The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective.

Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival.

The implementation of research studies is a highly complex process. All decisions with respect to the study design impact the statistical analyses and interpretation of the results. Within the ICare research project (EU H2020 Grant agreement 634757) seven research trials are conducted to generate evidence on efficacy, effectiveness and the dissemination potential of online interventions targeting eating disorders, common mental health problems and resilience. Within the project a central biometrical unit was established to manage and coordinate data collection, processing and statistical data analysis. This allows for harmonized trial planning, conduct, data management processes and analysis strategies. The purpose of this article is to describe the common concepts underlying all seven ICare trials. This includes development of (adaptive sequential) study designs, handling of missing values, general data management and processing as well as data protection aspects.

In pediatric patients with medulloblastoma (MB) the 5-year-OS rate dependent on risk group is 35% to 90%. In unresectable or metastatic recurrence longterm prognosis is poor. Aim of this study was to evaluate the role of irradiation in relapsed MB patients registered in the German studies HIT-MED, HIT-REZ-97/-2005 and HIT-REZ-Registry between July 1997 and December 2016. Data analyzed at relapse were age, gender, stage, primary/relapse therapy, and follow-up. Kaplan-Meier analysis and log rank test were used to estimate the PFS/OS after 1st recurrence and (re)irradiation. 257 patients with recurrent/refractory MB [75 female/182 male, median age 11.0 years (0.8-37.9), median PFS after 1st diagnosis 24.8 months (2.6-270.2), 81% metastatic disease at relapse] were included in this analysis. Median PFS and OS after first relapse were 12.3 months (95%CI: 9.4;15.2) and 23.8 months (95%CI: 19.3-28.3), the 5-year-PFS and 5-year-OS rate were 6.8%±1.7% and 19.3%±2.7%, respectively. The PFS and OS differed significantly between 4 different cohorts: patients (A) with 1st irradiation at 1st relapse (n=29), (B) with re-irradiation (n=54), (C) without re-irradiation at 1st relapse (n=164), and (D) without irradiation at any time (10). The best 5-year-PFS and 5-year-OS rate were observed in cohort A with 20.1% ±7.8 and 34.2% ±9.3, respectively. Looking for different strata significant differences were seen in patients with metastatic disease. Radiotherapy at relapse can be used as salvage therapy in patients without primary irradiation. It can lead to prolonged PFS and OS especially in patients with metastatic disease. Supported by German Children’s Cancer Foundation.