Subsequent primary neoplasms after childhood cancer therapy - design and description of the German nested case-control study STATT-SCAR.

BACKGROUND: Subsequent primary neoplasms (SPN) are among the most severe late effects and the second most frequent cause of death in childhood cancer patients. In this paper we introduce method and properties of the STATT-SCAR study (Second Tumor After Tumor Therapy, Second Cancer After Radiotherapy), which is a joint nested matched case-control study to evaluate the impact of chemotherapy (STATT) as well as radiotherapy (SCAR) on the risk of developing a SPN. METHODS: Based on the cohort of the German childhood cancer registry (GCCR), we selected patients diagnosed with a first neoplasm before age 15 or younger between 1980 and 2014. We selected those with a SPN at least half a year after the first neoplasm, and matched up to four controls to each case. Therapy data were acquired from various sources, including clinical study centers and treating hospitals. To analyze the impact of radiotherapy, organ doses were estimated by using reconstructed treatment plans. The effect of chemotherapy was analyzed using substance groups summarized after isotoxic dose conversion. RESULTS: 1244 cases with a SPN were identified and matched with 4976 controls. Treatment data were acquired for 83% of all match groups (one case and at least one control). Based on preliminary analyses, 98% of all patients received chemotherapy and 54% of all patients were treated with radiotherapy. CONCLUSIONS: Based on our data, detailed analyses of dose response relationships and treatment element combinations are possible, leading to a deeper insight into SPN risks after cancer treatments. TRIAL REGISTRATION: The study is registered at the German clinical trial register (DRKS) under number DRKS00017847 [45].

Equivalent doses for anticancer agents used in pediatric oncology: A literature review and evaluation of a novel approach for conversion factors.

BACKGROUND: Epidemiological research on late effects of therapy shows the necessity to aggregate chemotherapy agents to substance classes. This requires using conversion factors by substance classes. AIMS: The aim of this study was to identify previously used conversion factors from the literature, to present a novel approach for additional factors, and to compare these approaches. METHODS AND RESULTS: A literature review was performed, which identified two main principles of deriving conversion factors: effect-equivalence and equimolar. Thirty-five articles presenting effect equivalence-based factors in the widest sense were found in the literature. Ten articles presented the equimolar approach which can be applied to almost all chemotherapy substances. Based on a comprehensive list of treatment protocols used in German pediatric oncology, we derived alternative conversion factors from typical doses. We compared the conversion factors using Pearson correlation coefficients and linear regression. At least two types of conversion factor were available for each of the 49 substances included. The equivalent effect-based and the typical dose-based factors were highly correlated with a regression coefficient close to 1. The equimolar factors are independent. CONCLUSIONS: For substances for which no conversion factor based on some type of effect equivalence has been published so far, a factor based on a typical doses-approach may be used in epidemiological late effects research. Doses aggregated based on the equimolar approach may not be compatible with doses aggregated based on equivalent effects.

Survival of malignant mesothelioma and other rare thoracic cancers in Germany and the United States: A population-based study.

Evidence on survival of malignant mesothelioma (MM) and other rare thoracic cancers is limited due to the rarity of these cancer sites. Here, we provide a comprehensive overview of MM incidence and survival after MM and other rare thoracic cancers in Germany and the United States (US). Incidence was estimated from a German National Cancer Database and from the Surveillance, Epidemiology and End Results (SEER) 18 database for 2000-2014. Patients diagnosed in 1997-2013 with malignant epithelial tumors of the trachea (Etra), epithelial tumors of the thymus (Ethy) and MM were extracted from a German cancer survival database and from the SEER 13 database. Period analysis was employed to compute 5-year relative survival (RS). During 2000-2014, an annual average of 0.9 and 0.6 MM cases per 100,000 person-years was diagnosed in Germany and the US. Rates decreased in Germany and in the US. Patients with Ethy had highest 5-year RS with US patients surviving longer (69.1% compared to 63.7%, p = 0.02). Survival after Etra was comparable in both countries (Germany 33.6%, US 34.4%, p = 0.07). Survival in MM patients was poor overall (Germany 11.8%, US 12.1%, p < 0.01). Survival improvements were only observed in MM patients in Germany (10.8% [2002-2007] vs. 13.0% [2008-2013], p < 0.01). The lack of progress in survival for Etra and Ethy patients underlines the need of novel preventive, therapeutic and diagnostic approaches. MM incidence significantly decreased in Germany and in the US. Further monitoring of MM incidence is warranted given that a peak in incidence is expected in 2020-2030 in Western countries.

