Malignant Tumors
Conditions
Keywords
lodine-125 Seed Brachytherapy, Immune Checkpoint Inhibitors, Local-Systemic Synergy, Recurrent or Refractory Tumors
Brief summary
This prospective randomized trial evaluates the efficacy and safety of combining 125I seed interstitial brachytherapy with immune checkpoint inhibitor therapy in patients with primary, recurrent, or metastatic malignant tumors. Immunotherapy has become an important systemic treatment option, yet many patients experience limited benefit due to low tumor immunogenicity, insufficient T-cell infiltration, and an immunosuppressive tumor microenvironment. 125I seed brachytherapy provides continuous low-dose-rate radiation to the tumor, promoting antigen release, enhancing dendritic cell activation, and potentially converting immunologically cold tumors into more responsive hot lesions. Integrating localized radiation with systemic immunotherapy may improve tumor response, prolong progression-free survival, and reduce recurrence. Patients will be randomized 1:1 to receive 125I seed implantation plus immunotherapy or immunotherapy alone. The primary endpoints are objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints include failure-free survival (FFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), local control, recurrence rate, adverse events, and quality of life. Exploratory analyses will assess radiomics features, subgroup responses, and different patterns of recurrence. This study aims to determine whether adding 125I seed brachytherapy enhances the clinical benefits of immunotherapy across diverse malignant tumors.
Detailed description
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.
Interventions
DRUGImmune Checkpoint Inhibitors
Examples include PD-1/PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, camrelizumab, sintilimab) Administered per standard dosing schedule (e.g., every 2-3 weeks)
PET/CT-guided implantation or CT-guided implantation Dose planning: D90 typically 90-140 Gy (adjusted per tumor type and size) Post-implant dosimetry: D90, V100, V150 recorded
Sponsors
Li Min
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Due to the procedural nature of 125I seed implantation, blinding of participants and treating clinicians is not feasible. However, imaging evaluators-including independent radiologists and nuclear medicine physicians responsible for tumor response assessment and imaging-based efficacy evaluations-will remain blinded to treatment allocation.
Intervention model description
This is a two-arm, parallel-group, phase II trial in which eligible patients with recurrent or refractory, unresectable malignant tumors are randomized in a 1:1 ratio to receive either 125I seed interstitial brachytherapy combined with immune checkpoint inhibitor therapy or immune checkpoint inhibitor therapy alone. Treatment allocation remains fixed throughout the study; no crossover between arms is planned. Patients will be treated and followed according to the assigned arm until disease progression, unacceptable toxicity, withdrawal of consent, or study completion.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to 24 months | Time from randomization to radiographic disease progression or death from any cause. |
| Objective Response Rate (ORR) | Every 6-12 weeks, up to 24 months | Proportion of patients achieving complete response (CR) or partial response (PR) as defined by RECIST 1.1 or iRECIST, assessed via CT/MRI/PET-CT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 36 months | Time from randomization to death from any cause. |
| Disease Control Rate (DCR) | Every 6-12 weeks, up to 24 months | Percentage of patients achieving CR, PR, or stable disease (SD), according to RECIST 1.1/iRECIST. |
| Duration of Response (DoR) | Up to 24 months | Time from first documentation of CR/PR until radiographic progression or death. |
| Local Control Rate (LCR) | Up to 24 months | Proportion of treated lesions without local progression, based on imaging (CT/MRI/PET-CT) and dosimetric correlation of the implanted region. |
| Failure-Free Survival (FFS) | Up to 24 months | Time from randomization to the first occurrence of treatment failure, including disease progression, local recurrence, distant metastasis, discontinuation due to adverse events, or death. |
| Treatment-Related Adverse Events (TRAEs) | From baseline until 90 days after last treatment | Incidence, severity, and type of adverse events associated with treatment, graded according to CTCAE v5.0. |
| Immune-Related Adverse Events (irAEs) | Up to 24 months | Incidence and grade of immunotherapy-related toxicities such as pneumonitis, colitis, dermatitis, endocrinopathies. |
| Quality of Life (QoL) | Baseline, Week 12, Week 24, and every 6 months up to 24 months | Assessed using validated patient-reported instruments (e.g., EORTC QLQ-C30). |
| Tumor Recurrence Rate | Up to 24 months | Rate of local or regional tumor recurrence, defined by new lesions or regrowth within the same anatomical region as confirmed by imaging. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Radiomics Features and Predictive Modeling | Up to 24 months | Extraction of radiomic features from PET/CT or CT images to explore associations with ORR, PFS, recurrence pattern, and treatment response. |
| Patterns of Failure / Recurrence Patterns | Up to 24 months | Classification of failure patterns (local, regional, distant) and correlation with dosimetry (D90, V100) and imaging biomarkers. |
| Subgroup Analyses | Up to 24 months | Assessment of treatment effect by clinical subgroups (primary vs recurrent vs metastatic disease, tumor type, PD-L1 expression, inflammatory markers). |
Countries
China
Contacts
Primary ContactMin Li, Dr.
Backup ContactMin Li, Dr.
Outcome results
None listed