High-Dose Chemotherapy vs Standard Chemotherapy and Whole-Lung Irradiation in Ewing Sarcoma With Pulmonary Metastases

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As reported in the Journal of Clinical Oncology by Dirksen et al, the R2Pulm trial showed no significant event-free or overall survival benefit with busulfan/melphalan high-dose chemotherapy with autologous stem cell rescue (BuMel) vs standard chemotherapy with whole-lung irradiation in patients with Ewing sarcoma with pulmonary or pleural metastases. The R2Pulm trial is a component of the successive Euro-E.W.I.N.G. 99 and EWING2008 studies.

Study Details

The R2Pulm trial included eligible patients enrolled between February 2000 and December 2015 from 144 centers in 14 countries into either Euro-E.W.I.N.G. 99 or EWING2008. Eligible patients were aged < 50 years old and had newly diagnosed, biopsy-proven Ewing sarcoma with pulmonary or pleural metastases and no other distant metastases. Patients who required radiotherapy to an axial primary site were excluded from randomization to avoid excess toxicity from interaction between radiotherapy and busulfan.

A total of 287 patients were randomly assigned to the BuMel group (n = 144) or the VAI (vincristine/dactinomycin/ifosfamide) plus whole-lung irradiation group (n = 143). Patients received six courses of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) and one course of VAI before one course of BuMel (BuMel group) or before seven courses of VAI and whole-lung irradiation (VAI plus WLI group).

The primary endpoint was event-free survival in the intent-to-treat population. The current analysis represents the final analysis of the trial on the basis of data as of January 2017.


  • Busulfan/melphalan high-dose chemotherapy with autologous stem-cell rescue was not associated with significant improvement in event-free or overall survival vs standard chemotherapy with whole-lung irradiation.
  • Event-free survival was 56.6% vs 50.6% at 3 years and 52.9% vs 43.1% at 8 years.

Event-Free and Overall Survival

Median follow-up was 8.1 years. Event-free survival was 50.6% in the VAI plus WLI group vs 56.6% in the BuMel group at 3 years and 43.1% vs 52.9% at 8 years, yielding an estimated hazard ratio (corrected for three prior interim analyses) of 0.79 (95% confidence interval [CI] = 0.56–1.10; P = .16).

Overall, there were 60 deaths in the VAI plus WLI group vs 58 in the BuMel group, yielding a hazard ratio of 1.00 (95% CI = 0.70–1.44, P = .99). Overall survival rates for VAI plus WLI vs BuMel were 68.0% vs 68.2% at 3 years and 54.2% vs 55.3% at 8 years.


Patients in the BuMel group had significantly higher rates of severe acute toxicities, particularly gastrointestinal and liver toxicity, hematologic toxicity, and infection, in addition to greater general condition deterioration. Four patients died from BuMel-related toxicity, and none died from toxicity associated with standard chemotherapy.

The investigators concluded, “In [Ewing sarcoma] with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.”

Uta Dirksen, MD, of University Hospital Essen, Pediatrics III, West German Cancer Centre, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the FP7-EURO EWING Consortium, Association Enfants et Santé, Société Française de Lutte Contre les Cancers et les Leucémies de l’Enfant et de l’Adolescent, Unicancer, Cancer Research UK, UK National Institute for Health Research, Deutsche Krebshilfe, US National Cancer Institute, and others. For full disclosures of the study authors, visit

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