Comparison of Combination Chemotherapy Regimens in Treating Patients With Ewing's Sarcoma or Neuroectodermal Tumor

OBJECTIVES:

• Compare the effect of interval-compressed vs standard chemotherapy in terms of event-free survival and overall survival in patients with newly diagnosed, localized Ewing's sarcoma or peripheral primitive neuroectodermal tumor.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 18 years vs 18 years and over) and location of primary disease (pelvic vs nonpelvic). Patients are randomized to 1 of 2 treatment arms for induction and continuation therapy.

• Induction therapy (weeks 1-12):

• Arm I: Patients receive alternating courses of chemotherapy consisting of vincristine IV on day 1, doxorubicin IV continuously over 48 hours on days 1 and 2, and cyclophosphamide IV over 1 hour on day 1 for courses 1 and 3 and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 for courses 2 and 4. Beginning 24 hours after the last dose of chemotherapy for each course, patients receive filgrastim (G-CSF) subcutaneously (SC) daily until blood counts recover. Treatment continues every 3 weeks for 4 courses.
• Arm II: Patients receive alternating courses of chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide as in arm I for courses 1, 3, and 5 and ifosfamide and etoposide as in arm I for courses 2, 4, and 6. Patients also receive G-CSF as in arm I. Treatment continues every 2 weeks for 6 courses.

After completion of induction therapy, patients in both arms receive local control treatment to the primary tumor. Patients receive continuation chemotherapy after surgery or concurrently with radiotherapy.

• Continuation therapy:

• Arm I (weeks 13-42): Patients receive additional alternating courses of chemotherapy as in arm I of induction therapy with the exception of vincristine and cyclophosphamide alone for courses 7 and/or 11 and/or 13. Patients also receive G-CSF as in induction therapy. Treatment continues every 3 weeks for 10 courses.
• Arm II (weeks 13-29): Patients receive additional alternating courses of chemotherapy as in arm II of induction therapy with the exception of vincristine and cyclophosphamide alone for courses 9 and/or 11 and/or 13. Patients also receive G-CSF as in induction therapy. Treatment continues every 2 weeks for 8 courses.

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

PROJECTED ACCRUAL: Approximately 528 patients will be accrued for this study within 4-5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed localized Ewing's sarcoma or peripheral primitive neuroectodermal tumor (PNET) of the bone or soft tissues

• Diagnostic biopsy of primary tumor within 30 days of study
• Paraspinal or bony skull tumors of extradural origin allowed

• No intradural soft tissue tumors
• Askin's tumor of the chest wall allowed

• Chest wall tumors with ipsilateral pleural effusions or ipsilateral pleural-based secondary tumor nodules allowed
• No contralateral pleural effusions
• No metastatic disease or distant node involvement

• One pulmonary or pleural nodule greater than 1 cm in diameter OR more than 1 nodule greater than 0.5 cm in diameter are considered pulmonary metastasis
• Solitary lung nodules of 0.5-1 cm OR multiple nodules of 0.3-0.5 cm allowed unless biopsy positive for tumor
• Light microscopic appearance (hematoxylin and eosin stained) consistent with Ewing's sarcoma or peripheral PNET
• No immunohistochemical or ultrastructural evidence of rhabdomyosarcoma
• No esthesioneuroblastoma
• Clinically or pathologically involved regional lymph nodes allowed
• No CNS involvement

PATIENT CHARACTERISTICS:

Age:

• 50 and under at diagnosis

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Bilirubin no greater than 1.5 mg/dL

Renal:

• Creatinine normal for age
• Creatinine clearance or isotope glomerular filtration rate at least 75 mL/min

Cardiovascular:

• Shortening fraction at least 28% by echocardiography OR
• Ejection fraction at least 55% by radionuclide angiogram

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other prior malignancy except skin cancer diagnosed at least 5 years ago and currently in remission

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior immunotherapy for skin cancer
• No concurrent sargramostim (GM-CSF)
• No concurrent pegfilgrastim

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• Prior complete or partial excision of primary tumor allowed