This is a prospective, single-center, single-arm, open-label phase II exploratory study to evaluate the efficacy, safety, and immune remodeling effects of stereotactic body radiotherapy (SBRT) combined with reduced-dose anthracycline chemotherapy and the PD-1 inhibitor toripalimab as neoadjuvant therapy, followed by postoperative stratified maintenance therapy, in patients with localized high-risk undifferentiated pleomorphic sarcoma (UPS). A Simon two-stage design will be used, with 39 patients planned (stage 1: 13 patients; 35 patients in total, including a 10% dropout rate). Treatment consists of SBRT (8-10 Gy in 5 fractions) followed by toripalimab (240 mg intravenously every 3 weeks, 3 cycles in the neoadjuvant phase) combined with liposomal doxorubicin (30-40 mg/m² intravenously every 3 weeks, 2 cycles in the neoadjuvant phase). After response evaluation, radical surgery is performed. Postoperative stratified maintenance therapy is delivered according to pathological response: patients achieving major pathologic response (MPR) or hyalinized pathologic response (HPR) receive toripalimab monotherapy (240 mg every 3 weeks, up to 14 cycles), while those not achieving MPR/HPR receive toripalimab combined with liposomal doxorubicin (2-4 cycles). The primary endpoint is the rate of major pathologic response (MPR). Secondary endpoints include the rate of hyalinized pathologic response (HPR), radiologic objective response rate (ORR), R0 resection rate, limb salvage rate, and safety.
Male or female, aged 18 to 75 years.
Histologically confirmed UPS, screened locally and confirmed by central pathology before enrollment. Adequate IHC (at least CK, S100, SOX10, SMA, desmin, MDM2, CDK4) and NGS when feasible (MDM2/CDK4 amplification mandatory) to exclude dedifferentiated liposarcoma and other differentiated tumors.
UPS of extremities or trunk. Max diameter >5 cm, or <=5 cm with any of: encasement of major neurovascular bundle >180 degrees; expected limb functional loss >50% after resection; MDT deems R0 difficult. SBRT-feasible anatomy with >3 mm margin to critical neurovascular structures or joint.
Regional nodes evaluated by imaging (US/CT/MRI/PET-CT). Suspicious nodes (short axis >=10 mm, abnormal morphology, or high FDG) require pathology. Uninvolved nodes must not be irradiated; involved nodes included with radical dose or resected.
Other malignancy, except completed treatment with no recurrence/metastasis within 2 years.
Major surgery within 4 weeks, or systemic steroids (>10 mg/day prednisone equivalent) or immunosuppressants within 2 weeks.
Active infection requiring systemic therapy; active HBV (DNA >=2000 IU/mL), HCV, syphilis, or HIV positive.
Active or relapsing autoimmune disease.
Single group
Toripalimab
DrugToripalimab 240 mg IV q3w; 3 neoadjuvant doses from SBRT start; maintenance up to 14 cycles until progression, death, or unacceptable toxicity.
Liposomal doxorubicin
DrugLiposomal doxorubicin 30-40 mg/m2 IV q3w; 2 neoadjuvant cycles. Non-MPR/HPR: 2-4 adjuvant cycles (2 cycles if HPR \>30%).
Stereotactic body radiotherapy (SBRT)
RadiationSBRT 8-10 Gy x 5 (median 8 Gy x 5), over 5-10 days in weeks 1-3, IGRT required.
Rate of Major Pathologic Response (MPR)
Rate of Hyalinized Pathologic Response (HPR)
Objective Response Rate (ORR)
R0 Resection Rate
Limb Salvage Rate
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