Personality and the use of cancer screenings - Results of the German National Cohort.

Objective: To determine the association between personality characteristics and use of different cancer screenings. Methods: We used data from the German National Cohort (NAKO; mean age was 53.0 years (SD: 9.2 years)) - a population-based cohort study. A total of 132,298 individuals were included in the analyses. As outcome measures, we used (self-reported): stool examination for blood (haemoccult test, early detection of bowel cancer), colonoscopy (screening for colorectal cancer), skin examination for moles (early detection of skin cancer), breast palpation by a doctor (early detection of breast cancer), x-ray examination of the breast ("mammography", early detection of breast cancer), cervical smear test, finger examination of the rectum (early detection of prostate cancer), and blood test for prostate cancer (determination of Prostate-Specific Antigen level). The established Big Five Inventory-SOEP was used to quantify personality factors. It was adjusted for several covariates based on the Andersen model. Unadjusted and adjusted multiple logistic regressions were computed. Results: A higher probability of having a skin examination for moles, for example, was associated with a higher conscientiousness (OR: 1.07, p < 0.001), higher extraversion (OR: 1.03, p < 0.001), higher agreeableness (OR: 1.02, p < 0.001), lower openness to experience (OR: 0.98, p < 0.001) and higher neuroticism (OR: 1.07, p < 0.001) among the total sample. Depending on the outcome used, the associations slightly varied. Conclusions: Particularly higher levels of extraversion, neuroticism and conscientiousness are associated with the use of different cancer screenings. Such knowledge may help to better understand non-participation in cancer screening examinations from a psychological perspective.

Overall survival in 92,991 colorectal cancer patients in Germany: differences according to type of comorbidity.

BACKGROUND: Poorer survival in cancer patients with vs. without comorbidity has been reported for various cancer sites. For patients with colorectal cancer (CRC), limited data are available so far. METHODS: Patients with CRC diagnosed between 2010 and 2018 were identified in a health claims database covering 20% of the German population. We assessed the prevalence of comorbidities at cancer diagnosis and categorized the patients into the groups: 'none', 'somatic only', 'mental only' or 'both' types of comorbidities. Hazard ratios (HR, with 95% confidence intervals) for five-year overall survival were estimated by Cox proportional hazard models, adjusted for age, sex and stage at diagnosis (advanced vs. non-advanced). RESULTS: We included 92,991 patients (females: 49.1%, median age: 72 years) with a median follow-up of 30 months. The proportions assigned to the groups 'none', 'somatic only', 'mental only' or 'both' were 24.7%, 65.5%, 1.4% and 8.4%. Overall, 32.8% of the patients died during follow-up. Compared to patients without comorbidities ('none'), the adjusted HR regarding death from any cause was 1.11 (95% CI: 1.07-1.14) in the group 'somatic only', 1.74 (95% CI: 1.58-1.92) in the group 'mental only' and 1.92 (95% CI: 1.84-2.00) in the group 'both'. For patients with 'mental only' comorbidities, the adjusted HR was higher in males than in females (HR = 2.19, 95% CI: 1.88-2.55 vs. HR = 1.55, 95% CI: 1.37-1.75). CONCLUSIONS: Our results suggest that patients with CRC and with mental comorbidities, particularly males, have a markedly lower overall survival compared to those without any or only somatic comorbidities.

German mammography screening program: program sensitivity between 2010 and 2016 estimated based on German health claims data.

BACKGROUND: Program sensitivity is a key quality indicator for mammography screening programs (MSP). Estimating program sensitivity usually requires a linkage of screening and cancer registry data. For the German MSP, such data linkage-based estimates have only been reported for two out of 16 federal states. We aimed to explore the potential of estimating program sensitivity for the German MSP based on information available in health claims data. METHODS: We used data from the second-largest statutory health insurance fund in Germany, BARMER (~ 9 million members all over Germany). We included women aged 50 to 69 years with a non-initial screening mammography between 2010 and 2016 and followed them up for two years. We estimated the rate of screen-detected and interval cancers as well as program sensitivity. RESULTS: Per year, we included 212,400 to 303,667 women (mean age: 60-61 years). Overall, 1,992,287 non-initial MSP screening examinations conducted in these women between 2010 and 2016 were considered for the analyses. Age-standardized program sensitivity ranged between 69.9% [95% CI: 67.3-72.0%] and 71.7% [95% CI: 69.5-73.9%] during the study period. Per 1,000 non-initial screening examinations, the rate of screen-detected breast cancer ranged between 4.6 and 5.3, and the rate of interval breast cancer rates ranged between 0.6 and 0.8 for the first and between 1.3 and 1.4 for the second year after screening. CONCLUSIONS: Our results were plausible and consistent with quality indicators estimated for the German MSP based on data linkage and thus support the value of German health claims data in this regard. The quality indicators estimated in our study are in line with levels expected according to European Guidelines.

