Lead-Time Corrected Effect on Breast Cancer Survival in Germany by Mode of Detection.

(1) Background: Screen-detected breast cancer patients tend to have better survival than patients diagnosed with symptomatic cancer. The main driver of improved survival in screen-detected cancer is detection at earlier stage. An important bias is introduced by lead time, i.e., the time span by which the diagnosis has been advanced by screening. We examine whether there is a remaining survival difference that could be attributable to mode of detection, for example, because of higher quality of care. (2) Methods: Women with a breast cancer (BC) diagnosis in 2000-2022 were included from a population-based cancer registry from Schleswig-Holstein, Germany, which also registers the mode of cancer detection. Mammography screening was available from 2005 onwards. We compared the survival for BC detected by screening with symptomatic BC detection using Kaplan-Meier, unadjusted Cox regressions, and Cox regressions adjusted for age, grading, and UICC stage. Correction for lead time bias was carried out by assuming an exponential distribution of the period during which the tumor is asymptomatic but screen-detectable (sojourn time). We used a common estimate and two recently published estimates of sojourn times. (3) Results: The analysis included 32,169 women. Survival for symptomatic BC was lower than for screen-detected BC (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.21-0.25). Adjustment for prognostic factors and lead time bias with the commonly used sojourn time resulted in an HR of 0.84 (CI: 0.75-0.94). Using different sojourn times resulted in an HR of 0.73 to 0.90. (4) Conclusions: Survival for symptomatic BC was only one quarter of screen-detected tumors, which is obviously biased. After adjustment for lead-time bias and prognostic variables, including UICC stage, survival was 27% to 10% better for screen-detected BC, which might be attributed to BC screening. Although this result fits quite well with published results for other countries with BC screening, further sources for residual confounding (e.g., self-selection) cannot be ruled out.

Initial Evidence of a Possible Effect of HPV Vaccination on Cancer Incidence in Germany.

BACKGROUND: Infection with human papillomavirus (HPV) is one of the more common sexually transmitted diseases in Germany. Vaccination against HPV was introduced in Germany in 2007. In this study, we sought to detect a population-based decline in the incidence of cervical cancer in women under age 30 who were eligible for vaccination in the first 11 years after its introduction. METHODS: Data on new diagnoses of HPV-associated cervical cancer from 2004 to 2018 were obtained from the cancer registries of the German federal states (Bundesländer) through the German Center for Cancer Registry Data (ZfKD). Trends in the incidence of invasive and in situ cervical cancer were determined with log-linear joinpoint regression and age-period-cohort models. RESULTS: The incidence of cervical cancer, which had been rising in the previous decades, has been falling since 2010, with a marked decline among women in all age groups eligible for vaccination (e.g., from 70.0 to 41.8 cases per 100 000 persons per year from 2010 to 2018 in women aged 24 to 26). Women born in 1992 were the first to become eligible for vaccination and have a 24% lower incidence than the reference cohort of women born in 1989 (relative risk 0.76, 95% confidence interval [0.68; 0.86]). Larger effects were found in later birth cohorts, in which vaccination was more widespread. CONCLUSION: Eleven years after the introduction of HPV vaccination, a drop in the incidence of cervical cancer was observable at the population level in the birth cohorts eligible for vaccination.

Longer Survival From Melanoma in Germany.

BACKGROUND: New treatment options for cutaneous melanomas with a poor prognosis have been available since 2011, including immune therapies and targeted drugs. Randomized controlled trials have demonstrated that these treatments improve survival, but no population- level studies have been available to date. METHODS: All patients in the database of the Center for Cancer Registry Data (Zentrum für Krebsregisterdaten) who had a diagnosis of melanoma (ICD10: C43) in the years 2000 to 2019 were included in the study. The relative five-year survival (5YRS) was calculated for four 5-year periods (2000-04, 2005-09, 2010-14, 2015-19). The data were standardized/stratified according to sex, age group, and UICC stage to correct for differences between regions and over time. Regression models were used to detect statistically significant secular trends. RESULTS: 301 486 individuals were included in the study. The overall 5YRS rose from 93% (2000-04) to 95% (2015-19). The 5YRS in 2015-19 was similar to or greater than that in 2000-04 for all subgroups. The largest rises in 5YRS were between 2010-14 and 2015-19, and specifically in advanced stages: for UICC stage IV tumors, the 5YRS rose from 31% to 36%. There was a significant rising trend across the four time periods (p < 0.001). CONCLUSION: The survival of melanoma patients has improved over the past 20 years. From 2010-14 to the most recent period, the largest changes were seen in advanced tumor stages. This favorable development coincided with the introduction of new therapies.

