women n = 328 and pT4: men n = 113, women n = 114. The male:female ratio continuously declined from 1.5 for pT1 tumors to 1.4 for pT2 tumors, 1.2 for pT3 tumors and 1.0 for pT4-tumors. In the entire cohort the 5­year cumulative overall mortality was 57 % for women versus 50 % for men (p = 0.0002). For pT1 (women 33 %, men 31 %) and pT2 stage tumors (women 45 %, men 45 %) the 5­year overall mortality was comparable between both sexes. In pT3 (women 68 %, men 62 %) and pT4 (women 95 %, men 87 %) tumors women had a higher overall mortality rate. The 5­year cancer-specific mortality (CSM) of the entire cohort was 12 % for women and 10 % for men (p = 0.067): pT1 women 5 % men 3 %, pT2 women 9 % men 10 %, pT3 women 14 % men 11 % and pT4 women 29 % men 27 %. CONCLUSIONS: In this population-based nationwide analysis, sex differences were notable for UTUC. Women tended to have more advanced tumor stages at diagnosis and a higher overall and cancer-specific mortality in advanced tumor stages.

Sex Differences of ≥ pT1 Bladder Cancer Survival in Austria: A Descriptive, Long-Term, Nation-Wide Analysis Based on 27,773 Patients.

INTRODUCTION: In recent days, the relationship between gender, tumour stage and survival of bladder cancer has attracted interest. MATERIALS AND METHODS: The Austrian cancer registry was linked to the national death statistics. All patients with urothelial cancer of the urinary bladder with stages pT1, pT2, pT3 and pT4 diagnosed between 1983 until 2012 were followed for up to 15 years. Overall and cancer-specific mortality were estimated by cumulative incidence. RESULTS: A total of 27,773 patients were analysed. The male:female ratio declined from 3:1 for stage pT1-tumours (n = 16,416) to 2.6:1 for pT2 (n = 6,548), 2.1:1 for pT3 (n = 3,111) and 1.9:1 for pT4 (n = 1,698). The 5 years cumulative overall death rate for pT1 tumours was slightly lower for women (0.31 vs. 0.32; p = 0.016). The opposite was observed for more advanced tumour stages: pT2: women 0.66, men: 0.60 (p = 0.0001); pT3: women 0.76, men 0.72 (p = 0.0004) and for pT4: women 0.90, men 0.85 (p = 0.0001). Cancer-specific survival was identical for pT1-tumours in both sexes, while women had a worse cancer-specific survival in both age cohorts (<70 years and ≥70 years) with higher tumour stages. CONCLUSIONS: This population-based study demonstrates that (1) a rise of advanced bladder cancer stages in women and (2) that women with tumour stages >pT1 have a shorter cancer-specific and overall survival.

Epidemiological trends of hepatocellular carcinoma in Austria.

BACKGROUND/AIMS: The heterogeneous epidemiology of hepatocellular carcinoma (HCC) with the highest incidence rates in East Asia, sub-Saharan Africa and Melanesia results from variations in the main risk factors. We investigated epidemiological trends, including incidence and mortality, of patients diagnosed with HCC over a 20-year period in Austria. METHODS: Data on age-adjusted incidence rates of HCC were obtained from the Austrian National Cancer Registry, which compiles nationwide data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). RESULTS: Of 24,939 patients diagnosed with hepatobiliary tumors between 1990 and 2009, 8,561 subjects had HCC (m/f ratio 75/25%; mean age 69 years). Lymph node and distant metastases were present in 7.5 and 12.2%, respectively. The age-adjusted incidence rate was significantly higher in men than women (m/f ratio 4.5/1) and markedly increased in men (4.68/5.10) but remained stable in women (1.18/1.11). Similarly, the age-adjusted mortality rate was significantly higher in men than women (m/f ratio 4.5/1), increased in men (4.02/4.98) and remained stable in women (0.92/1.0). The median overall survival was 4.5 months for men and 3.2 months for women with 1-/5-year survival rates of 33/11% and 28/10%, respectively. CONCLUSION: HCC is the most common hepatobiliary neoplasia in Austria and has a very poor prognosis. The age-adjusted incidence and mortality rates were higher in males, increased over time in men and remained stable in women. Extrahepatic metastases were rarely diagnosed and associated with dismal survival.

Incidence and mortality trends for biliary tract cancers in Austria.

BACKGROUND & AIMS: The epidemiology of biliary tract cancers (BTC) varies between geographical regions and has changed over time globally. We investigated the incidence and mortality trends of patients diagnosed with BTC over a 20-year period in Austria. METHODS: Patients diagnosed with intrahepatic (iCCC)/extrahepatic cholangiocarcinoma (eCCC), ampullary carcinoma, gall bladder carcinoma (GBC), overlapping lesions or unspecified carcinomas of the biliary tract and liver were included. Data on age-adjusted incidence were obtained from the Austrian National Cancer Registry which compiles data on all newly diagnosed cancers. Data on age-adjusted mortality were obtained from the national death registry (Statistics Austria). RESULTS: Between 1990 and 2009, 15201 patients were diagnosed with BTC (m/f=42/58%; mean age, 73 years). The median survival of all patients with BTC was 4.8 months with a 1-/5-year survival rate of 31%/10%. In iCCC, the incidence and mortality rates increased from 1990 to 2009 in both men and women while in eCCC, the incidence and mortality rates decreased over time in both sexes. In ampullary carcinoma, the incidence slightly decreased in men and remained stable in women. The mortality rate remained stable in both sexes. In GBC, the age-adjusted incidence and mortality rates dramatically decreased in both sexes. CONCLUSIONS: GBC and iCCC were the most common entities amongst BTC. While incidence and mortality rates of iCCC increased in men and women over time, incidence and mortality rates of eCCC and GBC decreased in both sexes. Other carcinomas of the biliary tract i.e. ampullary carcinoma were rarely diagnosed.

Incidence of atypical teratoid/rhabdoid tumors in children: a population-based study by the Austrian Brain Tumor Registry, 1996-2006.

BACKGROUND: Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population-based data on the incidence of these tumors are not yet available. METHODS: A nation-wide survey of malignant high-grade CNS tumors (World Health Organization grade III/IV), diagnosed in children (aged birth to 14 years) from 1996 to 2006 was conducted by the Austrian Brain Tumor Registry. A central histopathology review was performed including the assessment of SMARCB1 (INI1) protein status. RESULTS: A total of 311 newly diagnosed, malignant CNS tumors were included. Atypical teratoid/rhabdoid tumors constituted the sixth most common entity (6.1%), referring to an age-standardized incidence rate of 1.38 per 1,000,000 person-years in children. Peak incidence was found in the birth to 2 years age group, where they were as common as CNS primitive neuroectodermal tumors and medulloblastomas. A total of 47.4% of atypical teratoid/rhabdoid tumors were initially diagnosed, whereas 52.6% were retrospectively detected by the central review. The 5-year survival of atypical teratoid/rhabdoid tumor patients was 39.5%, with 66.7% in the correctly diagnosed group versus 15.0% in the not recognized group (P = .0469). CONCLUSIONS: Clinicians and pathologists should be aware of the high incidence of atypical teratoid/rhabdoid tumors in young children to optimize diagnostic and therapeutic management of patients with these tumors.