Oxygen Response Index: A Potential <scp>OE‐MRI‐Derived</scp> Non‐Invasive Biomarker for Assessing Radiation Treatment Efficacy

ABSTRACT Purpose The goal of this study was to develop an optimized oxygen‐enhanced MRI (OE‐MRI) protocol for longitudinal monitoring of tumor oxygenation during radiation therapy in a pre‐clinical model and to introduce the Oxygen Response Index (ORI) as a potential early biomarker of treatment efficacy. Methods A high‐throughput mouse imaging protocol was designed for a clinical 3 T MRI system using optimized variable flip angle T 1 mapping for relaxometry. Six male C3H mice bearing SCC7 tumors underwent longitudinal OE‐MRI during fractionated radiation therapy (2 Gy/day for 7 days), followed by a single 60 Gy dose. Tumor oxygenation response was quantified as the change in longitudinal relaxation rate (ΔR 1 ) between normoxic and hyperoxic breathing. ORI was defined as the product of the baseline‐normalized longitudinal relaxation rate under normoxia (R 1 21% /R 1,0 21% ) and the baseline‐normalized fraction of oxygen‐responsive tumor voxels (∆R 1 + /∆R 1,0 + ), providing a composite index of oxygenation competence. Results During fractionated irradiation, ORI declined progressively, with the change‐point analysis identifying treatment response inflection at scan 4 (day 8), one scan interval before tumor volume at scan 5 (day 10). After the 60‐Gy dose, conversion of putatively hypoxic tissue to oxygen‐responsive tissue was observed. Spatial analysis revealed persistent oxygen‐response gradients, with tumor regions adjacent to normoxic tissue demonstrating greater responsiveness than non‐adjacent tumor areas. Conclusion ORI captured longitudinal changes in tumor oxygenation during both ineffective and effective treatment phases and may provide a useful complementary biomarker for monitoring treatment response.