TY - JOUR
T1 - High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma
AU - Koch, Raphael
AU - Gelderblom, Hans
AU - Haveman, Lianne
AU - Brichard, Benedicte
AU - Jürgens, Heribert
AU - Cyprova, Sona
AU - Van Den Berg, Henk
AU - Hassenpflug, Wolf
AU - Raciborska, Anna
AU - Ek, Torben
AU - Baumhoer, Daniel
AU - Egerer, Gerlinde
AU - Eich, Hans Theodor
AU - Renard, Marleen
AU - Hauser, Peter
AU - Burdach, Stefan
AU - Bovee, Judith
AU - Bonar, Fiona
AU - Reichardt, Peter
AU - Kruseova, Jarmila
AU - Hardes, Jendrik
AU - Kühne, Thomas
AU - Kessler, Torsten
AU - Collaud, Stephane
AU - Bernkopf, Marie
AU - Butterfaß-Bahloul, Trude
AU - Dhooge, Catharina
AU - Bauer, Sebastian
AU - Kiss, János
AU - Paulussen, Michael
AU - Hong, Angela
AU - Ranft, Andreas
AU - Timmermann, Beate
AU - Rascon, Jelena
AU - Vieth, Volker
AU - Kanerva, Jukka
AU - Faldum, Andreas
AU - Metzler, Markus
AU - Hartmann, Wolfgang
AU - Hjorth, Lars
AU - Bhadri, Vivek
AU - Dirksen, Uta
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - PURPOSEEwing 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).METHODSPhase 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 Müller-Schäfer method.RESULTSBetween 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.CONCLUSIONIn 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.
AB - PURPOSEEwing 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).METHODSPhase 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 Müller-Schäfer method.RESULTSBetween 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.CONCLUSIONIn 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.
UR - http://www.scopus.com/inward/record.url?scp=85130126587&partnerID=8YFLogxK
U2 - 10.1200/JCO.21.01942
DO - 10.1200/JCO.21.01942
M3 - Article
C2 - 35427190
AN - SCOPUS:85130126587
SN - 0732-183X
VL - 28
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
M1 - JCO.21.01942
ER -
