This open-label, randomized Phase II trial evaluates whether sequential iodine-125 seed implantation followed by cryoablation improves local tumor control versus single-modality local therapy (125I seeds alone or cryoablation alone) in unresectable solid tumors.
The study is based on a complementary treatment rationale: cryoablation provides rapid cytoreduction of the dominant tumor component, while 125I seed brachytherapy delivers sustained low-dose-rate irradiation that may better suppress residual viable tumor at the periphery and microscopic extension zones. The trial is designed to determine whether this spatial and temporal complementarity translates into superior local disease control without unacceptable toxicity.
Participants will be randomized in parallel to one of three arms: (1) sequential 125I seed implantation followed by cryoablation within a protocol-defined interval, (2) 125I seed implantation alone, or (3) cryoablation alone. Treatment assignment is open label; imaging-based efficacy endpoints will be assessed using a standard blinded assessment process (blinded evaluators), according to protocol-defined criteria.
The primary endpoint is local control rate (LCR) of prespecified target lesions and progression-free survival (PFS). Key secondary endpoints are local progression-free survival (LPFS), overall survival (OS), early pain response, technical success, target-lesion re-intervention rate, and safety (including grade ≥3 treatment-emergent adverse events, CTCAE v5.0). Exploratory analyses include dosimetry-outcome associations, imaging/radiomics biomarkers, and peripheral blood biomarker dynamics.
Adults aged ≥18 years;
Histologically or cytologically confirmed solid tumor that is unresectable and for which local therapy is clinically appropriate;
At least one prespecified target lesion suitable for percutaneous image-guided treatment and considered technically feasible for both 125I seed implantation and cryoablation per investigator assessment (and protocol-defined anatomic/dosimetric safety criteria);
ECOG performance status 0-2;
Prior 125I seed implantation or cryoablation to the same target lesion(s), or other local therapy to the target lesion(s);
Target lesion location or anatomy that, in the investigator's judgment, makes either procedure unsafe or unlikely to achieve protocol-defined coverage/ablation (e.g., inability to meet organ-at-risk constraints or required safety margins);
Uncontrolled bleeding risk or coagulopathy not correctable per protocol; inability to safely hold/bridge anticoagulants/antiplatelets as required.
Clinically significant uncontrolled comorbidities that increase procedural risk;
Parallel
Iodine-125 (125I) Seed Implantation
Procedure/SurgeryPercutaneous, image-guided implantation of 125I radioactive seeds into the prespecified target lesion(s) according to a protocol-defined treatment plan. Key planning and dosimetric parameters (e.g., prescription dose, target coverage, and organ-at-risk constraints) are recorded per protocol.
cryoablation
Procedure/SurgeryPercutaneous, image-guided cryoablation of the prespecified target lesion(s) performed using a standardized protocol-defined technique (e.g., applicator placement and freeze-thaw cycles) with documentation of technical success and peri-procedural events per protocol.
Sequential 125I Seed Implantation Followed by Cryoablation
Procedure/SurgeryCombined sequential local therapy consisting of 125I seed implantation followed by cryoablation within a protocol-defined interval; both procedures are performed under image guidance and documented according to protocol-specified standards.
Local Control Rate (LCR)
Proportion of prespecified target lesion(s) without local progression/recurrence as determined by protocol-defined imaging criteria. Imaging-based assessments are performed by blinded independent reviewers with adjudication as needed.
Progression-Free Survival (PFS)
Time from randomization to first documentation of disease progression (per protocol-defined criteria) or death from any cause, whichever occurs first.
Local Progression-Free Survival (LPFS)
Time from randomization to local progression of the prespecified target lesion(s) or death from any cause, whichever occurs first.
Overall Survival (OS)
Time from randomization to death from any cause.
Early Pain Response
Pain intensity from baseline to 1 month postoperatively will be assessed using the Visual Analogue Scale (VAS; 0-10 points, where 0 indicates no pain and 10 indicates the worst pain imaginable; higher scores indicate more severe pain) and will be expressed as the absolute change (ΔVAS = VAS\_\[1 month postoperatively\] - VAS\_\[baseline\], unit: points; ΔVAS \< 0 indicates pain relief).
Technical Success
Successful completion of the assigned procedure(s) per protocol-defined technical criteria (e.g., planned seed implantation achieved; cryoablation delivered as planned).
Dosimetry-Outcome Associations
Association between target D90 (unit: Gy; derived from the treatment planning system/DVH) and the incidence of Grade ≥3 treatment-related toxicity (unit: % of participants; assessed per CTCAE v5.0) from baseline through 12 months.
Radiomics Biomarkers
Imaging-derived and radiomics features evaluated for association with local control and/or early response.
Peripheral Blood Biomarker Dynamics
Longitudinal changes in protocol-specified peripheral blood biomarkers and their associations with efficacy/toxicity outcomes.
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Li Min
Lead sponsor
Jinan Military General Hospital
Sponsor institution
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