German mammography screening program: adherence, characteristics of (non-)participants and utilization of non-screening mammography-a longitudinal analysis.

BACKGROUND: In Germany, all women aged 50-69 have been invited to biennial mammography screening since 2009. We aimed to assess longitudinal adherence over ten years in women aged 50 in 2009 and characterize the different adherence groups. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD, ~ 20% of the German population), we included women aged 50 in 2009 (baseline) with continuous health insurance coverage and without breast cancer or in-situ-carcinoma. We followed them until age 59 and categorized them according to mammography screening participation into the following groups: never, 1-2, 3-4, 5-6 times. We characterized these groups, inter alia, regarding the use of other preventive measures, non-screening mammography (i.e., mammography outside the organized screening program) and menopausal hormone therapy. RESULTS: Overall, 82,666 women were included. Of these, 27.6% never participated in the screening program, 15.1% participated 1-2 times, 31.7% participated 3-4 times and 25.6% participated regularly (5-6 times). Among regular participants, 91% utilized other preventive measures (e.g., cervical cancer screening, general health checkup) before baseline as compared to 66% among non-participants. Menopausal hormone therapy was least common among non-participants (11% vs. 18% among regular participants). Among non-participants, the proportions using ≥ 1, ≥ 2, and ≥ 3 non-screening mammographies between age 50-59 were 25%, 18%, and 15%, respectively. CONCLUSIONS: Using a large cohort based on claims data, this study provides novel insights into longitudinal adherence to the mammography screening program and the use of mammography outside of the program in Germany. Between age 50-59, 57% of eligible women participated at least three times in the German mammography screening program and 28% (~ 3 in 10 women) never participated. Among non-participants, 15% had at least three non-screening mammographies during this period, indicating potential gray screening. Participants more often utilized other preventive measures as compared to non-participants.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Methodology of the brodalumab assessment of hazards: a multicentre observational safety (BRAHMS) study.

INTRODUCTION: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections. METHODS AND ANALYSIS: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed. ETHICS AND DISSEMINATION: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS30280.

Polyp detection rate and cumulative incidence of post-colonoscopy colorectal cancer in Germany.

Studies have shown that the quality of colonoscopy influences the incidence of post-colonoscopy colorectal cancer (PCCRC). However, data from Germany on this association are lacking. We aimed to assess cumulative incidence of PCCRC in persons undergoing colonoscopy in Germany according to the physician's polyp detection rate (PDR). Using the German Pharmacoepidemiological Research Database (GePaRD) with claims data of ~20% of the German population, we included persons with a baseline colonoscopy between 2008 and 2017 and categorized them according to the procedure at baseline (snare polypectomy, forceps polypectomy, no polypectomy). In each subgroup, we distinguished between persons examined by physicians with a PDR in the lowest quartile vs higher quartiles and described cumulative CRC incidence during follow-up. Overall, 822 715 persons examined by 1752 physicians were included. One quarter of the physicians had a PDR ≤21.8% (lowest quartile). In all subgroups, the 5-year cumulative CRC incidence was statistically significantly higher in persons examined by physicians with a PDR ≤21.8% vs >21.8%: It was 69% higher in persons with snare polypectomy (0.88% vs 0.52%), 87% higher in persons with forceps polypectomy (0.58% vs 0.31%), and 48% higher in persons without polypectomy at baseline (0.31% vs 0.21%). In conclusion, we found a substantially increased PCCRC risk in persons examined by physicians with a low PDR in Germany, irrespective of the baseline findings. Our study highlights the importance of a high-quality colonoscopy to maximize the preventive effect of colonoscopy on CRC incidence.

