Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma

PRIMARY OBJECTIVES:

I. Define a risk-based treatment strategy comprising observation only, adjuvant radiotherapy,
or adjuvant chemoradiotherapy or neoadjuvant chemoradiotherapy, surgery, and adjuvant
chemotherapy with or without radiotherapy in young patients with non-rhabdomyosarcoma soft
tissue sarcoma (NRSTS).

II. Assess event-free and overall survival of patients treated with these regimens.

III. Assess the pattern of treatment failure in these patients.

SECONDARY OBJECTIVES:

I. Assess the feasibility of a neoadjuvant chemoradiotherapy approach in patients with
intermediate- or high-risk NRSTS.

II. Assess the imaging and pathologic responses to neoadjuvant chemoradiotherapy in patients
with intermediate- or high-risk NRSTS.

III. Correlate imaging and pathologic response with clinical outcomes in patients with
intermediate- or high-risk disease who undergo neoadjuvant chemoradiotherapy.

IV. Prospectively define clinical prognostic factors associated with event-free survival,
overall survival, local recurrence, and distant recurrence in these patients.

V. Correlate patient outcomes with findings of biologic studies performed on tissue specimens
collected on protocol COG-D9902 from these patients.

VI. Determine whether the diagnosis and histologic grade of NRSTS assigned by the enrolling
institution correlates with the diagnosis and histologic grade established by central expert
pathology reviewers.

VII. Compare the Pediatric Oncology Group (POG) and Fédération Nationale des Centres de Lutte
Contre le Cancer (French Federation of Cancer Centers [FNCLCC]) pathologic grading systems to
determine which better correlates with clinical outcomes.

OUTLINE: This is a multicenter study. Patients are divided into 3 risk groups according to
presence of metastatic disease (yes vs no), status of prior surgery (resected vs unresected),
grade of tumor (low vs high), and size of primary tumor (≤ 5 cm vs > 5 cm). Patients are
assigned to different treatment regimens based on disease extent (nonmetastatic vs
metastatic), tumor size (≤ 5 cm vs > 5 cm), extent of resection of primary tumor (resected vs
unresected), extent of resection of metastases (complete or microscopic residual vs gross
residual), microscopic tumor margins (negative vs positive), and tumor grade (low vs high).

GROUP 1 (low risk [nonmetastatic, grossly resected disease, except high-grade tumor > 5 cm]):
Patients with low-grade tumor with either negative or positive microscopic margins or
high-grade tumor ≤ 5 cm (in maximum diameter) with negative microscopic margins are assigned
to regimen A. Patients with high-grade tumor ≤ 5 cm (in maximum diameter) with positive
microscopic margins are assigned to regimen B.

REGIMEN A (observation only): Patients undergo observation only.

REGIMEN B (adjuvant radiotherapy): Beginning between 6-42 days after surgical resection,
patients undergo a total of 31 fractions of adjuvant radiotherapy.

GROUP 2 (intermediate risk [nonmetastatic, resected or unresected disease]): Patients with
grossly resected, high-grade tumor > 5 cm (in maximum diameter) are assigned to regimen C.
Patients with unresected tumor are assigned to regimen D.

REGIMEN C (adjuvant chemoradiotherapy): Patients receive ifosfamide IV over 3 hours on days
1-3 in weeks 1, 4, 7, 10, 13, and 16 and doxorubicin hydrochloride IV over 24 hours on days 1
and 2 in weeks 1, 4, 13, 16, and 19. Beginning in week 4, patients also undergo a total of 31
fractions of radiotherapy.

*NOTE: *Patients who receive brachytherapy will initiate radiotherapy in Week 1. If
brachytherapy is administered, chemotherapy should begin within 2 weeks of completion of
brachytherapy and the Weeks 1 and 19 doxorubicin should be given instead at Weeks 7 and 10.

REGIMEN D (neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy with or without
radiotherapy): Neoadjuvant chemoradiotherapy and surgery: Patients receive ifosfamide IV over
3 hours on days 1-3 in weeks 1, 4, 7, and 10 and doxorubicin hydrochloride IV over 24 hours
on days 1 and 2 in weeks 1 and 4. Beginning in week 4, patients also undergo a total of 31
fractions of radiotherapy**. Patients undergo surgical resection in week 13.

NOTE: **Patients with primary hepatic tumors do not receive radiotherapy in week 4.

Adjuvant chemotherapy with or without radiotherapy: Patients receive ifosfamide IV over 3
hours on days 1-3 in weeks 16 and 19 and doxorubicin hydrochloride IV over 24 hours on days 1
and 2 in weeks 16, 19***, and 22. Beginning in week 16, patients achieving gross total
resection with positive microscopic margins undergo a total of 6 fractions of adjuvant
radiotherapy. Patients achieving less than total gross resection undergo a total of 11
fractions of adjuvant radiotherapy. Patients achieving total gross resection with negative
microscopic margins do not receive adjuvant radiotherapy.

NOTE: ***Patients who receive adjuvant radiotherapy in week 16 receive doxorubicin
hydrochloride in week 25 instead of week 19.

GROUP 3 (high risk [metastatic, resected, incompletely resected, or unresected disease]):
Patients with low-grade, all-sites resected tumor with either negative or positive
microscopic margins are assigned to receive treatment as in group 1 regimen A. Patients with
high-grade, grossly resected primary tumor, and metastatic disease are assigned to receive
treatment as in group 2 regimen C. Patients with unresected, high-grade metastatic tumor are
assigned to receive treatment as in group 2 regimen D.

In all groups, treatment continues in the absence of disease progression. After completing
study treatment, patients are followed periodically for at least 5 years.

