Combination Chemotherapy With or Without Peripheral Stem Cell Transplantation, Radiation Therapy, and/or Surgery in Treating Patients With Ewing’s Sarcoma

Overview

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and kill more tumor cells. It is not yet known if combination chemotherapy is more effective with or without radiation therapy and/or surgery in treating Ewing's sarcoma.

PURPOSE: This randomized phase III trial is studying different combination chemotherapy regimens to see how well they work when given with or without peripheral stem cell transplantation, radiation therapy, and/or surgery in treating patients with Ewing's sarcoma.

Full Title of Study: “European Ewing Tumour Working Initiative of National Groups Ewing Tumour Studies 1999 (EURO-E.W.I.N.G.99)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Primary Purpose: Treatment
  • Study Primary Completion Date: December 2011

Detailed Description

OBJECTIVES:

Primary

- Compare the event-free and overall survival of patients with tumor of the Ewing's family treated with standard induction chemotherapy comprising vincristine, dactinomycin, ifosfamide and etoposide (VIDE) followed by consolidation chemotherapy comprising vincristine, dactinomycin, and ifosfamide versus high-dose busulfan and melphalan (Bu-Mel) followed by autologous peripheral blood stem cell (PBSC) transplantation with or without radiotherapy and/or surgery.

Secondary

- Determine the prognostic significance of EWS-Flil transcript in these patients.

- Determine the frequency and prognostic value of minimal disease in bone marrow and PBSC, as determined by the presence or absence of EWS-Flil transcript, in these patients.

- Determine the feasibility and toxicity of VIDE induction chemotherapy in these patients.

- Determine the response of these patients to VIDE induction chemotherapy.

- Determine the feasibility and toxicity of VAI consolodation chemotherapy in these patients.

- Determine the feasibility and toxicity of Bu-Mel consolodation chemotherapy in these patients.

- Determine event-free survival and overall survival of patients treated with these regimens by prognostic group analysis.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and local treatment of the primary tumor (yes vs no).

Patients receive induction chemotherapy comprising vincristine IV on day 1 and ifosfamide IV over 3 hours, doxorubicin IV over 4 hours, and etoposide IV over 1 hour on days 1-3 (VIDE). Treatment repeats every 21 days for 4 courses in the absence of unacceptable toxicity. Peripheral blood stem cells (PBSC) are collected after course 3 and/or 4. Patients are evaluated after course 4. Patients in need of early radiotherapy due to an axial tumor or patients who require radiotherapy to the brain and/or spinal cord (at any time during study) are assigned to group 1. Patients not needing early radiotherapy are assigned to group 2.

- Group 1: Patients receive 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Patients requiring radiotherapy to the axial tumor also undergo concurrent radiotherapy 5 days a week. Some patients may then undergo surgical resection of the tumor. All patients will then receive vincristine IV on day 1 and dactinomycin IV and ifosfamide IV over 3 hours on days 1 and 2 (VAI). Treatment repeats every 21 days for 8 courses (courses 7-14). Patients requiring radiotherapy to the brain and/or spinal cord also undergo concurrent radiotherapy.

- Group 2: Patients undergo 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Some patients may then undergo surgical resection of the tumor. All patients receive VAI chemotherapy as in group 1 for 1 course. Patients are randomized to 1 of 2 consolidation therapy arms.

- Arm I: Patients receive 7 additional courses of VAI chemotherapy (courses 8-14). Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent whole-lung radiotherapy for 6-12 days.

- Arm II: Patients receive high-dose chemotherapy comprising oral busulfan every 6 hours on days -6 to -3 and melphalan IV over 30 minutes on day -2. Patients receive autologous PBSC IV on day 0. Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent radiotherapy 5 days a week for at least 5 weeks.

Patients are followed every 3 months for 4 years, every 6 months for 1 year, and then periodically thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: Approximately 1,200 patients will be accrued for this study within approximately 7 years.

Interventions

  • Biological: dactinomycin
    • Given IV
  • Drug: busulfan
    • Given orally and IV
  • Drug: doxorubicin hydrochloride
    • Given IV
  • Drug: etoposide
    • Given IV
  • Drug: ifosfamide
    • Given IV
  • Drug: melphalan
    • Given orally and IV
  • Drug: vincristine sulfate
    • Given IV
  • Procedure: autologous hematopoietic stem cell transplantation
    • Given IV
  • Procedure: conventional surgery
    • Given to patients deemed to require it
  • Radiation: radiation therapy
    • Given to patients deemed to require it

