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Results of the EICESS-92 Study: Two Randomized Trials of Ewing's Sarcoma Treatment—Cyclophosphamide Compared With Ifosfamide in Standard-Risk Patients and Assessment of Benefit of Etoposide Added to Standard Treatment in High-Risk Patients

Michael Paulussen, Alan W. Craft, Ian Lewis, Allan Hackshaw, Carolyn Douglas, Jürgen Dunst, Andreas Schuck, Winfried Winkelmann, Gabriele Köhler, Christopher Poremba, Andreas Zoubek, Ruth Ladenstein, Henk van den Berg, Andrea Hunold, Anna Cassoni, David Spooner, Robert Grimer, Jeremy Whelan, Anne McTiernan, Herbert Jürgens

From the Department of Paediatric Haematology/Oncology, University Children's Hospital Münster; Departments of Radiotherapy and Orthopedic Surgery, and Gerhard Domagk Institute of Pathology, University of Münster; Department of Radiotherapy, University of Schleswig-Holstein, Lübeck; Institute of Pathology, University of Düsseldorf; Department of Paediatric Haematology and Oncology, University Hospital Giessen, Giessen, Germany; The Royal Victoria Infirmary, Institute of Child Health, Newcastle upon Tyne; Regional Paediatric Oncology Unit, St James University Hospital, Leeds; Cancer Research United Kingdom and University College London Cancer Trials Centre, University College London; Department of Oncology, University College Hospital, London; Children's Cancer and Leukaemia Group Data Centre, Cancer Studies and Molecular Medicine, University of Leicester; Queen Elizabeth II Hospital; and The Royal Orthopaedic Hospital, Birmingham, United Kingdom; St Anna Children's Hospital, Vienna, Austria; Department of Paediatric Oncology, Emma Children's Hospital Academisch Medisch Centrum, University of Amsterdam, Amsterdam, the Netherlands; and Department of Paediatric Oncology/Haematology, University Children's Hospital Universitäts-Kinderspital Beider Basel, Switzerland

Corresponding author: Michael Paulussen, MD, Department of Paediatric Oncology/Haematology, University Children's Hospital (UKBB) Basel, Römergasse 8, CH-4005 Basel, Switzerland; e-mail: michael.paulussen{at}ukbb.ch

Purpose The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients.

Patients and Methods SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume 100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS).

Results A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, –35% to 5%; P = .12) and 15% reduction in dying (95% CI, –34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84).

Conclusion Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.

Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT0000251.

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