Quantifying biological effects of spatially heterogeneous carbon ion dose distributions using EUD

This study aimed to experimentally investigate the cell survival responses of tumor and normal cell lines to spatially heterogeneous carbon ion dose distributions with varying peak-to-valley dose ratios (PVDRs) and linear energy transfer (LET) conditions, and to assess the utility of equivalent uniform dose (EUD) as a quantitative metric for analyzing these responses. HSGc-C5 (tumor) and Nuli-1 (normal tissue) cell lines were irradiated using carbon ion beams with different spatial dose patterns (Grid, Frame, Half) and two PVDR levels under low LET conditions (~10 keV μm^-1). Additionally, high LET (~50 keV μm^-1) Spread Out Bragg Peak (SOBP) Grid patterns were used for the HSGc-C5 cells. Clonogenic survival assays were performed to evaluate biological response. Survival data were analyzed both as a function of delivered physical dose and EUD, calculated using an LQ model-based formulation. Tumor cells exhibited enhanced cytotoxic effects under high LET and high PVDR conditions (the dose required to reach SF = 0.1 was approximately 40% lower at PVDR = 4.0 and 10% lower at PVDR = 1.64 compared with the simulation results), whereas normal cells showed a slight sparing effect under low LET irradiation. Even at the same total dose and PVDR, different spatial dose patterns produced measurable differences in survival, underscoring the impact of spatial heterogeneity. EUD-based analysis further enabled quantitative comparison between heterogeneous and uniform dose distributions. These findings indicate that spatial dose heterogeneity and LET can be leveraged to enhance tumor control while reducing normal tissue damage in carbon ion therapy. The EUD approach may offer a practical tool for treatment plan evaluation in spatially modulated particle therapy.