Evaluation of skin cancer screening in Germany - Spatiotemporal associations between skin cancer screening and skin cancer mortality based on ambulatory claims data.

BACKGROUND: There are regional differences in skin cancer screening uptake in Germany. So far, it is unclear whether a high uptake of screening services leads to a reduction in mortality. This article presents study results on the investigation of spatiotemporal associations between skin cancer screening and mortality. The methods used are discussed regarding their suitability. MATERIAL AND METHODS: The basis is ambulatory claims data on the utilization of early skin cancer detection as well as data on skin cancer mortality from the cause-of-death statistics of the years 2011-2015 at county level in Germany. In addition to a descriptive evaluation, spatiotemporal cluster analyses and regression models were used to investigate the relationship between the uptake of early detection and mortality. In addition to age, adjustments were also made for other selected socio-economic and socio-graphical variables. RESULTS: The descriptive results show striking spatial patterns of skin cancer screening and mortality. Cluster analyses identified regions with significantly higher and lower cases of early detection and skin cancer mortality. The spatiotemporal regression analyses show no clear association. Only early detection by a dermatologist, adjusted for age, shows an association with mortality. CONCLUSIONS: No clear association between early skin cancer detection and mortality can be derived from the results. However, the study design used with a spatiotemporal cluster and regression analysis has shown that these methods allow in-depth statements about the relationship between early skin cancer detection and mortality.

Evaluation of early skin cancer detection in Germany with cancer registry data - challenges, solutions and current trends.

BACKGROUND AND AIMS: The evidence for the benefit of the skin cancer screening introduced in Germany in 2008 is weak. We investigate to what extent data from the German epidemiological cancer registries are suitable to contribute to the evaluation of skin cancer screening and report these evaluation results. MATERIAL AND METHODS: Skin cancer-related cancer registry data from 1999-2019 were described in terms of completeness and comprehensiveness. Regional pools with data of different validity were defined, missing data were multiply imputed where appropriate, and temporal trends were analyzed. In addition, data from the cause of death statistics were used. RESULTS: Reliable estimates of completeness are only available for malignant melanoma (ICD-10: C43). Based on a regional data pool covering approximately 21% of the German population, melanoma-related incidence can be validly described since 2005. Sufficient information for multiple imputation is available for T-stage and localization. The trend analyses show incidence changes that can be expected in the short term in the temporal context of the introduction of early detection, which changes into a long-lasting high incidence. The rate of advanced stages does not decrease significantly. From 2014 onwards, the melanoma mortality rate, which had been rising until then, decreases. CONCLUSIONS: Adequately selected and processed cancer registry data are suitable for population-based evaluation of skin cancer screening. An explanation of the persistently high incidence level is not possible based on the cancer registry data. Overdiagnosis or an increase in the background incidence can be considered. The benefit of skin cancer screening remains open.

Evaluation of skin cancer screening in Germany - participation, tumor detection and interval tumors based on SHI data.

