Most patients with metastatic cancer eventually develop resistance to systemic therapy. A subset of patients experience oligoprogression, characterized by progression at a limited number of lesions while other disease sites remain controlled by ongoing systemic therapy. This randomized phase 2 trial evaluates whether image-guided 125I seed implantation targeting all oligoprogressive extracranial lesions, combined with standard-of-care systemic therapy, improves progression-free survival compared with standard-of-care systemic therapy alone in patients with metastatic NSCLC or CRC.

This is a prospective, open-label, randomized phase 2 controlled trial enrolling adults with histologically confirmed metastatic NSCLC or colorectal cancer who developed extracranial oligoprogression (≤5 progressive lesions) on PET/CT or CT while receiving at least first-line systemic therapy (including maintenance). Eligible patients will be randomized 1:1 to (1) standard-of-care systemic therapy per treating physician discretion, or (2) image-guided 125I seed implantation to all oligoprogressive lesions plus standard-of-care systemic therapy.

Oligoprogression will be determined by predefined imaging response criteria (RECIST and/or PERCIST, depending on baseline imaging modality), with confirmation by designated study radiologists. Follow-up imaging will be performed at 8 weeks (±2 weeks) after randomization and every 12 weeks (±2 weeks) thereafter to assess disease status. The primary endpoint is progression-free survival measured up to 12 months. Secondary endpoints include overall survival, time to initiation of a new systemic therapy, local control of implanted lesions, safety, and quality of life. Optional exploratory objectives may include circulating tumor DNA dynamics and metabolic PET parameters.

Inclusion Criteria:

• Age ≥ 18 years.
• Histologically or cytologically confirmed metastatic non-small cell lung cancer (NSCLC) or colorectal cancer (CRC).
• Presence of metastatic disease with extracranial oligoprogression, defined as progression in up to five (≤5) individual lesions on CT or PET/CT imaging, while other known disease sites remain stable or controlled.
• Received at least one prior line of standard systemic anticancer therapy, including maintenance therapy, for metastatic disease.
• All oligoprogressive lesions are technically feasible and considered safe for image-guided 125I seed implantation, as determined by the treating interventional team.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Adequate organ function to undergo interventional procedures and systemic therapy, per institutional standards.
• Ability to understand and willingness to sign written informed consent.

Exclusion Criteria:

• Pregnancy or breastfeeding.
• Leptomeningeal disease or diffuse central nervous system involvement. Uncontrolled infection or serious medical comorbidities that, in the investigator's judgment, would preclude safe participation or interventional procedures.
• Prior radiotherapy or brachytherapy requiring re-irradiation to the same tumor location planned for 125I seed implantation.
• Known bleeding diathesis or uncorrectable coagulation disorders contraindicating interventional procedures.
• Any other condition that, in the investigator's judgment, would make the patient unsuitable for the study.

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.

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.

Qualified researchers affiliated with academic institutions or recognized research organizations may request access to de-identified individual participant data (IPD), including imaging-derived parameters, dosimetric results, and clinical outcome data.

Requests must include a brief research proposal describing the scientific rationale, objectives, and planned analyses. Approval will be granted by the study's principal investigator and institutional ethics committee. Data will be shared through secure institutional data transfer systems after execution of a formal data sharing agreement that ensures patient confidentiality and compliance with applicable privacy regulations.