SEED-CRYO: Sequential 125I Seed Implantation Followed by Cryoablation vs Single-Modality Local Therapy in Unresectable Solid Tumors

A Randomized Phase II Study of Sequential Iodine-125 Seed Implantation Followed by Cryoablation Versus Iodine-125 Seed Implantation Alone or Cryoablation Alone in Unresectable Solid Tumors

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.

This open-label, randomized Phase II trial aims to evaluate, in patients with unresectable solid tumors, whether a sequential local treatment strategy-percutaneous image-guided iodine-125 (125I) seed implantation followed by cryoablation within a protocol-specified time window-can achieve superior tumor local control compared with single-modality local therapy (125I seed implantation alone or cryoablation alone), while maintaining acceptable safety, thereby providing methodological support and effect-size estimates for subsequent Phase III confirmatory studies.

The study is based on the "spatial-temporal complementarity" of two local modalities. Cryoablation can rapidly induce cytotoxic tumor destruction and reduce tumor burden; however, residual viable cells may persist in the peripheral infiltrative zone, sub-millimeter microscopic remnants, and low-temperature gradient regions near the ablation margin. 125I seed brachytherapy delivers continuous low-dose-rate irradiation and may provide sustained suppression of marginal residual disease and microscopic extension. The trial hypothesis is that, under standardized image guidance and treatment planning/quality control, combining the rapid debulking effect of cryoablation with the sustained inhibitory effect of ^125I seeds will reduce the risk of local recurrence/progression, prolong local disease control, and improve overall local efficacy without a disproportionate increase in severe toxicity.

Eligible participants who complete baseline assessments will be randomized in parallel at a 1:1:1 ratio to one of three treatment arms: (1) sequential combination arm-125I seed implantation followed by cryoablation within a protocol-defined interval; (2) 125I seed implantation alone arm-standardized 125I seed implantation only; or (3) cryoablation alone arm-standardized cryoablation only. Owing to the nature of the interventions, treatment allocation is open label. To minimize assessment bias, all imaging-based efficacy endpoints will be evaluated using a prespecified blinded assessment process by independent assessors who are not involved in treatment delivery and are blinded to treatment assignment; adjudication will be performed when necessary to ensure objective and consistent endpoint determination.

All participants will undergo baseline evaluations before treatment, including tumor burden assessment and confirmation of target lesions, prior treatment history, physical examination and laboratory tests, pain and quality-of-life instruments, and imaging-based staging and target-lesion measurements. Target lesions will be prespecified at baseline as the subjects of subsequent local endpoint assessments. 125I seed implantation will be performed under CT or other site-qualified imaging guidance, with standardized documentation of key planning and dosimetric parameters, including prescription dose, target coverage, and organ-at-risk constraints. Cryoablation will likewise be performed under image guidance according to uniform technical specifications, and technical success and peri-procedural events will be recorded in a standardized manner. In the sequential combination arm, the interval between the two procedures will be explicitly defined in the protocol to ensure comparability of the treatment window across centers.

Endpoints are focused on local control, disease progression, and safety. The primary endpoints are the local control rate (LCR) of prespecified target lesions and progression-free survival (PFS). Key secondary endpoints include local progression-free survival (LPFS), overall survival (OS), early pain response, technical success, target-lesion re-intervention rate, and safety (with particular attention to grade ≥3 treatment-emergent adverse events graded and attributed per CTCAE v5.0). Exploratory analyses include associations between dosimetric parameters and efficacy/toxicity outcomes, imaging/radiomics biomarkers, and the dynamics of peripheral blood biomarkers, to inform protocol refinement and future patient stratification.

Inclusion Criteria:

• 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;
• Adequate organ function, acceptable coagulation status, and the ability to safely undergo percutaneous image-guided procedures;
• Written informed consent provided.

Exclusion Criteria:

• 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.

Active, uncontrolled infection, including uncontrolled local infection at the intended procedure site;

• Clinically significant uncontrolled comorbidities that increase procedural risk;
• Severe organ dysfunction that precludes procedures or follow-up, per protocol-defined thresholds.;
• Pregnancy or breastfeeding;
• Known hypersensitivity to materials/medications essential for the procedures (e.g., contrast agents or anesthetics) that cannot be adequately managed;
• Any condition that would impair reliable outcome assessment or adherence (e.g., inability to undergo required imaging, expected poor compliance), per investigator judgment.