Strengthening health data on a rare and heterogeneous disease: sarcoma incidence and histological subtypes in Germany.

BACKGROUND: The population-based incidence of sarcoma and its histological subtypes in Germany is unknown. Up-to-date information on a disease with an incidence comparable to other cancer entities is of high public health relevance. The aim of this study was to determine this incidence and to detect significant changes in incidence trends using data from German epidemiological cancer registries. METHODS: Pooled data from the German Centre for Cancer Registry Data with a primary diagnosis occurring in 2013 were used. To date, this is the latest data on cancer incidence available for Germany. All German cancer registries with sufficient completeness were included (10 out of 11), covering a population of 70.0 million people, representing 87% of the German population. All malignant sarcomas according to the RARECARE Project and the WHO classification 2002 were considered for analysis and, above all, gastrointestinal stromal tumours (GIST) of uncertain behaviour. Sensitivity analysis was performed excluding certain histologies. RESULTS: The analysis included 3404 cases in men and 3442 cases in women diagnosed in 2013. The age adjusted sarcoma incidence (European standard) was 7.4 (men) and 6.6 (women) per 100,000 inhabitants. About 70% of sarcomas were soft tissue sarcomas, about 22% GIST, and about 9% bone sarcomas. The most common histological subtypes besides GIST were fibrosarcomas (14%) and liposarcomas (12%) in men and complex mixed and stromal neoplasms (22%), non-uterine leiomysarcomas (10%) and fibrosarcomas (9%) in women. Considering the trend for the years of diagnosis 2004 to 2013, there was a significant increase in incidence for GIST while the incidence of soft tissue sarcomas (only men) as well as of bone sarcoma stayed constant over time. As to soft tissue sarcoma in women, the incidence stayed constant up to the year 2009 and significantly decreased afterwards. CONCLUSION: This study is the first detailed analysis of a German-wide population-based sarcoma incidence showing results comparable to the incidence detected in the RARECARE Project.

Survival for patients with rare haematologic malignancies: Changes in the early 21st century.

INTRODUCTION: Population-level survival has improved for common haematologic malignancies in the early 21st century. However, relatively few population-level data are available for rare haematologic malignancies. METHODS: Data were extracted from 12 cancer registries in Germany and the Surveillance, Epidemiology and End Results database in the United States (US). Cases of haematologic malignancies with an incidence of less than 1 per 100,000 were selected for analysis. Period analysis was used to determine 5-year relative survival (RS) for the years 2003-2012, and modelled period analysis was used to determine changes in survival between 2003-2007 and 2008-2012. RESULTS: Seven individual haematologic malignancies which met criteria were identified. Overall 5-year age-adjusted RS was 62.4% in Germany and 57.0% in the US in 2003-2012, with a good deal of variability by individual haematologic malignancy, ranging from less than 30% for chronic monomyeloid leukaemia to greater than 85% for hairy cell leukaemia and mycosis fungoides. Five-year RS increased significantly between 2003-2007 and 2008-2012 for patients with mantle cell lymphoma, Burkitt's lymphoma and hairy cell leukaemia in Germany and for patients with mantle cell lymphoma and anaplastic large-cell kinase+ anaplastic lymphoma in the US. CONCLUSIONS: Survival for rare haematologic malignancies varied considerably by cancer entity. Overall 5-year RS was slightly higher in Germany compared to the US. Survival estimates increased for a minority of haematologic malignancies between 2003-2007 and 2008-2012. Further research into the best treatment options for rare malignancies is needed to further improve survival.

Risk of second primary cancers in women diagnosed with endometrial cancer in German and Swedish cancer registries.

