Analysis of longitudinal data from the betaseron multiple sclerosis clinical trial

Longitudinal data sets consist of repeated observations for each subject over time; and often a corresponding set of covariates is available. Analysis of longitudinal data is often based on summaries over time. Summarizing the data allows one to use simple techniques for analysis but does not allow analysis of the patterns over time and does not take advantage of the within subject information. In many fields, repeated measures analysis of variance and multivariate analysis of variance are commonly used to analyze longitudinal data on continuous responses. Such analyses are appropriate only when the responses for each subject are multivariate Gaussian with a common covariance matrix for all subjects. In addition, all subjects are required to have measurements at exactly the same times, and no missing values may be present. In many cases, however, the longitudinal response does not satisfy these assumptions. Therefore, application of the traditional methods of analysis is limited even for continuous responses. This thesis discusses and compares several more recently developed methods for the analysis of longitudinal data. One method, the generalized estimating equations approach, requires only minimal assumptions about the true correlation structure in the data for each subject to yield consistent estimates of regression parameters and their standard errors. The method can be applied to binary and count data as well as to continuous data. Another method, the random effects regression model, is limited to the analysis of continuous responses. An advantage of this method is that in addition to estimating population average parameters it also allows estimation of individual parameters for each subject. Finally, the modification of the random effects regression approach for the analysis of ordinal responses, the mixed effects ordinal logistic regression model, is presented. The methods are extensively illustrated using the data from the Betaseron clinical trial in relapsing-remitting multiple sclerosis (MS). These methods facilitated the examination of patterns over time, therefore they not only identified the presence of treatment effect, but also indicated the nature of the effect. Hence, these methods enable much more information to be extracted from the MS data set than the traditional ANOVA-based methods, and therefore provide useful and powerful tools for researchers in this subject area.Science, Faculty ofStatistics, Department ofGraduat

Epidemiology of Adult Soft-Tissue Sarcomas in Germany

We conducted a retrospective cohort study using data compiled from the regional German cancer registries by the Centre for Cancer Registry Data (ZfKD) at the Robert Koch Institut (RKI) to describe the epidemiology of adult soft-tissue sarcomas (STS) in Germany in 2003–2012, focusing on advanced STS. We identified 33,803 incident adult cases of STS (other than the Kaposi sarcoma and gastrointestinal stromal tumors). The incidence of STS was 6.05 (95% confidence interval (CI), 5.82–6.29) per 100,000 in 2012 (4,079 cases). During 2003–2012, the most common histologic categories were leiomyosarcoma (19%), liposarcoma (16%), and STS not otherwise specified (14%). The overall STS-specific mortality rate in 2012 was 2.31 (95% CI, 2.06–2.57) per 100,000, and the median overall survival from initial diagnosis was 5.83 (95% CI, 5.50–6.08) years. Using STS mortality rates as a proxy for incidence of advanced STS in Germany and applying the age- and sex-specific rates to the corresponding German population, we estimated that 1,581 incident adult advanced STS cases occurred in Germany in 2012. Our findings contribute to a refined understanding of the population burden of STS in Germany, including the number of patients with advanced STS who may be candidates for systemic treatment

Cost-Effectiveness of Olaratumab in Combination with Doxorubicin for Patients with Soft Tissue Sarcoma in the United States

Background. Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US) Food and Drug Administration conditionally approved olaratumab in combination with doxorubicin (Olara + Dox) based on a randomized phase II trial that reported a significant 11.8-month improvement in median survival versus single-agent doxorubicin (Dox). The present study investigated the cost-effectiveness of Olara + Dox compared with Dox and five other standard-of-care regimens from the US payer perspective. Methods. An economic model was constructed to estimate costs and outcomes over patients’ lifetimes from start of therapy. Progression-free and overall survival were based on survival analysis of patient-level data and a meta-analysis. Adverse-event rates were based on trials. Costs were from published sources. Results. Olara + Dox resulted in an estimated additional 1.27 life-years (LYs) compared with Dox, with an increase in total expected lifetime costs of $133,653. The incremental cost-effectiveness ratio (ICER) was estimated at$105,408 per LY gained; in a fully incremental analysis, all other regimens were dominated (higher costs and lower LYs or a higher ICER). Conclusion. Olara + Dox is cost-effective for STS treatment compared with Dox and other standard-of-care regimens at willingness-to-pay thresholds of $150,000 per LY and above

Treatment Patterns and Survival among Adult Patients with Advanced Soft Tissue Sarcoma: A Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France

Objective. To describe real-world treatment patterns and outcomes for patients with advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy in the United Kingdom, Spain, Germany, and France. Methods. Physicians completed a web-based medical record abstraction for adult patients with advanced STS (other than Kaposi’s sarcoma or gastrointestinal stromal tumor) who received ≥1 line of systemic therapy. Clinical characteristics, treatments, tumor responses, and mortality data were recorded. Results. A total of 130 physicians provided data for 807 patients. Patients’ mean age at advanced STS diagnosis was 57.1 (±12.3) years; 59% were male. The most commonly identified histologic categories were leiomyosarcoma (28%), liposarcoma (13%), and rhabdomyosarcoma (11%). Overall, 57% of patients received only 1 line of therapy, 32% received 2 lines of therapy, and 11% received ≥3 lines of therapy. The most common first-line regimens were doxorubicin alone (41%), doxorubicin plus ifosfamide (19%), docetaxel plus gemcitabine (9%), paclitaxel alone (4%), and ifosfamide (4%). Median overall survival from start of treatment was estimated to be 17.6 months (95% confidence interval, 15.6–19.0 months). Conclusions. In real-world clinical practice, advanced STS is most commonly treated with older therapies in the United Kingdom, Spain, Germany, and France. New therapies that improve overall survival in advanced STS are needed