Alpha-Particle Microdosimetry

With the increasing availability of alpha emitters, targeted alpha-particle therapy has emerged as a solution of choice to treat haematological cancers and micrometastatic and minimal residual diseases. Alpha-particles are highly cytotoxic because of their high linear energy transfer (LET) and have a short range of a few cell diameters in tissue, assuring good treatment specificity. These radiologic features make conventional dosimetry less relevant for that context. Stochastic variations in the energy deposited in cell nuclei are important because of the microscopic target size, low number of alpha-particle traversals, and variation in LET along the alpha-particle track. Microdosimetry provides a conceptual framework that aims at a systematic analysis of the stochastic distribution of energy deposits in irradiated matter. The different quantities of microdosimetry and the different methods of microdosimetric calculations were described in the early eighties. Since then, numerous models have been published through the years and applied to analyse experimental data or to model realistic therapeutic situations. Major results have been an accurate description of the high toxicity of alpha-particles, and the description of the predominant effect of activity distribution at the cellular scale on toxicity or efficacy of potential targeted alpha-particle therapies. This last factor represents a major limitation to the use of microdosimetry in vivo because determination of the source-target distribution is complicated. The future contributions of microdosimetry in targeted alpha-particle therapy research will certainly depend on the ability to develop high-resolution detectors and on the implementation of pharmaco-kinetic models at the tumour microenvironment scale.