Colorectal Cancer After Screening Colonoscopy: 10-Year Incidence by Site and Detection Rate at First Repeat Colonoscopy.

INTRODUCTION: We aimed to describe cumulative colorectal cancer (CRC) incidence after screening colonoscopy stratified by tumor location, age, and sex as well as CRC detection rate at first repeat colonoscopy. METHODS: Using the German Pharmacoepidemiological Research Database, we included persons with screening colonoscopy and assessed cumulative CRC incidence after baseline screening colonoscopy with snare polypectomy (cohort 1) and without polypectomy (cohort 2). We also determined the CRC detection rate at first repeat colonoscopy by time since screening colonoscopy. RESULTS: Overall, 1,095,381 persons were included. The 10-year cumulative CRC incidence was 1.5% in cohort 1 and 0.6% in cohort 2. The proportion of proximal CRC increased with age: In women of cohort 1, 47% of CRCs in the age group 55-64 years were proximal (men: 42%) while in the age group 65-74 years, this proportion was 55% (men: 49%). In cohort 2, similar patterns were observed. In cohort 1, the CRC detection rate at first repeat colonoscopy among persons examined within 6-8 years after screening colonoscopy was more than twice as high compared with those examined within 4-6 years (1.7% vs 0.8%). DISCUSSION: Among persons followed up after screening colonoscopy, we observed a steadily increasing predominance of proximal CRC, and this shift showed distinct patterns by age and sex. Because our study suggests higher CRC detection rates among persons with a later repeat colonoscopy, the role of delayed surveillance and the benefit of a reminder system should be explored.

Effectiveness of Mammography Screening on Breast Cancer Mortality - A Study Protocol for Emulation of Target Trials Using German Health Claims Data.

Background: The efficacy of mammography screening in reducing breast cancer mortality has been demonstrated in randomized trials. However, treatment options - and hence prognosis - for advanced tumor stages as well as mammography techniques have considerably improved since completion of these trials. Consequently, the effectiveness of mammography screening under current conditions is unclear and controversial. The German mammography screening program (MSP), an organized population-based screening program, was gradually introduced between 2005 and 2008 and achieved nation-wide coverage in 2009. Objective: We describe in detail a study protocol for investigating the effectiveness of the German MSP in reducing breast cancer mortality in women aged 50 to 69 years based on health claims data. Specifically, the proposed study aims at estimating per-protocol effects of several screening strategies on cumulative breast cancer mortality. The first analysis will be conducted once 10-year follow-up data are available. Methods and Analysis: We will use claims data from five statutory health insurance providers in Germany, covering approximately 37.6 million individuals. To estimate the effectiveness of the MSP, hypothetical target trials will be emulated across time, an approach that has been demonstrated to minimize design-related biases. Specifically, the primary contrast will be in terms of the cumulative breast cancer mortality comparing the screening strategies of "never screen" versus "regular screening as intended by the MSP". Ethics and Dissemination: In Germany, the utilization of data from health insurances for scientific research is regulated by the Code of Social Law. All involved health insurance providers as well as the responsible authorities approved the use of the health claims data for this study. The Ethics Committee of the University of Bremen determined that studies based on claims data are exempt from institutional review. The findings of the proposed study will be published in peer-reviewed journals.

Framework and baseline examination of the German National Cohort (NAKO).

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.

[Outpatient medical specialist care (ASV): A multiperspective study on status quo, challenges and perspectives]. / Ambulante Spezialfachärztliche Versorgung (ASV): eine multiperspektivische Studie zu Status quo, Herausforderungen und Perspektiven.