BACKGROUND AND GOALS: The rising incidence of skin cancer in Germany has increased the need for secondary prevention measures. For this purpose, a statutory skin cancer screening for insured persons aged 35 and older was introduced on 1 June 2008. The aim of this work package in the Innovation Fund project "Perspectives of a multimodal evaluation of early skin cancer detection" (Pertimo) was to test an evaluation of skin cancer screening using secondary data. PATIENTS AND METHODS: The data basis was statutory insured persons of the DAK Health from the age of 35 who were insured as of 31 December 2010 and were followed up until the end of 2015. The rates of participation, skin tumors detected in skin cancer screening (tumor detections), and interval tumors that occurred within two years after a finding-free skin cancer screening were calculated. RESULTS: The biennial skin cancer screening take-up rate in 2014 and 2015 was 33.6% for women and 32.6% for men. Of those screened, 4.2% had a skin cancer finding (tumor detection) in the course of skin cancer screening. Of all incident skin cancer diagnoses (2012-2015), 50.1% were detected in skin cancer screening. In 1.5% of the insured persons with skin cancer screening without findings, an incidental skin tumor was diagnosed in the following two years (interval tumor). CONCLUSIONS: The data from the statutory health insurance mapped the skin cancer screening occurrence in Germany and highlighted the importance of dermatologists in the screening process. The analysis provided important new insights.

Association of early-stage incidence and mortality in malignant melanoma - a population-based ecological study.

BACKGROUND: Germany-wide skin cancer screening was introduced in 2008 to reduce skin cancer mortality and morbidity. However, the effectiveness of the program is still unclear. We explore the relationship between early-stage melanoma incidence and melanoma mortality in subsequent years, using early-stage melanoma incidence as surrogate for screening participation and early detection. PATIENTS AND METHODS: Data on melanoma incidence for 2005-2016 and melanoma mortality for 2005-2018 were obtained for 244 German counties. We investigated the correlation between several measures of incidence and mortality with correlation analyses and linear regressions. RESULTS: Melanoma incidence of early stages (in situ and T1) rose by 69% between pre-screening (2005-2007) and screening period (2008-2010). In contrast, there was no temporal trend in mortality over time. Correlation coefficients between incidence and mortality variables ranged between -0.14 and 0.10 (not significant). Linear regression indicated that mortality 6 years after screening introduction decreases with increasing change in early-stage incidence (b = -0.0029, 95% confidence interval [-0.0066, 0.0007]). CONCLUSIONS: The estimated population-based effects of skin cancer screening on melanoma mortality were minimal and not significant. A potential effectiveness cannot be demonstrated.

Does the morphology of cutaneous melanoma help to explain the international differences in survival? Results from 1 578 482 adults diagnosed during 2000-2014 in 59 countries (CONCORD-3).

BACKGROUND: CONCORD-3 highlighted wide disparities in population-based 5-year net survival for cutaneous melanoma during 2000-2014. Clinical evidence suggests marked international differences in the proportion of lethal acral and nodular subtypes of cutaneous melanoma. OBJECTIVES: We aimed to assess whether the differences in morphology may explain global variation in survival. METHODS: Patients with melanoma were grouped into the following seven morphological categories: malignant melanoma, not otherwise specified (International Classification of Diseases for Oncology, third revision morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722-8723, 8726-8727, 8730, 8740-8741, 8746, 8761, 8770-8774, 8780). We estimated net survival using the nonparametric Pohar Perme estimator, correcting for background mortality by single year of age, sex and calendar year in each country or region. All-ages survival estimates were standardized using the International Cancer Survival Standard weights. We fitted a flexible parametric model to estimate the effect of morphology on the hazard of death. RESULTS: Worldwide, the proportion of nodular melanoma ranged between 7% and 13%. Acral lentiginous melanoma accounted for less than 2% of all registrations but was more common in Asia (6%) and Central and South America (7%). Overall, 36% of tumours were classified as superficial spreading melanoma. During 2010-2014, age-standardized 5-year net survival for superficial spreading melanoma was 95% or higher in Oceania, North America and most European countries, but was only 71% in Taiwan. Survival for acral lentiginous melanoma ranged between 66% and 95%. Nodular melanoma had the poorest prognosis in all countries. The multivariable analysis of data from registries with complete information on stage and morphology found that sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes. CONCLUSIONS: This study provides the broadest picture of distribution and population-based survival trends for the main morphological subtypes of cutaneous melanoma in 59 countries. The poorer prognosis for nodular and acral lentiginous melanomas, more frequent in Asia and Latin America, suggests the need for health policies aimed at specific populations to improve awareness, early diagnosis and access to treatment. What is already known about this topic? The histopathological features of cutaneous melanoma vary markedly worldwide. The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin. What does this study add? We aimed to assess the extent to which these differences in morphology may explain international variation in survival when all histological subtypes are combined. This study provides, for the first time, international comparisons of population-based survival at 5 years for the main histological subtypes of melanoma for over 1.5 million adults diagnosed during 2000-2014. This study highlights the less favourable distribution of histological subtypes in Asia and Central and South America, and the poorer prognosis for nodular and acral lentiginous melanomas. We found that later stage at diagnosis does not fully explain the higher excess risk of death for nodular and acral lentiginous melanoma compared with superficial spreading melanoma.

