Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NSC# 737754)

• Note: eligible patients must have a body surface area \>= 0.5 m\^2 AND be able to swallow whole tablets

• Newly diagnosed and histopathologically confirmed, potentially resectable NRSTS of the extremity and trunk will be eligible for the chemotherapy or non-chemotherapy cohort based on:

‣ Evidence of chemotherapy sensitivity of the histologic sarcoma subtype based on existing evidence from prior clinical trials

⁃ Sufficient risk of metastatic disease to warrant chemotherapy based on size and grade and

⁃ Medically deemed able or unable to undergo chemotherapy

⁃ Notes: an incisional biopsy or core biopsy is preferred; fine needle aspiration biopsy is not acceptable to establish the diagnosis

• ELIGIBLE SITES:

‣ Extremities: upper (including shoulder) and lower (including hip)

⁃ Trunk: body wall

• INELIGIBLE SITES: Head and neck, visceral organs (with the exception of embryonal sarcoma of the liver), retroperitoneum, peritoneum, pelvis within the confines of the bony pelvis

• ELIGIBILITY FOR CHEMOTHERAPY COHORT:

• Stage T2a/b (\> 5 cm) and grade 2 or 3 AND

• One of the following chemosensitive histologies as defined in the World Health Organization (WHO) classification of soft tissue tumors (with some evidence of good response to chemoradiation and of sufficient high risk of metastases, or clear evidence of metastases):

‣ Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a specific pathologic category in the WHO classification (often called undifferentiated soft tissue sarcoma or soft tissue sarcoma not otherwise specified \[NOS\])

⁃ Synovial sarcoma

⁃ Angiosarcoma of soft tissue

⁃ Adult fibrosarcoma

⁃ Mesenchymal (extraskeletal) chondrosarcoma

⁃ Leiomyosarcoma

⁃ Liposarcoma (excluding myxoid liposarcoma)

⁃ Undifferentiated pleomorphic sarcoma

⁃ Embryonal sarcoma of the liver

• Patients meeting the above criteria (histology, size, and grade) with the EXCEPTION of histologies noted above may enroll on the chemotherapy cohort or the non-chemotherapy cohort at the discretion of the enrolling investigator; patients meeting these criteria with the EXCEPTION of histologies noted above but medically deemed unable to receive chemotherapy or who elect not to receive chemotherapy are eligible for the non-chemotherapy cohort

• Patients with the following histologies are only eligible for the chemotherapy cohort and cannot enroll on the non-chemotherapy cohort:

‣ Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a specific pathologic category in the WHO classification (often called undifferentiated soft tissue sarcoma or soft tissue sarcoma NOS) in patients \< 30 years of age

⁃ Synovial sarcoma

⁃ Embryonal sarcoma of the liver

• ELIGIBILITY FOR NON-CHEMOTHERAPY COHORT:

• Patients with any size of grade 2 or 3 of the following intermediate (rarely metastasizing) or malignant tumors, as defined in the WHO classification of soft tissue tumors for which we have consensus data of chemotherapy-resistance are eligible only for the non-chemotherapy cohort:

‣ So-called fibrohistiocytic tumors - plexiform fibrohistiocytic tumor, giant cell tumor of soft tissues

⁃ Fibroblastic/myofibroblastic tumors - solitary fibrous tumor, malignant solitary fibrous tumor, inflammatory myofibroblastic tumor, low grade myofibroblastic sarcoma, myxoinflammatory fibroblastic sarcoma, atypical myxoinflammatory fibroblastic tumor, myxofibrosarcoma, low grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma

⁃ Tumors of uncertain differentiation - epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma, ossifying fibromyxoid tumor, myoepithelioma, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, neoplasms with perivascular epithelioid cell differentiation (PEComa), intimal sarcoma, atypical fibroxanthoma, mixed tumor NOS, phosphaturic mesenchymal tumor, malignant ossifying fibromyxoid tumor, malignant mixed tumor, malignant phosphaturic mesenchymal tumor

⁃ Chondro-osseous tumors - extraskeletal osteosarcoma

⁃ Pericytic (perivascular) tumors - malignant glomus tumor

⁃ Nerve sheath tumors - malignant peripheral nerve sheath tumor, malignant granular cell tumor, epithelioid malignant peripheral nerve sheath tumor, malignant Triton tumor

⁃ Undifferentiated sarcomas (with a specific pathologic category in the WHO classification) - undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, undifferentiated spindle cell sarcoma

• Patients meeting the criteria (histology, size, and grade) with the EXCEPTION of histologies noted above may enroll on the non-chemotherapy cohort at the discretion of the enrolling investigator; patients meeting these criteria with the EXCEPTION of histologies noted above but medically deemed unable to receive chemotherapy or who elect not to receive chemotherapy are eligible for the non-chemotherapy cohort; note that tumors arising in bone are NOT eligible for this study

• Extent of disease:

‣ Patients with non-metastatic and metastatic disease are eligible

⁃ Initially unresectable patients, with or without metastatic disease, are eligible as long as there is a commitment at enrollment to resect the primary tumor

• Sufficient tissue and blood must be available to submit for required biology studies

• Lansky performance status score \>= 70 for patients =\< 16 years of age

• Karnofsky performance status score \>= 70 for patients \> 16 years of age

• Absolute neutrophil count \>= 1500/uL; Note: no transfusions are permitted 7 days prior to laboratory studies to determine eligibility

• Platelet count \>= 100,000/uL; Note: no transfusions are permitted 7 days prior to laboratory studies to determine eligibility

• Hemoglobin \>= 8 g/dL for patients =\< 16 years of age; \>= 9 g/dL for patients \> 16 years of age; Note: no transfusions are permitted 7 days prior to laboratory studies to determine eligibility

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

‣ 2 to \< 6 years; 0.8 mg/dL male; 0.8 mg/dL female

⁃ \>= 16 years; 1.5 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

• Corrected QT interval (QTc) \< 480 msec

• No evidence of dyspnea at rest, no exercise intolerance, and a resting pulse oximetry reading \> 94% on room air if there is clinical indication for determination

• Patients on low molecular weight heparin or Coumadin (with a stable international normalized ratio \[INR\]) are eligible

• Patient must have a life expectancy of at least 3 months with appropriate therapy

• 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