High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma

Results of Euro-E.W.I.N.G.99 and Ewing-2008

Jeremy Whelan; Marie-Cecile Le Deley; Uta Dirksen; Gwénaël Le Teuff; Bernadette Brennan; Nathalie Gaspar; Douglas S. Hawkins; Susanne Amler; Sebastian Bauer; Stefan Bielack; Jean-Yves Blay; Stefan Burdach; Marie-Pierre Castex; Dagmar Dilloo; Angelika Eggert; Hans Gelderblom; Jean-Claude Gentet; Wolfgang Hartmann; Wolf-Achim Hassenpflug; Lars Hjorth; Marta Jimenez; Thomas Klingebiel; Udo Kontny; Jarmila Kruseova; Ruth Ladenstein; Valerie Laurence; Cyril Lervat; Perrine Marec-Berard; Sandrine Marreaud; Jean Michon; Bruce Morland; Michael Paulussen; Andreas Ranft; Peter Reichardt; Hendrik van den Berg; Keith Wheatley; Ian Judson; Ian Lewis; Alan Craft; Heribert Juergens; Odile Oberlin; on behalf of the Euro-E.W.I.N.G.99 and EWING-2008 Investigators


J Clin Oncol. 2018;36(31) 

In This Article

Abstract and Introduction


Purpose: For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse.

Methods: Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60).

Results: Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses.

Conclusion: BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.