Breast cancer incidence and mortality before and after implementation of the German mammography screening program.

Effective population-based mammography screening should impact breast cancer (BC) incidence, age and stage-specific incidence and BC mortality. We aim to investigate such effects in a time period of 10 years after implementation of the German mammography screening program. Data on 323,719 breast cancer patients from 2003 to 2014 for defined regions covering a population of 30 million inhabitants and official mortality data from 1998 to 2016 for almost the whole of Germany were used. We compared incidence and mortality rates for the prescreening time period (2003/2004) and the latest available data (2013/2014 and 2015/2016, respectively) and performed trend analyses using joinpoint regression models. In the screening exposed age groups (50-59 and 60-69 years), BC incidence showed a typical prevalence peak with the introduction of the mammography screening, mainly driven by an increase of early-stage BC. For Stage III and IV BC incidence in 2013/2014 was 24.2 and 23.0% (age group 50-59 years) and 28.3 and 24.2% (age group 60-69 years) lower than in the prescreening period. From 2003/2004 to 2015/2016 BC mortality decreased by 25.8 and 21.2%, respectively. As corresponding trends in nonexposed age groups were distinctly unfavorable, the reduction of late-stage BC incidence and BC mortality in the screening exposed age groups in Germany is most likely to be attributed to the introduction of the national mammography screening program. These positive effects are bought at the cost of a moderate occurrence of overdiagnosis, especially by a sharp increase of in situ cancers.

Long-term relative survival from melanoma in Germany 1997-2013.

Up-to-date melanoma relative survival (RS) estimates and trend analysis facilitate close monitoring of melanoma patients' prognosis. This study aimed to provide recent 5-year and 10-year RS from melanoma, stratified by prognostic factors, and identify latest survival trends. Data from 12 German cancer registries were analysed. We included patients with primary cutaneous malignant melanoma (ICD-10: C43.X) diagnosed in 1997-2013 who were at least 15 years old. Five-year and 10-year RS were estimated by period analysis. For 10-year RS analyses, we excluded patients who were 75 years of age or older. Analyses were stratified by sex, age, histology, tumour stage, and body site. We included 82 901 patients, of whom 51% were women. The median age at diagnosis was 62 years. Five-year and 10-year RS in 2007-2013 were 92.4 and 90.8%, respectively. RS was higher in women. The prognosis worsened with older age and higher stage. In superficial spreading melanoma and lentigo maligna melanoma, RS was high; it was lower in nodular, acral lentiginous and 'other' melanoma. RS was the highest for melanoma on the arms; RS for melanoma on unknown or overlapping sites of the skin was the lowest. Five-year and 10-year RS increased significantly from 2005-2007 and 2008-2010 to 2011-2013, by 3.5 and 3.3 percentage points, respectively. For melanoma of 'other' histology, 5-year and 10-year RS increased significantly. Ten-year RS also increased significantly in men with superficial spreading melanoma and T4 melanoma, and in women with T3 melanoma. Melanoma RS improved, especially in certain subgroups. The reasons for improvements need to be investigated further.

Colorectal cancer screening by colonoscopy and trends in disease-specific mortality: a population-based ecological study of 358 German districts.

