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

Abstract

Introduction: Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials.

Methods: We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models.

Results: The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group.

Conclusion: The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.

Keywords: Autologous hematopoietic stem cells transplantation; Ewing sarcoma (ES); High dose chemotherapy; Safety.

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). Centralized randomization software was used in all data centres, ensuring the concealment of the next patient allocation. The GPOH data centre used permuted blocks of four. In the other data centres, randomization was also balanced by the treating centre using dynamic allocation of treatment (minimization with a random factor set at 0.8).

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.