Along with the increasing incidence and favorable prognosis, more women diagnosed with endometrial cancer may develop second primary cancers (SPCs). We aimed at investigating risk of SPCs after endometrial cancer in Germany and Sweden to provide insight into prevention strategies for SPCs. Endometrial cancer patients diagnosed at age ≥15 years in Germany during 1997-2011 and in Sweden nationwide during 1997-2012 were selected. Standardized incidence ratios (SIRs), calculated as the ratio of observed to expected numbers of cases, were used to assess the risk of a specific second cancer after endometrial cancer for both German and Swedish datasets. Among 46,929 endometrial cancer survivors in Germany and 18,646 in Sweden, overall 2,897 and 1,706 SPCs were recorded, respectively. Significantly elevated SIRs were observed in Germany for ovarian (SIR = 1.3; 95%CI:1.1-1.5) and kidney cancers [1.6 (1.3-1.8)], while in Sweden the SIRs were 5.4 (4.6-6.3) and1.4 (1.0-1.9), respectively. Elevated risk for second ovarian endometrioid carcinoma was pronounced after early (<55 years) onset endometrial cancer in Germany [9.0 (4.8-15)] and Sweden [7.7 (5.1-11)]. In Germany elevated risks were found for second ovarian endometrioid carcinoma after endometrioid histology of first endometrial cancer [6.3 (4.0-9.4)] and for second kidney cancer after clear cell histology of endometrial cancer [4.9 (1.6-11)]. We found exceptionally elevated risk of second ovarian endometrioid carcinoma after endometrial cancer of the same histology or of early onset. Risk for second kidney cancer was also increased, particularly after endometrial cancer of clear cell histology. Cancer prevention strategies should focus on these cancers after endometrial cancer diagnosis.

Incidence of lip malignancies in Germany-data from nine population-based cancer registries.

BACKGROUND: The objective of this study was to analyse the incidence of lip malignancies in Germany. METHODS: Data from population-based cancer registries covering a population of 39 million inhabitants from 14 federal states were pooled. Lip malignancies were classified according to the International Classification of Diseases (ICD-10). Age-standardised incidence rates and annual percentage changes in the incidence trends of lip cancer (C00), melanoma of the lip (C43.0), and non-melanoma skin cancer of the lip (C44.0) were calculated. RESULTS: Lip cancer (C00) incidence rate was 0.57/0.15 per 100 000 (men/women) in 2003 and 0.52/0.18 in 2012. In women, the change was statistically significant. Melanoma lip cancer (C43.0) incidence rates both in men and women were 0.02 in 2003 and 0.01 in 2012. Incidence rates of non-melanoma skin cancer of the lip (C44.0) significantly increased from 1.6 in 2003 to 2.1 in 2012 in men and from 1.5 in 2003 to 2.4 in 2012 in women. In lip cancer (C00), the vast majority (98% in men/93% in women) were squamous cell carcinomas and 2%/7% were basal cell carcinoma. In men, 56% of non-melanoma skin cancers (C44.0) were squamous cell carcinoma, whereas these were only 27% in women. CONCLUSIONS: The incidences of non-melanoma skin cancer of the lip increased over time in Germany in both sexes. Lip cancer incidence increased in women, while it stayed stable in men. Melanoma of the lip did not change in incidence. The distribution of histology in non-melanoma skin cancer of the lip differed by sex.

Survival in patients with acute myeloblastic leukemia in Germany and the United States: Major differences in survival in young adults.

Previous epidemiologic studies on AML have been limited by the rarity of the disease. Here, we present population level data on survival of patients with AML in Germany and the United States (US). Data were extracted from 11 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results (SEER13) database in the US. Patients diagnosed with AML in 1997-2011 were included. Period analysis was used to estimate 5-year relative survival (RS) and trends in survival in the early 21st century. Overall 5-year age-adjusted RS for patients with AML in 2007-2011 was greater in Germany than in the US at 22.8% and 18.8%, respectively. Five-year RS was higher in Germany than in the US at all ages, with particularly large differences at ages 15-24 for whom 5-year RS was 64.3% in Germany and 55.0% in the US and 35-44, with 5-year RS estimates of 61.8% in Germany and 46.6% in the US. Most of the difference in 5-year RS was due to higher 1-year RS, with overall 1-year RS estimates of 47.0% in Germany and 38.5% in the US. A small increase in RS was observed between 2003-2005 and 2009-2011 in both countries, but no increase in survival was observed in either country for ages 75+. To our knowledge, this is the first detailed description of AML survival in Germany. Comparison to the US suggests that further analysis into risk factors for poor outcomes in AML in the US may be useful in improving survival.