PURPOSE: Screening for colorectal cancer (CRC) by colonoscopy was implemented in Germany in 2002. Although the procedure has proven to be effective in reducing disease-specific mortality in numerous clinical studies, its effect at the population level is unclear. We performed an ecological study at the level of 358 German districts, testing the hypothesis that a higher participation rate in screening colonoscopy is associated with a stronger decline in CRC mortality from 2001 to 2012. METHODS: Information on the use of colonoscopy in each district was extracted from settlement data, used for the remuneration of physicians of the ambulant sector from 2008 to 2011. Yearly mortality rates for each district from 2001 to 2012 were derived from the official mortality statistics. A spatial model was fitted, considering other factors which might influence early detection of CRC (fecal occult blood test (FOBT), diagnostic colonoscopy, material and social area deprivation, and rural-urban disparities). RESULTS: The population-weighted mean annual participation rate during 2008-2011 in screening colonoscopy was 2.0% (range 0.6 to 3.9%). The weighted mean annual percentage change (APC) of CRC mortality was - 2.9% (range - 7.8 to 1.2%). According to the fully adjusted model, a 1% higher annual participation rate in colonoscopy screening was associated with an additional annual change in CRC mortality rate of - 0.34% (p = 0.015). Given an annual 2.0% participation rate, colonoscopy screening attributed 23% to the observed decline. CONCLUSIONS: Our real-world data from Germany provide first evidence that colonoscopy screening for CRC is effective in reducing disease-specific mortality at the population level.

A population-based registry study on relative survival from melanoma in Germany stratified by tumor thickness for each histologic subtype.

BACKGROUND: Differences in relative survival (RS) of melanoma between histologic subtypes were discussed to be mainly caused by tumor thickness. OBJECTIVE: To investigate RS of melanoma, stratified by tumor thickness for each histologic subtype, and identify survival trends. METHODS: With use of cancer registry data on melanoma cases (International Classification of Diseases, 10th Revision, codes C43.0-C43.9) diagnosed in Germany in 1997-2013, 5- and 10-year age-standardized RS stratified by histologic subtype and stratified or standardized by T stage was estimated by standard and modeled period analyses. We restricted 10-year RS analyses to patients younger than 75 years. RESULTS: We analyzed 82,901 cases. Overall, the 5- and 10-year RS rates were 91.7% and 90.8%, respectively. Prognosis worsened with increasing T stage for all histologic subtypes, but T-stage distribution varied substantially. Survival differences by histologic subtype were strongly alleviated after adjustment for T stage but remained significant. Overall, 5-year RS increased significantly (by 3.8 percentage points) between the periods 2002-2005 and 2010-2013. This increase was no longer seen after adjustment for T stage. LIMITATIONS: Exclusion of cases on account of missing information on T stages, changes in the definition of T stages, and lack of information on screening and treatment limit our analyses. CONCLUSION: Differences in RS between histologic subtypes were strongly mediated by tumor thickness. Over time, RS of melanoma increased as a result of changes in T-stage distribution.

[Skin cancer screening in Germany: review after ten years]. / Hautkrebsscreening in Deutschland: Bilanz nach zehn Jahren.

In 2008, a nationwide population-based skin cancer screening program was introduced in Germany. Its potential to reduce the skin cancer-related burden of disease is the subject of a controversial debate. This article gives an overview on the epidemiology of cutaneous melanoma of the skin and nonmelanoma skin cancer, on the history and practice of the current program, and appraises the evidence of screening for skin cancer based on a selective search for literature and data.The incidence of skin cancer has increased markedly throughout the last decades. The available evidence indicates efficacy of screening for skin cancer, but on a low level. Randomized controlled trials are lacking and the available evidence is based largely on the pilot study SCREEN which was conducted in 2003/2004 in Schleswig-Holstein, Germany. Following this pilot study, a marked decline of melanoma mortality was observed. After implementation of nationwide skin cancer screening, a mortality reduction has not appeared so far.A comparison of nationwide skin cancer screening and the SCREEN project suggests a lower intensity of the current screening program. Its process and outcome quality requires further investigations. Improved documentation allowing for a linkage between screening procedures conducted by nondermatologists and dermatologists is desirable. Personal invitations could help to reach individuals who currently make little or no use of skin cancer screening but might benefit from it.

