A randomized trial found that for patients with newly diagnosed Ewing’s sarcoma, a chemotherapy regimen consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC/IE) offers better event-free survival (EFS) and overall survival (OS) than a regimen of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE; Abstract 11500).
The Euro EWING 2012 trial was conceived 10 years ago, when no novel agents were available to treat this malignancy, according to Bernadette Brennan, BSc, MBChB, MD, of Royal Manchester Children’s Hospital, in the United Kingdom, who presented the study during the ASCO20 Virtual Scientific Program. Dr. Brennan said that different chemotherapy regimens were used in Europe and in the United States, and it was considered worthwhile to compare the regimens directly in a randomized trial.
The study included 640 patients from 112 sites in 10 countries, randomly assigned to receive either VIDE or VDC/IE (320 patients in each group). Just over 40% of patients in each group were younger than age 14, and 58% were male. All patients had newly diagnosed Ewing’s sarcoma, including Ewing’s-like sarcoma without EWS translocation; 74% in each group had localized disease. The last patient was recruited in 2019, at which point an independent data monitoring committee advised the trial be discontinued because one regimen was demonstrating superior efficacy.
EFS favored the VDC/IE regimen (Figure). There were 175 total events, including 102 in the VIDE group (32%) and 73 in the VDC/IE group (23%). Progression and recurrence were the most common events; 4% of the events in the VIDE group and 3% of those in the VDC/IE group were second primary tumors, and 9% and 3%, respectively, were death without recurrence. The 3-year EFS rates were 58% with VIDE and 69% with VDC/IE. The hazard ratio (HR) for EFS favoring VDC/IE was 0.66 (95% CI [0.49, 0.90]); an analysis showed that the posterior probability of the true HR being below 1 was 100%, and the probability of it being below 0.8 was 89%. This met the prespecified threshold whereby one of the regimens would be preferred if there was an 80% chance that it offered better EFS.
A total of 105 patients in the study died, including 62 patients in the VIDE group (19%) and 43 in the VDC/IE group (13%). Most of the deaths were Ewing’s sarcoma–related; there were six deaths in the VIDE group related to the trial treatment, and no such deaths occurred in the VDC/IE group. The 3-year OS rates were 74% with VIDE and 82% with VDC/IE. The HR favoring VDC/IE was 0.64 (95% CI [0.43, 0.94]), and the posterior probability that the true HR was below 1 was 99%; for an HR of less than 0.8, the probability was 87%, again meeting the prespecified threshold.
The analysis considered only adverse events (AEs) of grade 3 to 5; 91% of patients in the VIDE group and 90% of those in the VDC/IE group had any such event during induction therapy. Some specific AEs did occur more frequently with VIDE, including hematologic AEs (85% vs. 77%) and febrile neutropenia (73% vs. 57%).
“The EURO EWING trial has demonstrated, with a high level of certainty, that EFS and OS are better in 2012 using VDC/IE,” Dr. Brennan said. “There is no excessive toxicity with VDC/IE, and it’s about 3 months shorter in treatment length, and there is some suggestion now that it is actually less toxic.” The results favoring VDC/IE were also confirmed in a subgroup analysis, she added, in which the regimen was better regardless of age, gender, disease type, tumor volume, or country.
“The EURO EWING trial has demonstrated, with a high level of certainty, that EFS and OS are better in 2012 using VDC/IE,” Dr. Brennan said.
Patrick Leavey, MD, of The University of Texas Southwestern Medical Center, was the discussant for the study. He noted that this study gave 14 cycles of chemotherapy, while others have opted for 17 cycles, and the optimal number remains in question. “Another chemotherapy question is yet to be answered,” he said. “And that is whether maintenance will be of value for a patient group in the localized setting.”
— Dave Levitan
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