This open-label, randomized Phase II trial evaluates whether a strategy-based, multimodal local treatment approach improves local control compared with single-modality local therapy in patients with high-burden metastatic disease characterized by multiple metastases and at least one bulky lesion.
In the experimental arm, prespecified target lesions are prospectively allocated to either iodine-125 (125I) seed implantation or cryoablation using protocol-defined anatomic and technical suitability criteria, and at least one bulky index lesion is treated using a tumor-zoned approach (e.g., core debulking with cryoablation and peripheral/high-risk margin control with 125I seeds) under predefined organ-at-risk constraints. The control arm treats all prespecified target lesions with a single local modality (either 125I seed implantation alone or cryoablation alone), with standardized supportive care and follow-up.
The primary objective is to determine whether the "lesion allocation plus tumor zoning" strategy can improve local control of treated target lesions with acceptable safety. Imaging-based efficacy endpoints are evaluated using protocol-defined criteria with standardized blinded independent imaging review. Key secondary endpoints include local progression-free survival of the bulky index lesion, overall response rate (RECIST), progression-free survival, time to systemic progression (including new lesions), overall survival, tumor-burden reduction metrics, technical success, and re-intervention rates. Safety is assessed throughout the study using CTCAE v5.0, including monitoring for procedure-related and radiation-related complications. Exploratory analyses assess dosimetry-outcome relationships, zonal response patterns within bulky lesions, imaging/radiomics biomarkers, and peripheral blood biomarker dynamics.
Age ≥18 years;
Histologically or cytologically confirmed solid malignancy with metastatic disease not amenable to curative surgery or definitive curative-intent radiotherapy;
High-burden metastatic disease, defined as: Multiple metastases: ≥3 metastatic lesions on imaging, and at least 2 measurable lesions (RECIST v1.1) planned as protocol target lesions; and Bulky lesion: at least 1 lesion meeting bulky criteria (e.g., longest diameter ≥7 cm or tumor volume ≥100 mL, per protocol) designated as the bulky index lesion;
At least 2 and up to 5 prespecified target lesions are suitable for protocol local therapy and can be assigned per protocol (lesion allocation and/or tumor zoning);
Lesions requiring emergent surgical decompression or other urgent intervention that cannot be deferred to protocol timelines;
Target lesions not safely accessible for percutaneous cryoablation and/or 125I seed implantation (e.g., no feasible needle path, unacceptable risk to critical structures despite protective maneuvers);
Active, uncontrolled infection; uncontrolled pleural effusion/ascites requiring frequent drainage (unless stabilized);
Severe cardiopulmonary comorbidity prohibiting anesthesia/sedation or percutaneous intervention (e.g., unstable angina, recent MI, uncontrolled arrhythmia, severe COPD with high oxygen requirement);
Parallel
Iodine-125 (125I) Seed Implantation (Low-Dose-Rate Brachytherapy)
Procedure/SurgeryImage-guided percutaneous implantation of 125I radioactive seeds into prespecified target lesions according to protocol-defined treatment planning and organ-at-risk constraints. Seed number and distribution are determined by pre-implant planning to achieve protocol-specified target coverage, with post-implant verification imaging and dosimetry as required.
cryoablation
Procedure/SurgeryImage-guided percutaneous cryoablation of prespecified target lesions using standardized probe placement and freeze-thaw cycles per protocol. The ablation zone is planned to achieve protocol-defined tumor coverage while maintaining safety margins to adjacent critical structures, with intraprocedural monitoring and post-procedure imaging assessment.
Lesion Allocation and Tumor Zoning Strategy
Other interventionProtocol-defined decision rules assign each prespecified metastatic target lesion to 125I seed implantation or cryoablation based on anatomic and technical suitability criteria. For at least one bulky index lesion, a tumor-zoned approach is applied (e.g., core debulking with cryoablation and peripheral/high-risk margin control with 125I seeds) under predefined organ-at-risk constraints and quality assurance requirements.
Local Control Rate (LCR) of Treated Target Lesions
Proportion of prespecified treated target lesions without local progression by blinded independent imaging review per protocol-defined criteria.
Local Progression-Free Survival (LPFS) of the Bulky Index Lesion
Time from randomization to local progression of the prespecified bulky index lesion or death from any cause, whichever occurs first, assessed by blinded independent imaging review.
Progression-Free Survival (PFS)
Time from randomization to radiographic disease progression (including new lesions) or death from any cause, whichever occurs first (RECIST v1.1, blinded independent review when applicable).
Overall Response Rate (ORR)
Proportion of participants achieving complete response or partial response at the patient level per RECIST v1.1.
Time to Systemic Progression
Time from randomization to systemic progression, including appearance of new lesions and/or progression of non-target/non-treated disease per protocol criteria.
Overall Survival (OS)
Time from randomization to death from any cause.
Zonal Response of Bulky Index Lesion
Core versus peripheral/high-risk margin response of the bulky index lesion assessed by volumetric and/or functional imaging (e.g., necrosis fraction, enhancement change, metabolic response when available) and its association with LPFS.
Peripheral Blood Biomarker Dynamics
Longitudinal changes in blood-based biomarkers (e.g., inflammatory indices, cytokines/immune subsets per site capability) and their associations with local control and systemic progression.
Patterns of Failure
Site and type of first progression (treated lesion vs untreated lesion vs new lesion), and spatial pattern of recurrence within bulky lesions (core vs margin) when assessable.
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Li Min
Lead sponsor
Jinan Military General Hospital
Sponsor institution
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