Observed and expected mortality in the German skin cancer screening pilot project SCREEN.

Objective The main purpose of skin cancer screening is melanoma mortality reduction. Before the implementation of nationwide German skin cancer screening, the pilot project SCREEN was conducted in Schleswig-Holstein in 2003-2004. We aimed to determine whether the pilot project had achieved a mortality reduction. Methods Using an incidence-based approach (patients with both melanoma diagnosis and death in 2003-2008), we compared the observed melanoma mortality of the SCREEN cohort to the melanoma mortality expected without screening in the general population of Saarland. Results The age- and sex-standardized melanoma mortality ratio (SMR) for 5.5 years of follow-up was 0.59 (95% confidence interval, 0.40-0.83). Conclusion Our results indicate reduced mortality in the SCREEN cohort. Several potential biases cannot be excluded, but most of them tend to inflate the SMR.

Association between risk factors and detection of cutaneous melanoma in the setting of a population-based skin cancer screening.

Early detection is considered to improve the prognosis of cutaneous melanoma. The value of population-based screening for melanoma, however, is still controversial. The aim of this study was to evaluate the predictive power of established risk factors in the setting of a population-based screening and to provide empirical evidence for potential risk stratifications. We reanalyzed data (including age, sex, risk factors, and screening results) of 354 635 participants in the Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany (SCREEN)project conducted in the German state of Schleswig-Holstein (2003-2004). In multivariable analysis, atypical nevi [odds ratio (OR): 17.4; 95% confidence interval (CI): 14.4-20.1], personal history of melanoma (OR: 5.3; 95% CI: 3.6-7.6), and multiple (≥40) common nevi (OR: 1.3; 95% CI: 1.1-1.6) were associated with an increased risk of melanoma detection. Family history and congenital nevi were not significantly associated with melanoma detection in the SCREEN. The effects of several risk-adapted screening strategies were evaluated. Hypothesizing a screening of individuals aged more than or equal to 35 years, irrespective of risk factors (age approach), the number needed to screen is 559 (95% CI: 514-612), whereas a screening of adults (aged ≥20) with at least one risk factor (risk approach) leads to a number needed to screen of 178 (95% CI: 163-196). Converted into one screen-detected melanoma, the number of missed melanomas is 0.15 (95% CI: 0.12-0.18) with the age approach and 0.22 (95% CI: 0.19-0.26) with the risk approach. The results indicate that focusing on individuals at high risk for melanoma may improve the cost-effectiveness and the benefit-to-harm balance of melanoma screening programs.

[The cartographic depiction of regional variation in morbidity : Data analysis options using the example of the small-scale cancer atlas for Schleswig-Holstein]. / Die kartografische Darstellung regionaler Unterschiede in der Morbidität : Möglichkeiten der Datenanalyse am Beispiel des kleinräumigen Krebsatlasses Schleswig-Holstein.

The cancer registry in Germany collects area-wide small-area data that can be presented in themes (disease mapping). Because of the occurrence of random extreme values of rates, mapping without prior spatial-statistical data analysis is problematic from a methodological and risk-communicative viewpoint - the extreme values easily mislead the card reader and obscure actual spatial patterns.The problem of data instability can generally be met by aggregation or by smoothing. The cancer atlas for Schleswig-Holstein is based on data from 1142 municipalities (median population: 721) for the diagnostic years 2001-2010. Maps for incidence (as a standardized incidence ratio), mortality (as a standardized mortality ratio), and relative survival (as a relative excess risk) were smoothed by using a Bayesian method (BYM model). The maps show that spatial differences can be made visible by smoothing.Data aggregation is the methodically simpler way, but means a loss of information. The atlas shows that small-scale mapping is possible while preserving the entire spatial information. The method of smoothing is complex, but useful for generating hypotheses. The spatial patterns found are complex, difficult to interpret, and require the collaboration of specialists from different professions, because of the diverse influencing factors (data collection, lifestyle factors, early detection, risk factors, etc.). The effort required to explain the methodology in a language easy to understand should not be underestimated.