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.

Study Overview

• Status: Not yet recruiting
• Conditions: High-Burden Metastatic Solid Tumors
• Intervention / Treatment: Other: Lesion Allocation and Tumor Zoning Strategy; Procedure: Iodine-125 (125I) Seed Implantation (Low-Dose-Rate Brachytherapy); Procedure: cryoablation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Min Li, Dr.; Phone Number: 0531-51665482; Email: liminyingxiang.@163.com
• Study Contact Backup: Name: Min Li, Dr.; Email: 924787237@qq.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250031
      • The 960th Hospital of People's Liberation Army (PLA)
      • Contact: Min Li, Dr.; Phone Number: 0531-51665482; Email: liminyingxiang.@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lesion-Allocated + Tumor-Zoned Combined Local Therapy (125I Seeds + Cryoablation); Participants receive strategy-based multimodal local therapy. Prespecified metastatic target lesions are prospectively allocated to either iodine-125 (125I) seed implantation or cryoablation according to protocol-defined anatomic and technical suitability criteria. In addition, 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. Standardized follow-up and supportive care are provided per protocol.	Other: Lesion Allocation and Tumor Zoning Strategy; Protocol-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.
Active Comparator: Single-Modality Local Therapy (Cryoablation Alone or ^125I Seeds Alone); Participants receive single-modality local therapy for all prespecified target lesions, using either cryoablation alone or iodine-125 (125I) seed implantation alone as specified by the protocol and/or center capability, with standardized supportive care and follow-up. Imaging-based efficacy endpoints are assessed per protocol with standardized blinded independent review.	Procedure: Iodine-125 (125I) Seed Implantation (Low-Dose-Rate Brachytherapy); Image-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.; Procedure: cryoablation; Image-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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months after completion of protocol local therapy
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.	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 12 months
Overall Response Rate (ORR)	Proportion of participants achieving complete response or partial response at the patient level per RECIST v1.1.	First assessment at ~8-12 weeks; up to 6 months
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.	Up to 12 months
Overall Survival (OS)	Time from randomization to death from any cause.	Up to 24 months
Tumor-Burden Reduction	Change from baseline in sum of diameters of measurable disease (RECIST) and/or total measurable tumor volume for the bulky index lesion (volumetric imaging) per protocol.	Baseline to 3 months and 6 months
Technical Success (Procedure-Level)	Successful completion of the assigned procedure(s) per protocol (e.g., planned seed placement/coverage or planned ablation zone achieved) without immediate major protocol deviation.	Day of procedure to 7 days post-procedure
Re-intervention Rate of Treated Target Lesions	Proportion of treated target lesions requiring repeat local intervention due to local progression or incomplete control per protocol.	Up to 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to 8-12 weeks and 6 months
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.	Baseline; post-procedure/early follow-up (~2-4 weeks); then through 6-12 months
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.	Up to 12 months

Collaborators and Investigators

• Sponsor: Li Min
• Investigators: Study Director: Min Li, The 960th Hospital of People's Liberation Army (PLA)

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: February 22, 2026
• First Submitted That Met QC Criteria: February 22, 2026
• First Posted (Actual): February 27, 2026

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 22, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Cryoablation; Local control; Iodine-125 seed implantation; High tumor burden; Multiple metastases; Lesion allocation; Tumor zoning
• Additional Relevant MeSH Terms: Surgical Procedures, Operative; Ablation Techniques; Cryosurgery; Iodine-125
• Other Study ID Numbers: 960HP20260222

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) will be made available to qualified researchers upon reasonable request after completion of the study and publication of the primary results. Data to be shared may include demographic information, treatment assignment, key efficacy outcomes, adverse events, and imaging-derived parameters. A data-sharing agreement will be required to ensure appropriate use of the dataset.
• IPD Sharing Time Frame: Individual participant data (IPD) will be available beginning 6 months after publication of the primary study results and will remain available for 5 years following publication, or until the main study database is closed, whichever occurs first.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No