Trends in survival of chronic lymphocytic leukemia patients in Germany and the USA in the first decade of the twenty-first century.

BACKGROUND: Recent population-based studies in the United States of America (USA) and other countries have shown improvements in survival for patients with chronic lymphocytic leukemia (CLL) diagnosed in the early twenty-first century. Here, we examine the survival for patients diagnosed with CLL in Germany in 1997-2011. METHODS: Data were extracted from 12 cancer registries in Germany and compared to the data from the USA. Period analysis was used to estimate 5- and 10-year relative survival (RS). RESULTS: Five- and 10-year RS estimates in 2009-2011 of 80.2 and 59.5%, respectively, in Germany and 82.4 and 64.7%, respectively, in the USA were observed. Overall, 5-year RS increased significantly in Germany and the difference compared to the survival in the USA which slightly decreased between 2003-2005 and 2009-2011. However, age-specific analyses showed persistently higher survival for all ages except for 15-44 in the USA. In general, survival decreased with age, but the age-related disparity was small for patients younger than 75. In both countries, 5-year RS was >80% for patients less than 75 years of age but <70% for those age 75+. CONCLUSIONS: Overall, 5-year survival for patients with CLL is good, but 10-year survival is significantly lower, and survival was much lower for those age 75+. Major differences in survival between countries were not observed. Further research into ways to increase survival for older CLL patients are needed to reduce the persistent large age-related survival disparity.

Survival of patients with gastric lymphoma in Germany and in the United States.

BACKGROUND AND AIM: This study aims to examine survival for gastric lymphomas and its main subtypes, mucosa-associated lymphoid tissue lymphoma (MALT), and diffuse large B-cell lymphoma (DLBCL), in Germany and in the United States. METHODS: Data for patients diagnosed in 1997-2010 were used from 10 population-based German cancer registries and compared to the data from the US Surveillance, Epidemiology and End Results (SEER) 13 registries database. Patients age 15-74 diagnosed with gastric lymphomas were included in the analysis. Period analysis and modeled period analysis were used to estimate 5-year and 10-year relative survival (RS) in 2002-2010 and survival trends from 2002-2004 to 2008-2010. RESULTS: Overall, the database included 1534 and 2688 patients diagnosed with gastric lymphoma in 1997-2010 in Germany and in the United States, respectively. Survival was substantially higher for MALT (5-year and 10-year RS: 89.0% and 80.9% in Germany, 93.8% and 86.8% in the United States) than for DLBCL (67.5% and 59.2% in Germany, and 65.3% and 54.7% in the United States) in 2002-2010. Survival was slightly higher among female patients and decreased by age for gastric lymphomas combined and its main subtypes. A slight, nonsignificant, increase in the 5-year RS for gastric lymphomas combined was observed in Germany and the United States, with increases in 5-year RS between 2002-2004 and 2008-2010 from 77.1% to 81.0% and from 77.3% to 82.0%, respectively. Five-year RS of MALT exceeded 90% in 2008-2010 in both countries. CONCLUSIONS: Five-year RS of MALT meanwhile exceeds 90% in both Germany and the United States, but DLBCL has remained below 70% in both countries.

Survival of adults with acute lymphoblastic leukemia in Germany and the United States.

BACKGROUND: Adulthood acute lymphoblastic leukemia (ALL) is a rare disease. In contrast to childhood ALL, survival for adults with ALL is poor. Recently, new protocols, including use of pediatric protocols in young adults, have improved survival in clinical trials. Here, we examine population level survival in Germany and the United States (US) to gain insight into the extent to which changes in clinical trials have translated into better survival on the population level. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database in the US and 11 cancer registries in Germany. Patients age 15-69 diagnosed with ALL were included. Period analysis was used to estimate 5-year relative survival (RS). RESULTS: Overall 5-year RS was estimated at 43.4% for Germany and 35.5% for the US (p = 0.004), with a decrease in survival with increasing age. Survival was higher in Germany than the US for men (43.6% versus 37.7%, p = 0.002) but not for women (42.4% versus 40.3%, p>0.1). Five-year RS estimates increased in Germany and the US between 2002 and 2006 by 11.8 and 7.3 percent units, respectively (p = 0.02 and 0.04, respectively). CONCLUSIONS: Survival for adults with ALL continues to be low compared with that for children, but a substantial increase in 5-year survival estimates was seen from 2002 to 2006 in both Germany and the US. The reasons for the survival differences between both countries require clarification.