Inclusion Criteria:

- Newly diagnosed non-rhabdomyosarcoma soft tissue sarcoma (STS), confirmed by central
pathology review via concurrent enrollment on protocol COG-D9902

- Metastatic or non metastatic disease

- Meets 1 of the following criteria:

- Intermediate (i.e., rarely metastasizing) or malignant STS, including any of the
following:

- Adipocytic tumor, including liposarcoma of any of the following histology
subtypes:

- Dedifferentiated

- Myxoid

- Round cell

- Pleomorphic type

- Mixed-type

- Not otherwise specified (NOS)

- Fibroblastic/myofibroblastic tumors, including any of the following:

- Solitary fibrous tumor

- Hemangiopericytoma

- Low-grade myofibroblastic sarcoma

- Myxoinflammatory fibroblastic sarcoma

- Adult fibrosarcoma*

- Myxofibrosarcoma

- Low-grade fibromyxoid sarcoma or hyalinizing spindle-cell tumor

- Sclerosing epithelioid fibrosarcoma

- So-called fibrohistiocytic tumors, including any of the following:

- Plexiform fibrohistiocytic tumor

- Giant cell tumor of soft tissues

- Pleomorphic malignant fibrous histiocytoma (MFH)/undifferentiated
pleomorphic sarcoma

- Giant cell MFH/undifferentiated pleomorphic sarcoma with giant cells

- Inflammatory MFH/undifferentiated pleomorphic sarcoma with prominent
inflammation

- Smooth muscle tumor (leiomyosarcoma)

- Pericytic [perivascular] tumor (malignant glomus tumor or glomangiosarcoma)

- Vascular tumor, including angiosarcoma

- Chondro-osseous tumors of any of the following types:

- Mesenchymal chondrosarcoma

- Extraskeletal osteosarcoma

- Tumors of uncertain differentiation, including any of the following:

- Angiomatoid fibrous histiocytoma

- Ossifying fibromyxoid tumor

- Myoepithelioma/parachordoma

- Synovial sarcoma

- Epithelioid sarcoma

- Alveolar soft-part sarcoma

- Clear cell sarcoma of soft tissue

- Extraskeletal myxoid chondrosarcoma ("chordoid type")

- Malignant mesenchymoma

- Neoplasms with perivascular epithelioid cell differentiation (PEComa)

- Clear cell myomelanocytic tumor

- Intimal sarcoma

- Malignant peripheral nerve sheath tumor

- Dermatofibrosarcoma protuberans meeting both of the following criteria:

- Non metastatic disease

- Tumor must be grossly resected prior to study enrollment

- Embryonal sarcoma of the liver

- Unclassified STS that is too undifferentiated to be placed in a specific
pathologic category (undifferentiated STS or STS NOS)

- Gross resection of the primary tumor ≤ 42 days prior to enrollment required except if
any of the following circumstances apply:

- Non metastatic high-grade tumor > 5 cm in maximal diameter and gross or
microscopic residual tumor is anticipated after resection

- Tumor of either high- or- low-grade that cannot be grossly excised without
unacceptable morbidity

- High-grade tumor with metastases

- Patients with metastatic low-grade tumor whose disease is amenable to gross
resection at all sites must undergo gross resection of all sites prior to
study entry

- Patients with a tumor recurrence after a gross total resection are not eligible

- Tumors arising in bone are not eligible

- Patients with epithelioid sarcoma, clear cell sarcoma, or clinical or radiologic
evidence of regional lymph node enlargement must undergo sentinel lymph node biopsies
or lymph node sampling to confirm the status of regional lymph nodes* NOTE: *Except in
cases where the study radiologist reviews the imaging and indicates that a biopsy is
not needed to confirm that the patient has lymph node involvement.

- If lymph node biopsies are positive for tumor (or the lymph nodes are classified
as positive by the study radiologist), formal lymph node dissection must be done
at the time of definitive surgery(prior to study entry for patients assigned to
study regimen C)

- Patients with metastatic disease must undergo a biopsy to confirm the presence of
metastatic tumor if all metastases are < 1 cm in maximal diameter (except in cases
where the study radiologist reviews the imaging and indicated that a biopsy is not
needed to confirm that the patient has metastatic disease)

- Lansky performance status (PS) 50-100% (for patients ≤ 16 years of age) OR Karnofsky
PS 50-100% (for patients > 16 years of age)

- Life expectancy ≥ 3 months

- Absolute neutrophil count ≥ 1,000/mm³*

- Platelet count ≥ 100,000/mm³*

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40
mL/min for infants < 1 year of age)* 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)

- Patients with urinary tract obstruction by tumor must meet the renal function criteria
listed above AND must have unimpeded urinary flow established via decompression of the
obstructed portion of the urinary tract

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)*

- Shortening fraction ≥ 27% by echocardiogram* OR ejection fraction ≥ 50% by
radionuclide angiogram*

- Not pregnant or nursing (patients undergoing radiotherapy and/or chemotherapy)

- No nursing for ≥ 1 month after completion of study treatment in study regimens C
or D

- Fertile patients must use effective contraception during and for ≥ 1 month after
completion of study treatment

- Negative pregnancy test

- No evidence of dyspnea at rest*

- No exercise intolerance*

- Resting pulse oximetry reading > 94% on room air (for patients with respiratory
symptoms)*

- Prior treatment for cancer allowed provided the patient meet the prior therapy
requirements

- No prior anthracycline (e.g., doxorubicin or daunorubicin) or ifosfamide chemotherapy
for patients enrolled on arm C or arm D

- No prior radiotherapy to tumor-involved sites