Arms, Groups and Cohorts

  • Experimental: Group 1
    • Patients receive 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Patients requiring radiotherapy to the axial tumor also undergo concurrent radiotherapy 5 days a week. Some patients may then undergo surgical resection of the tumor. All patients will then receive vincristine IV on day 1 and dactinomycin IV and ifosfamide IV over 3 hours on days 1 and 2 (VAI). Treatment repeats every 21 days for 8 courses (courses 7-14). Patients requiring radiotherapy to the brain and/or spinal cord also undergo concurrent radiotherapy.
  • Experimental: Group 2, arm I
    • Patients undergo 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Some patients may then undergo surgical resection of the tumor. All patients receive VAI chemotherapy as in group 1 for 1 course. Patients then receive 7 additional courses of VAI chemotherapy (courses 8-14). Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent whole-lung radiotherapy for 6-12 days.
  • Experimental: Group 2, arm II
    • Patients undergo 2 additional courses of VIDE induction chemotherapy (courses 5 and 6). Some patients may then undergo surgical resection of the tumor. All patients receive VAI chemotherapy as in group 1 for 1 course. Patients then receive high-dose chemotherapy comprising oral busulfan every 6 hours on days -6 to -3 and melphalan IV over 30 minutes on day -2. Patients receive autologous PBSC IV on day 0. Patients with unresectable, partially resected, or inadequately resected disease undergo concurrent radiotherapy 5 days a week for at least 5 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • Event-free survival
  • Overall survival

Secondary Measures

  • Feasibility, toxicity, and response at 1 month following induction therapy
  • Feasibility and toxicity of consolidation regimens at 1 month following consolidation therapy

Participating in This Clinical Trial

DISEASE CHARACTERISTICS:

  • Histologically confirmed tumor of the Ewing's family of bone or soft tissue
  • Ewing's sarcoma
  • Peripheral primitive neuroectodermal tumor
  • Disease meeting one of the following criteria:
  • Resectable localized disease (tumor volume less than 200 mL)
  • Localized disease previously resected at diagnosis
  • Unresectable disease (at least 200 mL tumor volume) but radiotherapy as local control can be delayed
  • Localized disease with early radiotherapy required
  • Pulmonary and/or pleural metastases only
  • Extrapulmonary/pleural metastases (skeleton, bone marrow, lymph nodes)
  • No more than 45 days since definitive biopsy

PATIENT CHARACTERISTICS:

Age:

  • Under 50

Performance status:

  • Not specified

Life expectancy:

  • Not specified

Hematopoietic:

  • Not specified

Hepatic:

  • Not specified

Renal:

  • Renal function normal
  • Glomerular filtration rate at least 60 mL/min

Cardiovascular:

  • Normal cardiac function
  • Fractional shortening at least 29%
  • Ejection fraction at least 40%

Other:

  • No medical, psychiatric, or social condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • Not specified

Chemotherapy:

  • No prior chemotherapy

Endocrine therapy:

  • Not specified

Radiotherapy:

  • Not specified

Surgery:

  • See Disease Characteristics

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 49 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Leicester
  • Collaborator
    • National Cancer Institute (NCI)
  • Overall Official(s)
    • Alan W. Craft, MD, Study Chair, Sir James Spence Institute of Child Health at Royal Victoria Infirmary
    • Ian J. Lewis, MD, Study Chair, Leeds Cancer Centre at St. James’s University Hospital
    • Odile Oberlin, MD, Study Chair, Gustave Roussy, Cancer Campus, Grand Paris
    • Ian R. Judson, MA, MD, FRCP, , Institute of Cancer Research, United Kingdom
    • Heribert F. Juergens, MD, Study Chair, University Hospital Muenster
    • Helmut Gadner, MD, FRCPG, Study Chair, St. Anna Kinderkrebsforschung
    • G. Ulrich Exner, MD, Study Chair, Balgrist Universitaetsklinik
    • Ruth Ladenstein, MD, Study Chair, St. Anna Kinderkrebsforschung
    • Douglas Hawkins, MD, Study Chair, Seattle Children’s Hospital

Citations Reporting on Results

Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O, van den Berg H, Dirksen U, Hjorth L, Michon J, Lewis I, Craft A, Jürgens H. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol. 2010 Jul 10;28(20):3284-91. doi: 10.1200/JCO.2009.22.9864. Epub 2010 Jun 14.

Le Deley MC, Delattre O, Schaefer KL, Burchill SA, Koehler G, Hogendoorn PC, Lion T, Poremba C, Marandet J, Ballet S, Pierron G, Brownhill SC, Nesslböck M, Ranft A, Dirksen U, Oberlin O, Lewis IJ, Craft AW, Jürgens H, Kovar H. Impact of EWS-ETS fusion type on disease progression in Ewing's sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol. 2010 Apr 20;28(12):1982-8. doi: 10.1200/JCO.2009.23.3585. Epub 2010 Mar 22.

Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9.

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