State-of-the-art and potential of experimental microdosimetry in ion-beam therapy.

In radiotherapy, radiation-quality should be an expression of the biological and physical characteristics of ionizing radiation such as spatial distribution of ionization or energy deposition. Linear energy transfer (LET) and lineal energy (y) are two descriptors used to quantify the radiation quality. These two quantities are connected and exhibit similar features. In ion-beam therapy (IBT), lineal energy can be measured with microdosimeters, which are specifically designed to cope with the high fluence of particles in clinical beams, while the quantification of LET is generally based on calculations. In pre-clinical studies, microdosimetric spectra are used for the indirect determination of relative biological effectiveness (RBE), e.g., using the microdosimetric kinetic model (MKM) or biophysical response functions. In this context it is important to consider saturation effects, which occur when the highest values of y become less biologically relevant compared to the relative contribution they make to the physical dose. Recent clinical data suggests that local tumor control and normal tissue effects can be linked to macroscopic and microscopic dosimetry parameters. In particular, positive clinical outcomes have been correlated to the highest LET values in the density distribution, and there is no evident link to the saturation discussed above. A systematic collection of microdosimetric information in combination with clinical data in retrospective studies may clarify the role of radiation quality at the highest LET. In the clinical setting, microdosimetry is not widely used yet, despite its potential to be linked with LET by experimentally-determined y values. Through this connection, both play an important role in complex therapy techniques such as intensity modulated particle therapy (IMPT), LET-painting and multi-ion optimization. This review summarizes the current state of microdosimetry for IBT and its potential, as well as research and development needed to make experimental microdosimetry a mature procedure in a clinical context.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.