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 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.