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

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. To evaluate initial volumetric tumor size as a prognostic factor for event free survival
(EFS) in patients with localized Ewing tumors.

II. To evaluate histologic response as a prognostic factor for EFS in patients with localized
Ewing tumors.

III. To 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.

IV. To evaluate imaging response by fludeoxyglucose F 18 (FDG)-positron emission tomography
(PET) as a prognostic factor for EFS.

V. To evaluate the effects of the type of local therapy on EFS and overall survival.

VI. To evaluate the effect of local surgical margins in conjunction with histologic response
on EFS in patients with localized Ewing tumors.

VII. To evaluate the effect of local therapy modality (surgery, radiotherapy, or a
combination) as well as the type of surgical reconstruction on musculoskeletal complications.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (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 IV 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 every 3 months for 3 years and
then every 6 months for 2 years.

Inclusion Criteria:

- Patients with newly diagnosed, biopsy confirmed, extracranial, non-metastatic Ewing
sarcoma or primitive neuroectodermal tumor (PNET) of bone or soft tissue are eligible
for this study; note:

- For the purpose of this study, chest wall tumors with ipsilateral pleural
effusions, ipsilateral positive pleural fluid cytology or ipsilateral pleural
based secondary tumor nodules will be considered localized disease

- Patients with regional node involvement, based on clinical suspicion confirmed by
pathologic documentation are considered to be non-metastatic

- Patients with discontinuous osseous lesions within the same bone are considered
to be non-metastatic

- Tumors arising in the bony skull (extra-dural) are considered to be extracranial

- Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by
institutional pathologist

- No prior chemotherapy or radiation therapy is allowed; patients should only have had a
biopsy of the primary tumor without an attempt at complete or partial resection;
patients will still be eligible if unplanned excision was attempted or accomplished as
long as adequate imaging was obtained prior to surgery

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73
m^2 or serum creatinine based on age/gender as follows:

- 1 month to < 6 months: 0.4 mg/dL

- 6 months to < 1 year: 0.5 mg/dL

- 1 to < 2 years: 0.6 mg/dL

- 2 to < 6 years: 0.8 mg/dL

- 6 to < 10 years: 1 mg/dL

- 10 to < 13 years: 1.2 mg/dL

- 13 to < 16 years: 1.5 mg/dL (male), 1.4 mg/dL (female)

- >= 16 years: 1.7 mg/dL (male), 1.4 mg/dL (female)

- Total bilirubin < 1.5 x upper limit of normal (ULN) for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age

- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
radionuclide angiogram

Exclusion Criteria:

- Patients must have no evidence of metastatic disease; metastatic disease:

- Are lesions which are discontinuous from the primary tumor, are not regional
lymph nodes and do not share a body cavity with the primary tumor; if there is
any doubt whether lesions are metastatic, a biopsy of those lesions should be
taken

- Skeletal lesions in adjacent bones (trans-articular)

- Contralateral pleural effusion and contralateral pleural nodules

- Distant lymph node involvement

- Patients with pulmonary nodules are considered to have metastatic disease if the
patient has:

- Solitary nodule > 0.5 cm or multiple nodules of > 0.3 cm unless biopsied and
negative for Ewing's

- Biopsies of solitary nodule =< 0.5 cm or multiple nodules =< 0.3 cm are not
required but if performed and positive indicate metastatic disease

- Patients whose tumors arise in the dural and intra-dural soft tissues of the cranium
and spine are not eligible

- Patients with pathologic diagnoses other than Ewing sarcoma will be excluded

- Patients diagnosed with Ewing Sarcoma as a second malignant neoplasm are not eligible
if they have received chemotherapy or radiation for the treatment of their primary
malignancy

- Pregnant women will not be entered on this study; pregnancy tests must be obtained in
female patients who are post-menarchal; lactating females may not participate unless
they have agreed not to breastfeed their infants; males or females of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method for the duration of the study treatment

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met