PURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan
and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous
hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk
Ewing sarcoma (EWS). METHODS Phase III, open-label, prospective, multicenter, randomized
controlled clinical trial. Eligible patients had disseminated EWS with metastases
to bone and/or other sites, excluding patients with only pulmonary metastases. Patients
received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction
and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation
therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further
treatment (control). The random assignment was stratified by number of bone metastases
(1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed
after the first interim analysis via Muller-Schafer method. RESULTS Between 2009 and
2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median
follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT
and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32,
intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT
and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in
the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared
with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5
to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from
TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI,
2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol
collective. This observation is supported by comparable results from the nonrandomized
trial EE99R3. CONCLUSION In patients with very high-risk EWS, additional TreoMel-HDT
was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit
for children age < 14 years. (c) 2022 by American Society of Clinical Oncology
