125I Seed Brachytherapy Combined With Immunotherapy for Primary, Recurrent, or Metastatic Malignant Tumors

Patients with malignant tumors-including primary, recurrent, and metastatic disease-often exhibit heterogeneous responses to immune checkpoint inhibitors (ICIs). Limited tumor antigen exposure, poor immune infiltration, and an immunosuppressive tumor microenvironment frequently restrict the efficacy of immunotherapy. Strategies capable of enhancing local tumor immunogenicity and promoting systemic immune activation may improve clinical outcomes.

125I seed interstitial brachytherapy delivers continuous low-dose-rate radiation precisely to the tumor, offering both durable local control and immunomodulatory effects. Low-dose-rate irradiation can induce immunogenic tumor cell death, increase tumor antigen presentation, enhance dendritic cell activation, and promote T-cell recruitment. This process may convert immunologically inactive ("cold") tumors into immunologically active ("hot") lesions, thereby synergizing with ICIs to enhance anti-tumor immunity. Combining these modalities may improve objective response, delay treatment failure, reduce recurrence, and prolong survival.

This prospective, randomized, open-label, parallel-group trial will compare 125I seed brachytherapy plus immunotherapy with immunotherapy alone. Eligible patients will be randomized 1:1. The combination arm will receive CT-guided seed implantation followed by ICI therapy; the control arm will receive ICI monotherapy. All patients will undergo standardized imaging and clinical evaluations at pre-defined intervals.

The primary endpoints are objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints include failure-free survival (FFS), overall survival, disease control rate, duration of response, local control rate, tumor recurrence rate, treatment-related and immune-related adverse events, and patient-reported quality of life. Exploratory analyses will investigate radiomics features associated with response, patterns of recurrence (local, regional, or distant), and subgroup differences across tumor types, disease stages, biomarker profiles, and treatment characteristics. These analyses may help identify imaging or clinical predictors of benefit, refine patient selection, and support biomarker-driven optimization of 125I seed brachytherapy combined with immunotherapy.

Inclusion criteria

• Age 18 to 80 years.
• Histologically or clinically confirmed primary, recurrent, or metastatic malignant tumor.
• At least one measurable lesion according to RECIST 1.1 or iRECIST.
• Tumor site suitable for 125I seed implantation under CT or PET/CT guidance.
• Planned to receive or eligible to receive an immune checkpoint inhibitor (ICI).
• ECOG performance status 0-2.
• Adequate organ function:

ANC ≥ 1.5 × 10⁹/L Platelets ≥ 80 × 10⁹/L Hemoglobin ≥ 90 g/L AST/ALT ≤ 3 × ULN (≤ 5 × ULN for liver metastasis) Creatinine clearance ≥ 50 mL/min

• Life expectancy ≥ 3 months.
• Ability to understand and sign informed consent.

Exclusion criteria

• Prior I-125 seed implantation at the planned treatment site.
• Active uncontrolled infection or systemic inflammatory disease.
• Known history of autoimmune disease requiring systemic immunosuppression.
• Prior treatment with immune checkpoint inhibitors within the last 4 weeks.
• Uncontrolled coagulopathy or contraindication to interventional seed implantation:

INR > 1.5 Platelets < 50 × 10⁹/L

• Tumor location that poses unacceptable procedural risk, including inability to obtain a safe puncture path.
• Severe cardiopulmonary dysfunction (e.g., heart failure, unstable arrhythmia, severe COPD).
• Pregnancy or breastfeeding.
• Known allergy or contraindication to radiopharmaceuticals, contrast agents, or anesthesia agents used during implantation.
• Any condition that, in the investigator's judgment, makes the participant unsuitable for the study (e.g., poor compliance, severe psychiatric disorder).