Impact of age on safety of Busulfan-Melphalan followed by autologous hematopoietic stem-cell transplantation versus standard chemotherapy in the patients of the EURO-E.W.I.N.G. 99 and Ewing 2008 clinical trials

Fig. 1. Study design and treatment regimens of the R2Loc and R2Pulm randomization trials of the Euro-E.W.I.N.G. 99 VIDE: Vincristine, Ifosfamide, Doxorubicin and Etoposide. VAI: Vincristine, Dactinomycin and Ifosfamide. BuMel: Busulfan and Melphalan, with intravenous Melphalan (140 mg/m² on day −2 before stem cell re-infusion) and Busulfan four daily doses over 4 days (days −6 to −3). (1) Busulfan was given per os before 2006 (cumulative dose of 600 mg/m² or 16 mg/kg if ≥60 kg) and intravenously afterwards with 0.8 mg/kg for patients with a body weight (BW) > 34 kg, 0.95 mg/kg if BW > 23 to 34 kg, 1.1 mg/kg if BW 16–23 kg, 1.2 mg/kg if BW 9 to < 16 kg, and 1 mg/kg if BW< 9 kg. Consolidation treatment was one VAI-course waiting for the assessment of histological response, allocated consolidation treatment was either seven VAI-courses (with 21-day intervals) or BuMel chemotherapy. Randomisation was balanced and stratified according to cooperative group, sex, age (younger than 25 years), and local treatment (resection after chemotherapy alone with or without postoperative radiotherapy versus initial surgery versus resection after chemotherapy and radiotherapy versus radiotherapy only).…

Fig. 2. Participant flowchart of the study population VAI: Vincristine, Dactinomycin and Ifosfamide. BuMel: Busulfan and Melphalan. PBC: Peripheral Blood collection. WLI: Whole lung irradiation.

Fig. 3. Risk of severe toxicity considering the whole treatment duration: Effect of age and heterogeneity of the treatment effect according to age group. Left and right panels represent age effect and treatment effect according to age, respectively. Odds ratios were estimated in the multivariable models including treatment, age, treatment-by-age interaction. Each effect was estimated for a toxicity category, separately.