BACKGROUND: In 2012, the so-called ambulatory medical specialist care (ASV) was implemented in accordance with para. 116b of Book V of the German Social Code (SGB V), enabling physicians in outpatient practices and hospitals to treat patients with rare diseases or complex courses of disease in a uniform framework. The implementation, however, is slow. The Joint Federal Committee (G-BA) has therefore commissioned an evaluation of the ASV with the aim to examine the reasons for this and to provide recommendations for further development. METHODS: The health services research study "GOAL-ASV" (Innovation Fund, 01VSF19002) included a multi-perspective design with primary data collection as well as secondary data analyses. Data from the ASV service center and the central association of statutory health insurances and the notification forms of the extended state committees were analyzed. Data from the Robert Koch-Institute, the Federal Joint Committee, the National Association of Statutory Health Insurance Funds and a literature database analysis were used in order to estimate the proportion of insured persons qualifying for ASV. Care was examined by analyzing pseudonymized routine data from the statutory health insurances using selected indicators. Participating and not participating physicians were asked to complete an online survey. RESULTS: Since the start of ASV, 615,531 insured persons have been treated in this form of care. At the time of analysis, 509 teams were operating, with 26,540 physicians treating 102,898 patients by the end of March 2021 in all indications. This comprises less than 9.8 %. of all approx. 1.05 million eligible patients. Especially in the case of rare diseases, a low willingness of participation can be seen. In addition, there was a relevant proportion of multiple uses of physicians within and outside ASV at 31 percent as well as indications of passive participation of doctors. We found significant regional differences in type and scope of the notification procedure as well as the implementation of teams with 13.4 teams per 1 million inhabitants in Schleswig-Holstein and no team in Mecklenburg-Vorpommern. Patient benefits (84 %), interdisciplinary (82 %) and cross-sectoral cooperation (75 %) were cited as motivations for participation. The main barriers reported by the respondents were the complex and laborious notification procedure (60 %), the administrative and documentation effort during participation (50 %), insufficient billing figures (49 %), and a small proportion of patients (32 %) with a consecutively unfavorable assessment of the cost to income ratio due to the current reimbursement system. DISCUSSION: Nearly ten years after its introduction, the ASV has not become established nationwide. The reasons for this probably are the complex notification procedure and the reimburesement system for rare diseases. In the case of rare diseases, the risk of underuse is becoming apparent. CONCLUSION: Strategies to further develop the ASV should, in particular, simplify the notification procedure and reduce the obstacles during participation. The remuneration system should take more account of the specific care required.

Screening colonoscopy similarly prevented distal and proximal colorectal cancer: a prospective study among 55-69-year-olds.

OBJECTIVES: We aimed to evaluate the effectiveness of screening colonoscopy in reducing incidence of distal vs. proximal colorectal cancer (CRC) in persons aged 55-69 years. STUDY DESIGN AND SETTING: Using observational data from a German claims database (German Pharmacoepidemiological Research Database), we emulated a target trial with two arms: Colonoscopy screening vs. no-screening at baseline. Adjusted cumulative incidence of total, distal, and proximal CRC over 11 years of follow-up was estimated in 55-69-year-olds at an average CRC risk and without colonoscopy, polypectomy, or fecal occult blood test before baseline. RESULTS: Overall, 307,158 persons were included (screening arm: 198,389 and control arm: 117,399). The adjusted 11-year risk of any CRC was 1.62% in the screening group and 2.38% in the no-screening group resulting in a relative risk of 0.68 (95% CI: 0.63-0.73). The relative risk was 0.67 for distal CRC (95% CI: 0.62-0.73) and 0.70 (95% CI: 0.63-0.79) for proximal CRC. The cumulative incidence curves of the groups crossed after 6.7 (distal CRC) and 5.0 years (proximal CRC). CONCLUSION: Our results suggest that colonoscopy is effective in preventing distal and proximal CRC. Unlike previous studies not using a target trial approach, we found no relevant difference in the effectiveness by location.

Initial and ten-year treatment patterns among 11,000 breast cancer patients undergoing breast surgery-an analysis of German claims data.

BACKGROUND: We aimed to explore the potential of German claims data for describing initial and long-term treatment patterns of breast cancer patients undergoing surgery. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD, ~ 20% of the German population) we included patients with invasive breast cancer diagnosed in 2008 undergoing breast surgery and followed them until 2017. We described initial and long-term treatment patterns and deaths. Analyses were stratified by stage (as far as available in claims data), age at diagnosis, and mode of detection (screen-detected vs. interval vs. unscreened cases). RESULTS: The cohort comprised 10,802 patients. The proportion with neoadjuvant therapy was highest in patients < 50 years (19% vs. ≤ 8% at older ages). The proportion initiating adjuvant chemotherapy within four months after diagnosis decreased with age (< 50 years: 63%, 50-69: 46%, 70-79: 27%, 80 + : 4%). Among women < 69 years, ~ 30% had two breast surgeries in year one (70-79: 21%, 80 + : 14%). Treatment intensity was lower for screen-detected compared to interval or unscreened cases, both in year one (e.g., proportion with mastectomy ~ 50% lower) and within 2-10 years after surgery (proportions with radiotherapy or chemotherapy about one third lower each). CONCLUSIONS: This study illustrates the potential of routine data to describe breast cancer treatment and provided important insights into differences in initial and long-term treatment by mode of detection and age.

