Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor

INTENSIVE THERAPY WITH GROWTH FACTOR SUPPORT FOR PATIENTS WITH EWING'S TUMOR METASTATIC AT DIAGNOSIS: A PEDIATRIC ONCOLOGY GROUP PHASE II STUDY

Phase II trial to study the effectiveness of combination chemotherapy in treating patients with newly diagnosed metastatic Ewing's sarcoma or primitive neuroectodermal tumor. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

OBJECTIVES:

I. Evaluate the response rate and duration of response of patients with newly diagnosed, metastatic Ewing's sarcoma or primitive neuroectodermal tumor treated with maximally intensified VAdrC (vincristine, doxorubicin, cyclophosphamide) alternating with IE (ifosfamide, etoposide).

II. Evaluate the response to new agents (first topotecan, then topotecan with cyclophosphamide) utilized in an upfront treatment window.

III. Assess the role of surgery with regard to local control of primary and metastatic sites and disease course.

IV. Evaluate whether individual variability in ifosfamide and cyclophosphamide metabolism correlates with toxicity and/or response.

V. Evaluate the rise in the absolute neutrophil count following one dose of filgrastim (G-CSF) given immediately prior to a chemotherapy course as an indicator of bone marrow reserve and subsequent myelosuppression.

VI. Determine if amifostine provides significant chemo-radio protection, particularly against the cumulative toxicities of this intensive therapy.

OUTLINE: This is a partially randomized, multicenter study.

Patients are treated on the investigational window first or proceed to induction therapy immediately, if aggressive treatment is necessary.

INVESTIGATIONAL WINDOW: Patients receive cyclophosphamide IV and topotecan IV over 30 minutes on days 1-5. Filgrastim (G-CSF) is administered subcutaneously (SQ) beginning day 6 until blood cell counts recover. Treatment is repeated at week 3.

INDUCTION THERAPY: Patients over 12 months old are randomized to receive amifostine or not. Patients receive etoposide IV over 45 minutes and ifosfamide IV over 2 hours on days 1-5. Amifostine IV over 15 minutes is also administered prior to ifosfamide. Patients receive G-CSF SQ (or IV over 2 hours) beginning on day 6. This course of treatment is administered on weeks 6, 12, and 18. Patients receive the VAdrC chemotherapy regimen on weeks 9 and 15. This regimen consists of vincristine IV and amifostine IV over 15 minutes on days 1, 8, and 15, cyclophosphamide IV over 30 minutes and doxorubicin IV over 48 hours on days 1 and 2, and G-CSF beginning on day 3. The VAdrC regimen is continued during local therapy on weeks 21-29 and 39-47, except the day 15 dose of vincristine is omitted, cyclophosphamide is administered on day 1 only on weeks 21, 24, 27, 39, 42, and 45, and doxorubicin is replaced with etoposide IV over 60 minutes on days 1-3 on weeks 24, 28, 42, and 45. Local therapy begins after 21 weeks of chemotherapy. Patients who respond to chemotherapy and have resectable disease undergo a complete resection with negative margins. Patients with unresectable disease or bulky lesions undergo radiotherapy. Some patients may undergo both surgery and radiotherapy. Local therapy of metastases is delayed until after week 39. Patients are followed every 3 months for 1 year, every 6 months for 2 years, then annually thereafter.

DISEASE CHARACTERISTICS:

• Newly diagnosed, pathologically confirmed Ewing's sarcoma or primitive neuroectodermal tumor (PNET)
• Diagnosis established from biopsy of primary tumor Light microscopy (hematoxylin and eosin stained) consistent with Ewing's sarcoma or PNET
• No immunohistochemical or ultrastructural characteristics inconsistent with Ewing's sarcoma or PNET or suggestive of rhabdomyosarcoma
• Metastatic disease required
• Biopsy of radiographically questionable metastases (e.g., pulmonary lesions) required
• Chest wall tumor with separate pleural mass considered metastatic
• No positive pleural fluid cytology alone

PATIENT CHARACTERISTICS:

• Age: 30 and under
• Absolute neutrophil count greater than 1,200/mm3
• Platelet count greater than 120,000/mm3
• Bilirubin less than 1.5 mg/dL
• AST/ALT less than 3 times normal
• Creatinine normal for age
• Significant renal abnormality/disease eligible only if nuclear GFR is normal and study coordinator approves
• Echocardiogram or MUGA normal

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy
• Resection at diagnosis is discouraged but does not exclude