Prospective Phase I/II Study Evaluating the Safety and Efficacy of Preoperative Carbon Ion Radiotherapy in Patients With Soft Tissue Sarcoma : The SARCOMA-01 Trial by the Severance sARCOma Multidisciplinary Team

• Carbon-Ion Radiotherapy (CIRT) (Radiation): Participants receive preoperative CIRT as the investigational intervention, delivered in 8 fractions, once daily, four times per week. In Phase I, three dose levels (DL1: 32.0 GyE, DL2: 34.0 GyE, DL3: 36.0 GyE) are evaluated using a 3+3 dose-escalation design to determine the recommended Phase II dose (RP2D). Three patients are initially enrolled per dose level, expanded to six if dose-limiting toxicities occur. In Phase II, all participants receive CIRT at the RP2D following a Simon's two-stage design (Stage I: 20 patients; Stage II: 22 additional if criteria met). Treatment uses fixed-beam or rotating gantry techniques. Post-treatment imaging (CT or MRI) is performed 4-6 weeks after CIRT, followed by surgical resection 6-8 weeks post-radiotherapy. All participants are followed for at least 12 months after surgery to assess postoperative wound complications, treatment completion, and overall outcomes.

Primary outcomes

• Phase I: Incidence of Dose-Limiting Toxicities (DLTs) [From initiation of CIRT to 30 days after surgery]: To evaluate the safety and tolerability of preoperative CIRT and identify the optimal tolerated dose level. DLTs are defined as grade ≥3 toxicities, including severe wound complications, prolonged hospitalization, or significant treatment delay, assessed according to CTCAE version 5.0.
• Phase II: Proportion of Patients Completing Both CIRT and Surgery Without Grade 3-5 Postoperative Wound Complications or Serious Adverse Events [From initiation of CIRT to 120 days after surgery]: To determine the clinical feasibility and safety of completing preoperative CIRT followed by surgical resection without major wound-healing complications or treatment-related serious adverse events (SAEs). The endpoint represents the proportion of patients achieving treatment completion without grade 3-5 wound complications or other SAEs within 120 days postoperatively.

Secondary outcomes

• Incidence of Acute Treatment-Related Toxicities [From initiation of CIRT to 30 days after surgery]: To record and grade all acute adverse events associated with preoperative carbon-ion radiotherapy using CTCAE v5.0 criteria to characterize the overall safety profile at each dose level.
• Surgery Feasibility and Completion Rate [From completion of CIRT to 30 days after surgery]: To assess the proportion of participants who successfully undergo and complete surgical resection following preoperative CIRT without protocol deviation or treatment interruption.
• Pathological Tumor Response Rate [At surgical specimen evaluation (6-8 weeks after CIRT)]: To determine the rate of pathological tumor regression or necrosis in resected specimens following preoperative CIRT, based on standardized histologic grading criteria.
• R0 Resection Rate [At surgery (6-8 weeks after CIRT)]: To evaluate the proportion of patients achieving microscopically margin-negative (R0) resection after preoperative CIRT, reflecting its impact on surgical resectability.
• Local Control and Progression-Free Survival [From date of surgery to 12 months postoperatively]: To estimate 1-year local control and progression-free survival using Kaplan-Meier analysis as measures of preliminary efficacy.
• Overall Survival [From initiation of CIRT to 12 months postoperatively]: To evaluate 12-month overall survival as an exploratory efficacy endpoint of preoperative CIRT.
• Quality of Life (EORTC QLQ-C30) [Baseline, post-CIRT, and 3, 6, and 12 months after surgery]: To assess longitudinal changes in patient-reported quality of life using the EORTC QLQ-C30 questionnaire throughout treatment and follow-up.
• Body Composition Change (InBody Analysis) : Skeletal-Muscle Mass Change [Baseline, post-CIRT, and 3, 6, and 12 months after surgery]: Unit of Measure: kg
• Body Composition Change (InBody Analysis) :Body-Fat Composition Change [Baseline, post-CIRT, and 3, 6, and 12 months after surgery]: Body-Fat Composition Change

Sex: All, ages: 19 Years to any

Inclusion Criteria:

* Adults aged 19 years or older.
* Histologically confirmed soft tissue sarcoma deemed suitable for curative resection.
* Determined by the Yonsei Cancer Center sarcoma multidisciplinary team that preoperative carbon-ion radiotherapy followed by surgery is appropriate, considering tumor histologic subtype, size, and location.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1 or Karnofsky Performance Status (KPS) ≥ 70.
* Adequate organ function (including hematologic, hepatic, and renal function) suitable for radiotherapy and surgery.
* Voluntarily provided written informed consent.

Exclusion Criteria:

* Presence of distant metastases.
* Inability to plan carbon-ion radiotherapy due to metallic implants or other factors at the tumor site.
* History of prior radiotherapy to the same anatomical region.
* Presence of other serious medical conditions or active infections that, in the investigator's judgment, could interfere with study participation.
* Presence of active implanted electronic devices (e.g., pacemaker or defibrillator) without established safety for carbon-ion radiotherapy.
* Pregnant or breastfeeding women.