Clinical translation of targeted alpha therapy: safety, dosimetry, radiation protection, and regulatory considerations.

Abstract

Targeted alpha therapy (TAT) has moved from a largely experimental approach into clinically relevant radiopharmaceutical therapy, although evidence varies across radionuclides and products. Alpha particles combine high linear energy transfer with a tissue range of only a few cell diameters. This permits dense, localized energy deposition but creates challenges in dosimetry, radiopharmaceutical production, quality control, contamination control, patient management, waste disposal, and regulation. This review examines evidence for safe clinical implementation and distinguishes established practice from emerging concepts and institution-specific choices. Radium-223 has the strongest clinical and regulatory foundation; actinium-225, lead-212, thorium-227, astatine-211, and bismuth-213 agents are at different stages of development. Particular attention is given to alpha recoil and daughter-radionuclide redistribution, Medical Internal Radiation Dose (MIRD)-based and small-scale dosimetry, route-dependent radionuclidic impurities, good manufacturing practice, prevention of internal contamination, renal and salivary-gland toxicity, marrow risk, and jurisdiction-specific regulatory requirements. Technologies already entering specialist workflows, including quantitative imaging, Monte Carlo transport, and voxel dosimetry, are distinguished from proof-of-concept automation and more aspirational artificial-intelligence applications. Evidence supports carefully governed TAT in selected indications and trials, but routine use remains limited by radionuclide supply, product-specific dosimetry, organ toxicity, manufacturing standardization, long-term safety data, and regulatory heterogeneity.