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The standard chemotherapy regimen used to treat patients with newly diagnosed Ewing sarcoma in the U.S. was more effective, less toxic, and shorter in duration than the previous standard used in Europe, a phase III randomized trial showed.

Over a median follow-up of 47 months, the 3-year event-free survival (EFS) rate among patients treated with the U.S. standard of care was 67% compared with 61% for patients treated with the standard European regimen (adjusted HR 0.71, 95% CI 0.55-0.92), reported Bernadette Brennan, MD, of Royal Manchester Children's Hospital in England, and colleagues.

Three-year overall survival (OS) rates among the 640 patients in the study were 82% and 74%, respectively (HR 0.62, 95% CI 0.46-0.85), they noted in .

Brennan and team determined that there was a greater than 99% chance that the U.S. regimen was more effective than the European regimen for both outcome measures.

"These findings are all clinically meaningful," the authors wrote. "Hence, these results have led to a practice change in Europe and many other countries. VDC plus IE chemotherapy has become the standard regimen for all newly diagnosed Ewing sarcomas in Europe, following its earlier adoption in the U.S."

The U.S. standard of care consists of vincristine [Oncovin], doxorubicin, and cyclophosphamide (VDC), plus ifosfamide and etoposide (IE) as induction chemotherapy, and alternating cycles of IE and vincristine and cyclophosphamide as consolidation chemotherapy, while the former European standard consisted of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by either vincristine, actinomycin D, and ifosfamide or cyclophosphamide as consolidation chemotherapy, or high-dose busulfan and melphalan.

Brennan and colleagues also pointed out that while grade 3-5 adverse events were similar between the groups, febrile neutropenia occurred less frequently during induction with VDC plus IE (58%) compared with VIDE (74%). There were no differences in gastrointestinal toxicities and infections and infestations between the two groups.

While more patients in the VIDE group (64%) required at least one platelet transfusion compared with those in the VDC plus IE group (43%), more patients required blood transfusions in the VDC plus IE group (89% vs 87%).

The length of treatment for VDC plus IE was also substantially reduced -- an average of 62 days shorter compared with the VIDE regimen.

The results of this study "are likely to be practice-changing internationally, and practice-confirming in the U.S.," noted Emily K. Slotkin, MD, and William D. Tap, MD, both of Memorial Sloan Kettering Cancer Center in New York City, in a . "Despite these consensus-building results, plateaued outcomes in patients with Ewing sarcoma continue to remain unacceptably low, particularly for those with metastatic, relapsed, or refractory disease."

Therefore, while the results of the study represent an important step in harmonizing treatment for Ewing sarcoma, and support the need for dose intensity in the disease, they wrote, there is still an urgent need "to incorporate novel agents rather than further intensifying cytotoxic chemotherapy and to identify and research treatment approaches that are effective at eradicating minimal residual disease" in Ewing sarcoma.

The open-label EURO EWING 2012 study began enrolling patients with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas, in 2014 across 110 sites in 10 countries. Eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in September 2016.

Patients were randomized 1:1 to either the European regimen or the U.S. regimen. All drugs were administered intravenously. Overall, 163 deaths were recorded -- 95 in the European group and 68 in the U.S. group.

Across both groups, median age was 15, and 58% were male. About three-quarters had localized disease. Most patients were from the U.K. and France.

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