As reported in The Lancet by Brennan et al, the European phase III EURO EWING 2012 trial found improved event-free survival with a standard U.S. chemotherapy regimen vs a standard European regimen in newly diagnosed patients with Ewing sarcoma.

As stated by the investigators, “Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the U.S. for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies.”

Study Details

Six hundred and forty patients were enrolled in the investigator-initiated open-label trial from sites in 10 European countries between March 2014 and May 2019. Patients aged 2 to 49 years with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue or Ewing-like sarcomas were eligible; a protocol amendment permitted enrollment of patients with extrapulmonary metastatic disease.

Patients were randomly assigned to either:

• A European regimen (n = 320) consisting of induction with VIDE (vincristine, ifosfamide, doxorubicin, etoposide) and consolidation regimens including VAI (vincristine, actinomycin D, ifosfamide), VAC (vincirstine/actinomycin D plus cyclophosphamide), and busulfan/melphalan
• A U.S. regimen (n = 350) consisting of induction with compressed VDC (vincristine, doxorubicin, cyclophosphamide) plus IE (ifosfamide/etoposide) and consolidation regimens including IE, VC (vincristine/cyclophosphamide), VAI, and busulfan/melphalan, with treatment given in fewer cycles compared with the European regimen.

The primary outcome measure was event-free survival.

Event-Free Survival

Median follow-up of surviving patients was 47 months (range = 0–84 months). Event-free survival at 3 years was 67% with the U.S. regimen vs 61% with the European regimen (adjusted hazard ratio [HR] = 0.71, 95% credible interval = 0.55–0.92). The probabilities that the true hazard ratios were < 1.0 and  <0.8 were > 99% and 81%, respectively.

Overall survival at 3 years was 82% with the U.S. regimen vs 74% with the European regimen (adjusted HR = 0.62, 95% credible interval = 0.46–0.85). The probabilities that the true hazard ratios were < 1.0 and < 0.8 were > 99% and 94%, respectively.

Adverse Events

Median duration of induction treatment was 238 days in the U.S. regimen group vs 300 in the European regimen group. Grade ≥ 3 adverse events occurred in 90% of patients in the U.S. regimen group vs 91% of the European regimen group during induction, including decreased platelets in 56% vs 69% and in 67% vs 66% during consolidation. Grade ≥ 3 febrile neutropenia occurred in 58% vs 74% of patients during induction. During induction, platelet transfusions were required in 43% vs 64% of patients and blood transfusions were required in 89% vs 87%. The median number of required unscheduled hospital visits during induction was 9 (interquartile range [IQR] = 2–21) vs 12 (IQR = 5–28). No differences in grade ≥ 3 gastrointestinal toxicity (42% vs 39%) or infections/infestations (20% vs 19%) were observed during induction.

The investigator concluded, “Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction, and should now be the standard of care for Ewing sarcoma.”

Bernadette Brennan, MD, of the Department of Paediatric Oncology and Haematology, Royal Manchester Children’s Hospital, Manchester, is the corresponding author for The Lancet article.

Disclosure: The study was funded by The European Union’s Seventh Framework Programme for Research, Technological Development, and Demonstration, Ligue contre le cancer, Cancer Research UK, and others. For full disclosures of the study authors, visit thelancet.com.