Preoperative Radiotherapy and Anlotinib With or Without Penpulimab for Soft Tissue Sarcoma

A Prospective Multicenter Randomized Controlled Study of Preoperative Radiotherapy Combined With Targeted Therapy With or Without Immunotherapy for Soft Tissue Sarcoma

Soft tissue sarcoma is a rare cancer that often requires surgery combined with radiotherapy. Preoperative radiotherapy can improve the chance of complete tumor removal and limb preservation, but some patients still experience local recurrence, distant metastasis, or poor tumor response.

This is a prospective, multicenter, randomized phase II study for patients with localized soft tissue sarcoma of the extremity or trunk who need preoperative radiotherapy. Participants will be randomly assigned to receive preoperative radiotherapy plus anlotinib, or preoperative radiotherapy plus anlotinib and penpulimab. Surgery will be performed after completion of neoadjuvant treatment according to the study protocol.

The main purpose of this study is to evaluate whether adding penpulimab to preoperative radiotherapy and anlotinib can improve 3-year disease-free survival. The study will also assess pathological response, wound complications, treatment-related adverse events, local control, distant metastasis-free survival, overall survival, limb function, quality of life, and exploratory biomarkers related to treatment response.

Preoperative radiotherapy is an established treatment approach for patients with localized soft tissue sarcoma of the extremity or trunk, particularly when limb preservation and complete surgical resection are important treatment goals. However, the pathological response to preoperative radiotherapy alone remains limited in some patients, and local recurrence or distant metastasis can still occur after multidisciplinary treatment.

Anlotinib is a multitarget tyrosine kinase inhibitor with antiangiogenic activity and has shown clinical activity in soft tissue sarcoma. Immune checkpoint blockade may further enhance antitumor effects when combined with radiotherapy and antiangiogenic therapy by modulating the tumor microenvironment. The optimal patient population and risk-benefit profile of this combined neoadjuvant strategy require prospective evaluation.

This study is designed to compare preoperative radiotherapy plus anlotinib with preoperative radiotherapy plus anlotinib and penpulimab in patients with localized soft tissue sarcoma who are candidates for neoadjuvant treatment followed by surgery. The study will evaluate whether the addition of penpulimab improves disease control while maintaining acceptable safety, surgical feasibility, and postoperative wound healing.

Participants will receive protocol-defined neoadjuvant treatment before surgery and will be followed after surgery for disease outcomes, safety, limb function, quality of life, and translational biomarker analyses. The study also includes collection and analysis of clinical, imaging, pathological, and molecular data to explore potential predictors of treatment response and resistance.

Inclusion Criteria:

• Primary or recurrent soft tissue sarcoma of the extremity or trunk with intermediate- to high-grade disease and tumor size >=5 cm or deep-seated tumor, for which radiotherapy is recommended after multidisciplinary evaluation.
• Age >=15 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3.
• Histologically confirmed soft tissue sarcoma.
• At least one evaluable lesion.
• Able to tolerate radiotherapy, anlotinib, and penpulimab treatment.
• Female participants of childbearing potential, or male participants with female partners of childbearing potential, must agree to use effective contraception during the treatment period and for 6 months after the last dose of study treatment.
• Able to provide written informed consent.
• Able and willing to comply with follow-up.

Exclusion Criteria:

• No gross tumor remaining after unplanned tumor resection performed at another hospital.
• Contraindications to targeted therapy or immunotherapy due to comorbidities, including allergy, autoimmune disease, active bleeding, ulcer, intestinal perforation, intestinal obstruction, uncontrolled hypertension, New York Heart Association class III-IV cardiac dysfunction, or severe hepatic or renal dysfunction.
• Dermatofibrosarcoma protuberans, desmoid fibromatosis, tenosynovial giant cell tumor, or other locally aggressive diseases.
• Benign tumors.
• Sarcoma subtypes for which chemotherapy is recommended as the preferred neoadjuvant treatment according to guidelines, such as embryonal rhabdomyosarcoma or Ewing sarcoma.
• Lipoma-like liposarcoma or well-differentiated liposarcoma.
• New malignant tumor within 5 years before enrollment, except cervical carcinoma in situ, early-stage basal cell carcinoma of the skin, or early-stage lung cancer.
• Soft tissue sarcoma that can be cured by wide local excision alone.
• Prior radiotherapy to the same anatomical site.
• Other severe medical comorbidities that would preclude surgery or participation in this study.