Radiodynamic Therapy as a Potential Strategy for Metastatic Control in Small-cell Lung Cancer: A Preclinical Study.

Small-cell lung cancer (SCLC) is a highly aggressive malignancy characterized by early metastatic dissemination and poor survival. Radiodynamic therapy (RDT), which combines radiation with a photosensitizer to enhance tumor control, has shown an improved therapeutic effect over conventional radiotherapy (RT) in preclinical solid tumor models. Given the limited effectiveness of conventional RT in controlling metastatic disease, we investigated whether RDT could provide a therapeutic advantage in a premetastatic SCLC model. To guide treatment timing, histological analysis of lung tissue from untreated control mice was performed at defined intervals after tumor cell inoculation, revealing early establishment of micrometastases. Using this framework, we treated immunocompetent C57BL/6 mice inoculated with KP1 SCLC cells with a single fraction of low-dose (0.1 Gy) or high-dose (2 Gy) RDT and evaluated metastasis progression and survival. MRI assessment of tumor burden revealed that both low-dose and high-dose RDT delayed metastasis progression compared to RT and control groups, which exhibited significant tumor burden at earlier time points. Kaplan-Meier survival data analysis demonstrated a significant survival benefit in RDT treated mice compared to RT and control groups, with statistical analysis confirming a significant extension of lifespan in both RDT cohorts (p < 0.004). These findings show that RDT reduces the rate of metastatic progression and improves survival outcomes in a premetastatic SCLC model, supporting its potential as a systemic therapeutic strategy for metastases.