Combination Chemotherapy in Treating Patients With Non-Metastatic Extracranial Ewing Sarcoma

• Event-free survival (EFS) [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]

• Histologic response [ Designated as safety issue: No ]
• Initial volumetric tumor size as a prognostic factor for EFS [ Designated as safety issue: No ]
• Prognostic significance of imaging response by FDG-positron emission tomography (PET) and EFS [ Designated as safety issue: No ]
• Effect of local surgical margins in conjunction with histologic response on EFS [ Designated as safety issue: No ]
• Effect of local therapy modality (surgery, radiotherapy or a combination) as well as the type of surgical reconstruction on musculoskeletal complications [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PURPOSE: This randomized phase III trial is studying combination chemotherapy in treating patients with non-metastatic extracranial Ewing sarcoma.

OBJECTIVES:

Primary

• Test the effect of the combination of vincristine, cyclophosphamide, and topotecan (VTC) added to the standard 5-drug chemotherapy interval-compressed backbone on event-free survival (EFS) and overall survival of children and young adults with Ewing sarcoma.

Secondary

• Evaluate initial volumetric tumor size as a prognostic factor for EFS in patients with localized Ewing tumors.
• Evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors.
• Continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on a Ewing sarcoma specimen-collection study.
• Evaluate imaging response by FDG-positron emission tomography (PET) as a prognostic factor for EFS.
• Evaluate the effects of the type of local therapy on EFS and overall survival.
• Evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients with localized Ewing tumors.
• Evaluate the effect of local therapy modality (surgery, radiotherapy, or a combination) as well as the type of surgical reconstruction on musculoskeletal complications.

OUTLINE: This is a multicenter study.

Patients are stratified according to age (≤ 17 years vs ≥ 18 years) and primary tumor site (pelvic vs non-pelvic vs extra-osseous). Patients are randomized to 1 of 2 treatment arms.

• Arm I:

  • Induction therapy: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11.
  • Consolidation therapy: Patients receive vincristine sulfate on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19.

• Arm II:

  • Induction therapy: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1 and 9, and on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm I; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11.
  • Consolidation therapy: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9, 13, and 19.

Patients with responsive or stable disease undergo may undergo surgery alone in week 13 if lesion can be complete resected with negative margins and with reasonable functional result. Patients with unresectable lesions or inadequate margins after surgery receive radiotherapy during weeks 1-7. Patients with bulky lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis, patients with a poor response to induction chemotherapy, or those patients in whom surgery would result in unacceptable functional results may undergo radiotherapy alone in weeks 1-7 of consolidation therapy, and surgery should be performed after completion of consolidation chemotherapy. Patients with microscopic residual disease after planned pre-operative radiotherapy receive additional radiotherapy.

After completion of study therapy, patients are followed up periodically for 10 years.

• Brain and Central Nervous System Tumors
• Kidney Cancer
• Sarcoma

• Drug: cyclophosphamide
  Given IV
• Drug: doxorubicin hydrochloride
  Given IV
• Drug: etoposide
  Given IV
• Drug: ifosfamide
  Given IV
• Drug: topotecan hydrochloride
  Given IV
• Drug: vincristine sulfate
  Given IV

• Experimental: Arm I
  Patients receive induction therapy comprising vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. Patients then receive consolidation therapy comprising vincristine sulfate on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19.
  Interventions:

  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide
  • Drug: ifosfamide
  • Drug: vincristine sulfate
• Experimental: Arm II
  Patients receive induction therapy comprising vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1 and 9, and on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm I; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. Patients then receive consolidation therapy comprising vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9, 13, and 19.
  Interventions:

  • Drug: cyclophosphamide
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide
  • Drug: ifosfamide
  • Drug: topotecan hydrochloride
  • Drug: vincristine sulfate

DISEASE CHARACTERISTICS:

• Newly diagnosed extracranial, non-metastatic Ewing sarcoma or primitive neuroectodermal tumors of bone or soft tissue

  • For the purpose of this study, any of the following are considered localized disease:

    • Chest wall tumors with ipsilateral pleural effusions
    • Ipsilateral positive pleural fluid cytology
    • Ipsilateral pleural-based secondary tumor nodules
  • Regional node involvement, based on clinical suspicion confirmed by pathologic documentation, are considered to be non-metastatic disease
  • Tumors arising in the bony skull (extra-dural) are considered to be extracranial

• No evidence of metastatic disease, including the following:

  • Lesions that are discontinuous from the primary tumor, are not regional lymph nodes, and do not share a body cavity with the primary tumor
  • Contralateral pleural effusion and contralateral pleural nodules
  • Distant lymph node involvement

  • Pulmonary nodules that meet the following criteria:

    • Solitary nodule > 0.5 cm or multiple nodules of > 0.3 cm unless biopsied and negative for Ewing sarcoma
    • Biopsies of solitary nodule < 0.5 cm or multiple nodules < 3.0 cm (are not required but if performed) positive for metastatic disease
• No tumors arising in the intra-dural soft tissue

PATIENT CHARACTERISTICS:

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age and/or gender as follows:

  • 0.4 mg/dL (1 month to < 6 months of age)
  • 0.5 mg/dL (6 months to < 1 year of age)
  • 0.6 mg/dL (1 year to < 2 years of age)
  • 0.8 mg/dL (2 years to < 6 years of age)
  • 1.0 mg/dL (6 years to < 10 years of age)
  • 1.2 mg/dL (10 years to < 13 years of age)
  • 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)
  • 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
• Total bilirubin < 1.5 times upper limit of normal (ULN)
• AST or ALT < 2.5 times ULN
• Shortening fraction of ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for the duration of study treatment

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy

• Prior biopsy of the primary tumor without an attempt at complete or partial resection allowed

  • Patients are still allowed if unplanned excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery
• No other concurrent chemotherapy or immunomodulating agents (including steroids unless used as an antiemetic)
• No concurrent sargramostim (GM-CSF)