Lesion-Allocated Therapy for Multiple Metastases and Tumor-Zoned Treatment for Bulky Tumors: A Phase II Study of Iodine-125 Seed Implantation Combined With Cryoablation in High-Burden Metastatic Disease

A Multicenter, Open-Label, Randomized Phase II Trial of Lesion-Allocated Iodine-125 Seed Implantation Combined With Cryoablation for Multiple Metastases and Tumor-Zoned Local Therapy for Bulky Tumors in Patients With High-Burden Metastatic Disease

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.

This open-label, randomized Phase II trial evaluates whether a strategy-based, multimodal local treatment approach can improve local control and disease outcomes compared with single-modality local therapy in patients with high-burden metastatic disease. The trial targets a population in which tumor burden is driven by both multiple metastatic deposits and at least one bulky lesion, where uniform local treatment is often limited by anatomic heterogeneity, safety constraints, and incomplete coverage of high-risk tumor regions.

The study is based on a complementary rationale at both the inter-lesion and intra-lesion levels. For multiple metastases, different lesions may be optimally treated with different modalities: cryoablation offers rapid cytoreduction and prompt symptom relief in appropriately accessible lesions with favorable safety margins, while iodine-125 (125I) seed implantation provides sustained low-dose-rate irradiation that can better sterilize residual disease in lesions where ablative margins are difficult to achieve or where durable peripheral control is prioritized. For bulky tumors, a tumor-zoned concept is applied to address intratumoral heterogeneity and margin risk: the core region is treated to achieve efficient debulking (typically with cryoablation), while the peripheral/high-risk margin zones are treated to enhance durable control (typically with 125I seeds) under protocol-defined organ-at-risk constraints. The trial is designed to determine whether this structured "allocation plus zoning" strategy translates into superior local disease control and meaningful tumor-burden reduction without unacceptable toxicity.

Participants will be randomized in parallel to one of two arms: (1) strategy-based combined local therapy, consisting of protocol-defined lesion allocation (each prespecified metastatic target lesion assigned to 125I seed implantation or cryoablation based on predefined anatomic/technical suitability criteria) plus tumor-zoned treatment for at least one prespecified bulky index lesion; or (2) single-modality local therapy, in which all prespecified target lesions are treated using a single local modality (either 125I seed implantation alone or cryoablation alone, as specified by the protocol and/or center capability) with standard supportive care. Treatment assignment is open label. To reduce assessment bias, imaging-based efficacy endpoints will be evaluated using a standardized blinded imaging review process by independent assessors according to protocol-defined criteria, with prespecified rules for target lesion selection, timing windows, and adjudication of progression events.

The primary endpoint is local control rate (LCR) of prespecified treated target lesions at a fixed time point and local progression-free survival (LPFS) of the bulky index lesion (as defined in the protocol). Key secondary endpoints include progression-free survival (PFS), overall response rate (ORR) (patient-level by RECIST), time to systemic progression (including appearance of new lesions), overall survival (OS), tumor-burden reduction metrics (e.g., change in sum of diameters and/or total measurable tumor volume), technical success rates for each procedure, need for re-intervention on treated target lesions.

Safety will be assessed throughout the study and includes procedure-related and radiation-related adverse events graded by CTCAE v5.0, with focused monitoring for clinically relevant risks such as bleeding, infection, fistula/organ injury, nerve or vascular injury, cryo-related complications, seed migration, radiation injury to adjacent organs, and any grade ≥3 treatment-emergent adverse events. Prespecified dose planning and procedural quality assurance measures will be implemented for 125I seed implantation, and standardized cryoablation parameters and post-procedure imaging checks will be used to ensure consistent delivery and safety oversight. Exploratory analyses will evaluate dosimetry-outcome relationships (e.g., coverage and dose-volume parameters for seed implants), zonal treatment response patterns within bulky lesions, imaging biomarkers and radiomics features associated with benefit, and the dynamics of peripheral blood biomarkers as potential correlates of local control and systemic progression.

Inclusion Criteria:

• 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);
• ECOG performance status 0-2;
• Adequate organ function;
• Willing and able to provide written informed consent.

Exclusion Criteria:

• 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);
• Prior local therapy to the same bulky index lesion that would confound response assessment (prior treatment to other non-index lesions may be allowed);
• Uncontrolled CNS metastases (symptomatic, requiring escalating steroids, or not stable after local therapy). Stable treated brain metastases may be allowed per protocol;
• Any condition that, in the investigator's judgment, would compromise protocol compliance or make participation unsafe.