Phase III Randomized Study Testing Non-Inferiority of Short-Course Ultra-Hypofractionated Radiation (UHRT-5) Versus Standard Fractionation (RT-25) for Stage II-IIIB, Extremity, Resectable Soft Tissue Sarcoma

Disease Related Criteria

Participants must have histological evidence of a soft tissue sarcoma from core or incisional biopsy. Participants must have a primary or locally recurrent tumor. Stage II-IIIB (by AJCC 8th edition) soft tissue sarcoma is required (Appendix 18.3)

Participants must not have prior partial excision or partial excisional biopsy of the tumor, even if there is evidence of gross residual disease.

Participants who have undergone any prior surgical procedure or biopsy resulting in complete removal of the tumor with no gross residual disease remaining are also not eligible.
Participants must have a primary site of disease in the extremity, including the shoulder girdle and hip girdle but excluding the hands and feet.
Participants with primary sites of trunk, head, neck, or intra-abdominal, intra pelvic, or retroperitoneal region are not eligible.

Participants with extension of the primary tumor into adjacent regions (e.g. torso, hands, feet) are eligible.

Participants must have an MRI of the primary site within 90 days prior to randomization. The MRI field of view must contain the entirety of the tumor (may be accomplished with multiple MRI scans). MRI must contain axial acquired T1 weighted with fat suppression, T1 weighted sequence with gadolinium contrast with fat suppression, and T2 weighted fat suppression sequence.

Participants must have no evidence of metastatic disease by CT imaging of the chest (or PET CT), within 28 days before randomization.
Given the lack of specificity of chest CT, pulmonary nodule(s) ≤5 mm without a histological diagnosis are not exclusionary.

Participants with pulmonary nodule(s) measuring 6-10 mm on chest CT are eligible if the nodules appear stable compared to prior chest imaging from at least 6 months ago, or if an 18FDG-PET scan indicates that the nodules are unlikely to be metastatic disease.

Pulmonary nodules >10 mm should be considered metastatic unless proven otherwise by biopsy/resection or stable appearance for at least 6 months on imaging.

Participants must not have fungating tumor. (i.e., tumor breakthrough of skin).

Participants must not have myxoid liposarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, gastrointestinal stromal tumor, osteosarcoma, NTRK-rearranged spindle cell neoplasm, desmoplastic small round cell tumor, Ewing sarcoma, or sarcoma arising from bone.

Participants must not have known brain metastases. Brain imaging studies are not required for eligibility if the participant has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.

Prior/Concurrent Therapy Criteria

Participants must have been evaluated by a surgeon, and it must have been determined that they are a good candidate for a limb salvage resection with an expectation of negative margins, within 35 days prior to randomization. Anticipated positive margins on fixed critical structures are allowed.

Participants must not have had prior treatment for the current tumor (systemic therapy, radiation, or complete surgical resection).

Participants must not have had prior radiation to the anatomical site.

Clinical/Laboratory Criteria

Participants must be OVER18 years old at the time of randomization.

Participants must have Zubrod Performance Status of 0-2 (see Section 10.5).

Participants must have medical history and physical exam within 28 days prior to randomization. History and physical examination must include a description of the location of the tumor, including lateralization and extremity.

Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen.

Participants must not have uncontrolled intercurrent illnesses or any other significant condition(s) that would make this protocol unreasonably hazardous.

Participants with a history human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration.

Additional Criteria

Participants registered by sites located in the United States only must be offered the opportunity to participate in specimen banking as outlined in Section 15.3.