10-year prevalence of diagnostic and screening colonoscopy use in Germany: a claims data analysis.

INTRODUCTION: Studies providing detailed information on colonoscopy use are important for the interpretation of patterns and trends in colorectal cancer incidence and mortality, but there is a lack of such studies from Germany. To fill this gap, we aimed to describe the 10-year prevalence of colonoscopy use based on German health claims data. METHODS: Using the German Pharmacoepidemiological Research Database (short GePaRD; claims data from ~20% of the German population), we determined the 10-year prevalence of colonoscopy use for the year 2017. We determined this prevalence for any colonoscopy, screening (reimbursable from age 55) and diagnostic colonoscopy, stratified by sex, age, educational level and regional factors (e.g. federal state, physicians density in the district of residence). RESULTS: In men, the 10-year prevalence of colonoscopy use was as follows (not all age groups reported): 30-34 years: 8%, 40-44 years: 12%, 50-54 years: 21%, 55-59 years: 33% (screening: 10%), 60-64 years: 44% (screening: 23%), 70-74 years: 53% (screening: 23%), 80-84 years: 52% (screening: 15%). In women, the prevalences were similar, with differences mostly less than or equal to 3 percentage points. Also, in analyses stratified by educational level or regional factors, prevalences were mostly similar or varied by less than or equal to 4 percentage points. CONCLUSION: In 2017, about 45-50% of men and women in Germany aged 60-84 years had any colonoscopy in the previous 10 years, and about 11-26% had a screening colonoscopy. Our findings suggest no relevant social or regional disparities in the utilization of colonoscopy in Germany.

Risk-stratified strategies in population screening for colorectal cancer.

Colorectal cancer (CRC) screening has been demonstrated to reduce CRC incidence and mortality. However, besides such benefits, CRC screening is also associated with potential harmful effects. In an ideal world, screening would only be directed to the small proportion of the population that might potentially benefit. Risk-based screening can be seen as a first step towards this ideal world, by redistributing screening resources from low-risk to high-risk individuals. In theory, this should result in scarce resources being used in individuals who benefit most, while intensity of screening is reduced in individuals who benefit less, hence improving the benefit-harm ratio among all invitees. Available strategies that have been proposed for risk-based CRC screening include using information on age, sex, prior screening history, lifestyle and/or genetic information. Implementation of risk-based screening requires careful consideration of reliable risk prediction models, participation with screening and informed decision-making. While it is important to recognise the limitations of current approaches, available evidence suggests that it might be feasible to start planning the introduction of tailored strategies within screening programmes. Implementing risk-based screening based on age, sex and prior screening history alone would already represent a substantial improvement over current uniform screening approaches. We propose that it is time that screening programmes start there and continue striving towards more comprehensive approaches embedding primary prevention as an effective approach to lower risk for everyone.

Avoiding Time-Related Biases: A Feasibility Study on Antidiabetic Drugs and Pancreatic Cancer Applying the Parametric g-Formula to a Large German Healthcare Database.

