Shifting the Spotlight to Low-Dose Rate Radiobiology in Radiopharmaceutical Therapies: Mathematical Modeling, Challenges, and Future Directions

Radiopharmaceutical therapy (RPT) is an established treatment modality and is of increasing interest for different cancer types. A key unmet need, both in the wider adoption of RPT and in the improvement of outcomes with existing RPTs, is in treatment planning and optimization. Research efforts have been hindered by the incomplete understanding of the radiobiology RPTs. Modeling in RPT often mirrors external beam radiotherapy (EBRT), despite key differences. The dose rate (DR) is notably distinct between the two, influencing radiation responses. In EBRT, radiation is acutely delivered in discrete transient fractions of relatively short duration, with a near-constant DR. In RPT, by contrast, exposure is gradual, protracted, and characterized by temporal nonuniformities arising from organ-specific radio-pharmacokinetics. As a result, low-DR (LDR) radiobiology adapted for RPT (LDR-RPT) has emerged as a vibrant area of research. In this review, we discuss the state-of-the-art understanding of the etiological mechanisms underlying cellular and tissue-level dose responses in LDR-RPT, with a focus on how this radiobiological knowledge is codified in mathematical and computational models. We also describe current feasibility and future prospects for utilizing such quantitative radiobiological models to perform personalized RPT planning and highlight research directions that should be prioritized to accelerate clinical adoption.