Emerging strategies in radiation therapy: promises and challenges of spatial fractionation, ultra-high dose rates, and nanoparticles

Radiation therapy (RT) employs ionizing radiation to kill cancerous cells. However, delivering radiation to tumors, typically embedded within normal tissues, inevitably exposes healthy organs to radiation, leading to collateral damage. This creates a tradeoff between the tumor control probability and normal tissue complication probability, ultimately limiting the dose that can be safely administered. While highly conformal RT techniques have improved tumor targeting and treatment efficacy, they remain inadequate for treating large and radioresistant tumors, pointing out the need for alternative strategies. Spatially fractionated RT, ultra-high dose rate RT, and nanoparticle-enhanced RT are emerging techniques with promise in enhancing tumor control while minimizing normal tissue toxicity. Successful clinical translation of these advanced techniques requires cross-disciplinary efforts aimed at technological innovation, a deeper understanding of the underlying radiobiological mechanisms, and the development of early-phase clinical trials. This paper provides an overview of these techniques and their associated challenges and opportunities.