PURPOSE: Investigating intended or unintended effects of sustained drug use is of high clinical relevance but remains methodologically challenging. This feasibility study aims to evaluate the usefulness of the parametric g-formula within a target trial for application to an extensive healthcare database in order to address various sources of time-related biases and time-dependent confounding. PATIENTS AND METHODS: Based on the German Pharmacoepidemiological Research Database (GePaRD), we estimated the pancreatic cancer incidence comparing two hypothetical treatment strategies for type 2 diabetes mellitus (T2DM), i.e., (A) sustained metformin monotherapy vs (B) combination therapy with DPP-4 inhibitors after one year metformin monotherapy. We included 77,330 persons with T2DM who started metformin therapy at baseline between 2005 and 2011. Key aspects for avoiding time-related biases and time-dependent confounding were the emulation of a target trial over a 7-year follow-up period and application of the parametric g-formula. RESULTS: Over the 7-year follow-up period, 652 out of the 77,330 study subjects had a diagnosis of pancreatic cancer. Assuming no unobserved confounding, we found evidence that the metformin/DPP-4i combination therapy increased the risk of pancreatic cancer compared to a sustained metformin monotherapy (risk ratio: 1.47; 95% bootstrap CI: 1.07-1.94). The risk ratio decreased in sensitivity analyses addressing protopathic bias. CONCLUSION: While protopathic bias could not fully be ruled out, and computational challenges necessitated compromises in the analysis, the g-formula and target trial emulation proved useful: Self-inflicted biases were avoided, observed time-varying confounding was adjusted for, and the estimated risks have a clear causal interpretation.

Associations between comorbidities and advanced stage diagnosis of lung, breast, colorectal, and prostate cancer: A systematic review and meta-analysis.

Comorbidities and advanced stage diagnosis (ASD) are both associated with poorer cancer outcomes, but the association between comorbidities and ASD is poorly understood. We summarized epidemiological evidence on the association between comorbidities and ASD of selected cancers in a systematic review and meta-analysis. We searched PubMed and Web of Science databases up to June 3rd, 2021 for studies assessing the association between comorbidities and ASD of lung, breast, colorectal, or prostate cancer. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using random-effects models. Also, potential variations in the associations between comorbidities and ASD by cancer type were investigated using random-effects meta-regression. Thirty-seven studies were included in this review, including 8,069,397 lung, breast, colorectal, and prostate cancer patients overall. The Charlson comorbidity index score was positively associated with ASD (stages III-IV) of breast cancer but was inversely associated with ASD of lung cancer (pinteraction = 0.004). Regarding specific comorbidities, diabetes was positively associated with ASD (OR = 1.17, 95%CI = 1.09-1.26), whereas myocardial infarction was inversely associated with ASD (OR = 0.84, 95%CI = 0.75-0.95). The association between renal disease and ASD differed by cancer type (pinteraction < 0.001). A positive association was found with prostate cancer (OR = 2.02, 95%CI = 1.58-2.59) and an inverse association with colorectal cancer (OR = 0.84, 95%CI = 0.70-1.00). In summary, certain comorbidities (e.g., diabetes) may be positively associated with ASD of several cancer types. It needs to be clarified whether closer monitoring for early cancer signs or screening in these patients is reasonable, considering the problem of over-diagnosis particularly relevant in patients with short remaining life expectancy such as those with comorbidities. Also, evaluation of the cost-benefit relationship of cancer screening according to the type and severity of comorbidity (rather than summary scores) may be beneficial for personalized cancer screening in populations with chronic diseases.

Characteristics and Absolute Survival of Metastatic Colorectal Cancer Patients Treated With Biologics: A Real-World Data Analysis From Three European Countries.

Introduction: Biologics were approved for the treatment of advanced colorectal cancer (CRC) based on favorable benefit-risk-assessments from randomized controlled trials (RCTs), but evidence on their use in the real-world setting is scarce. Based on descriptive analyses we therefore aimed to assess characteristics and survival of CRC patients treated with biologics using large healthcare databases from three European countries (Netherlands, Italy, Germany). Methods: We included CRC patients treated with a biologic in 2010 or 2014 and characterized them regarding age, sex, comorbidities, and absolute survival. Results: Among 4,758 patients, the mean age ranged from 64.8 to 66.8 years, the majority was male, and comorbidities used as exclusion criteria in RCTs were coded in up to 30% of these patients. The proportion of bevacizumab users decreased between 2010 (72-93%) and 2014 (63-85%). In 2014, the absolute 12-month survival in new users was 64% (95% CI 51-77%), 56% (30-80%), and 61% (58-63%) in the Dutch, Italian, and German database, respectively, varying by age and comorbidity. Conclusions: Our study suggests that in the real-world setting, CRC patients treated with biologics are older and less selected regarding comorbidities compared to patients in RCTs, potentially explaining the relatively low 12-month survival we found. Treatment decisions in the real-world setting may require careful evaluation given that the risk-benefit ratio may vary depending on age and co-existing conditions.