Phase II, national, multicentric, prospective, randomized (1:1) non-inferiority trial with two parallel groups, incorporating a concurrent observational cohort of eligible non-randomized patients, designed to address critical knowledge gaps by prospectively evaluating the safety, efficacy, and feasibility of preoperative ultra-hypofractionated radiotherapy (HFRT) in patients with soft tissue sarcomas (STS) of the extremities and trunk.

This study is designed to address critical knowledge gaps by prospectively evaluating the safety, efficacy, and feasibility of preoperative ultra-hypofractionated radiotherapy (HFRT) in patients with soft tissue sarcomas (STS) of the extremities and trunk. Eligible patients will be randomized to receive an ultra-hypofractionated RT regimen consisting of 30 Gy delivered in 5 fractions of 6 Gy, followed by surgical resection at one of two predefined intervals: either 1-2 weeks or 4-6 weeks after completion of radiotherapy. In parallel, a non-randomized observational cohort will be recorded, consisting of patients treated according to current standard practice - surgery alone or surgery preceded by nonventional RT (50 Gy in 25 fractions) - to provide a contemporaneous benchmark for comparison. The aim of this study is to gather high-quality clinical evidence on the impact of ultra-hypofractionated RT on oncologic outcomes, treatment-related toxicity, perioperative morbidity, and patient-reported quality of life. Evaluation of logistical and economic implications of treatment de-escalation, such as healthcare resource utilization and treatment burden are also an important point to be addressed.

By systematically assessing these endpoints, this study aims to inform future clinical guidelines and support the potential integration of ultra-hypofractionated RT into routine clinical practice for selected patients with localized STS.

Inclusion Criteria:

• Voluntary written informed consent, with the ability to fully understand and effectively communicate, before performance of any study-related procedure not part of normal medical practice, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Age > 18 years
• Proven diagnosis of primary, resectable extremity/trunk wall STS with low-medium risk (Sarculator© predicted 10y-OS > 60%)
• Measurable disease criteria (RECIST 1.1 and CHOI)
• ECOG: 0, 1 or 2 (if influenced by orthopedic condition and not by general status)
• No major contraindication to the planned radiotherapy or surgical treatment
• Active participation with adherence to requested treatment schedule and follow-up
• Female subject will undergo a negative pregnancy test
• Adequate bone marrow function (hemoglobin > 9g/dL, Leukocytes > 3000/mm³, platelets > 100,000/mm³). Patients with plasma creatinine ≤ 1.6 mg/dL, transaminase (AST-SGOT, ALT-SGPT) ≤ 2.5 times the UNL; total bilirubin ≤ 1.5 time the UNL; alkaline phosphatase ≤ 2.5 times the UNL are acceptable. CRP, LDH, total protein and albumin must also be recorded.
• HBV and HCV serologies must be performed prior to patient inclusion. If hepatitis B surface antigen (HBsAg) is positive, further evaluation is required to exclude active viral replication (i.e., testing for hepatitis B e antigen [HBeAg] and HBV DNA). If either of these markers is positive, study inclusion is not recommended. In such cases, prophylactic treatment with lamivudine may be considered at the investigator's discretion. If a potential participant tests positive for anti-HCV antibodies, active infection must be ruled out through a qualitative HCV PCR test. If PCR testing cannot be performed, or if it confirms active infection, the patient will not be eligible for the study. Patients must be HIV-seronegative, with a CD4+ T-cell count greater than 400/mm³. Individuals with clinically significant immunodeficiency-either congenital or acquired-are not eligible for enrollment

Exclusion Criteria:

• Age < 18y
• Soft tissue sarcomas (STS) originating at different sites (i.e., retroperitoneal, abdominal, pelvic, head and neck), gynecological sarcomas, as well as gastrointestinal stromal tumors (GISTs), desmoid-type fibromatosis and pediatric-type sarcomas (i.e., extraosseous Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, desmoplastic small round cell tumor) are excluded.
• Recurrent or metastatic condition or previous whoop-surgery for sarcoma (incisional biopsies are allowed if performed 6 months before referral).
• Unresectable tumors (with limb sparing surgery)
• Diagnosed oncological condition in the 5 years before enrollment (exceptions: Gleason <6 prostatic adenocarcinoma; In-situ cervical cancer and melanoma; basal cell skin carcinoma radically treated)
• Prior radiation treatment to the site designated for planned surgery or radiotherapy, regardless of indication
• Any medical condition that can impair and reduce life expectancy to less than 2 years including but not limited to significant systemic diseases grade 3 or higher on the CI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity
• Uncontrolled bacterial, fungal, or viral infections-either systemic or localized at the site of planned surgery or radiotherapy
• Severe psychiatric disorder, psychological, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
• Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion
• Patients who had received any other treatment for the disease under study including chemotherapy, radiotherapy, surgery or any other treatment with curative intent. incisional biopsies are allowed if performed 6 months before referral.
• Inability to comply with the requested follow-up
• Women who are pregnant or breast-feeding
• Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
• BMI > 40 and BMI < 18