Survival of endometrial cancer patients in Germany in the early 21st century: a period analysis by age, histology, and stage.

BACKGROUND: Population-based studies on endometrial cancer providing survival estimates by age, histology, and stage have been sparse. We aimed to derive most up-to-date and detailed survival estimates for endometrial cancer patients in Germany. METHODS: We used a pooled German national dataset including data from 11 cancer registries covering a population of 33 million people. 30,906 patients diagnosed with endometrial cancer in 1997-2006 were included. Period analysis was performed to calculate 5-year relative survival (RS) in 2002-2006. Trends in survival between 2002 and 2006 were examined using model-based period analysis. Age-adjustment was performed using five age groups (15-44, 45-54, 55-64, 65-74, and 75+ years). RESULTS: Overall, age-adjusted 5-year relative survival in 2002-2006 was 81%. A moderate age gradient was observed, with 5-year RS decreasing from 90% in the age group 15-49 years to 75% in the age group 70+ years. Furthermore prognosis varied strongly by histologic subtypes and stage, with age-adjusted 5-year RS ranging from 43% (for sarcoma) to 94% (for squamous metaplasia), and reaching 91% for localized, 51% for regional, and 20% for distant stage. Except for age group 65-74 years, no significant improvement in survival was seen during the recent 5-year period under investigation. CONCLUSION: In this comprehensive population-based survival analysis of patients with endometrial cancer from Germany, prognosis of endometrial cancer moderately varied by age, and strongly varied by histology and stage. While prognosis is rather good overall, further improvement in 5-year relative survival of endometrial cancer patients has been stagnating in the early 21(st) century.

Data analysis of epidemiological studies: part 11 of a series on evaluation of scientific publications.

INTRODUCTION: An important objective of epidemiological research is to identify risk factors for disease. Depending on the particular question being asked, cohort studies, case-control studies, or cross-sectional studies are conducted. METHODS: Methods of data analysis in different types of epidemiological studies are illustrated through examples with fictive data. Important measures of frequency and effect will be introduced. Different regression models will be presented as examples of complex analytical methods. RESULTS: Important frequency measures in cohort studies are incidence and mortality. Important effect measures such as the relative risk (RR), hazard ratio (HR), standardized incidence ratio (SIR), standardized mortality ratio (SMR), and odds ratio (OR) can also be calculated. In case-control or cross-sectional studies, the OR can be calculated as an effect measure. In cross-sectional studies, prevalence is the most important frequency measure. The interpretation of different frequency measures and effect measures will be discussed. CONCLUSION: The measures to be calculated and the analyses to be performed in an epidemiological study depend on the research questions being asked, the study type, and the available data.

Systematic literature reviews and meta-analyses: part 6 of a series on evaluation of scientific publications.

BACKGROUND: Because of the rising number of scientific publications, it is important to have a means of jointly summarizing and assessing different studies on a single topic. Systematic literature reviews, meta-analyses of published data, and meta-analyses of individual data (pooled reanalyses) are now being published with increasing frequency. We here describe the essential features of these methods and discuss their strengths and weaknesses. METHODS: This article is based on a selective literature search. The different types of review and meta-analysis are described, the methods used in each are outlined so that they can be evaluated, and a checklist is given for the assessment of reviews and meta-analyses of scientific articles. RESULTS: Systematic literature reviews provide an overview of the state of research on a given topic and enable an assessment of the quality of individual studies. They also allow the results of different studies to be evaluated together when these are inconsistent. Meta-analyses additionally allow calculation of pooled estimates of an effect. The different types of review and meta-analysis are discussed with examples from the literature on one particular topic. CONCLUSIONS: Systematic literature reviews and meta-analyses enable the research findings and treatment effects obtained in different individual studies to be summed up and evaluated.

TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies.

BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. FUNDING: German Research Foundation (DFG).