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

University of Leicester

Status and phase: Unknown; Phase 3

Conditions: Sarcoma

Treatments: Drug: etoposide; Drug: melphalan; Radiation: radiation therapy; Biological: dactinomycin; Procedure: autologous hematopoietic stem cell transplantation; Drug: busulfan; Drug: doxorubicin hydrochloride; Drug: vincristine sulfate; Drug: ifosfamide; Procedure: conventional surgery

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT00020566

COG-AEWS0331

EU-20213

GPOH-GERMANY-INTERGROUP-EE99

EURO-EWING-INTERGROUP-EE99

SFOP-INTERGROUP-EE99

CDR0000068608

SWS-SAKK-INTERGROUP-EE99

EORTC-62981

CCLG-INTERGROUP-EE99

EBMT-INTERGROUP-EE99

GPOH-AUSTRIA-INTERGROUP-EE99

Details and patient eligibility

About

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 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.

Enrollment: 1,200 estimated patients

Sex: All

Ages: Under 49 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

1,200 participants in 3 patient groups

Group 1

Experimental group

Description:

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.

Treatment:

Drug: etoposide

Radiation: radiation therapy

Drug: doxorubicin hydrochloride

Biological: dactinomycin

Procedure: conventional surgery

Drug: vincristine sulfate

Drug: ifosfamide

Group 2, arm I

Experimental group

Description:

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.

Treatment:

Drug: etoposide

Radiation: radiation therapy

Drug: doxorubicin hydrochloride

Biological: dactinomycin

Procedure: conventional surgery

Drug: vincristine sulfate

Drug: ifosfamide

Group 2, arm II

Experimental group

Description:

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.

Treatment:

Drug: busulfan

Drug: melphalan

Drug: etoposide

Radiation: radiation therapy

Procedure: autologous hematopoietic stem cell transplantation

Drug: doxorubicin hydrochloride

Biological: dactinomycin

Procedure: conventional surgery

Drug: vincristine sulfate

Drug: ifosfamide