No abstract

Different qualities of radiation are known to cause different biological effects at the same absorbed dose. Enhancements of the biological effectiveness are a direct consequence of the energy deposition clustering at the scales of DNA molecule and cell nucleus whilst absorbed dose is a macroscopic averaged quantity which does not take into account heterogeneities at the nanometer and micrometer scales. Microdosimetry aims to measure radiation quality at cellular or sub-cellular levels trying to increase the understanding of radiation damage mechanisms and effects. Existing microdosimeters rely on the well-established gas-based detectors or the more recent solid-state devices. They provide specific energy z spectra and other derived quantities as lineal energy (y) spectra assessed at the micrometer level. The interpretation of the radio-biological experimental data in the framework of different models has raised interest and various investigations have been performed to link in vitro and in vivo radiobiological outcomes with the observed microdosimetric data. A review of the major models based on experimental microdosimetry, with a particular focus on ion beam therapy applications and an emphasis on the microdosimetric kinetic model (MKM), will be presented in this work, enlightening the advantages of each one in terms of accuracy, initial assumptions, and agreement with experimental data. The MKM has been used to predict different kinds of radiobiological quantities such as the relative biological effects for cell inactivation or the oxygen enhancement ratio. Recent developments of the MKM will be also presented, including new non-Poissonian correction approaches for high linear energy transfer radiation, the inclusion of partial repair effects for fractionation studies, and the extension of the model to account for non-targeted effects. We will also explore developments for improving the models by including track structure and the spatial damage correlation information, by using the full fluence spectrum and by better accounting for the energy-deposition fluctuations at the intra- and inter-cellular level.

Variations of the Relative Biological Effectiveness (RBE) are allegedly one of the primary causes of unexpected normal tissue toxicities during tumor treatments with charged particles. Unlike carbon therapy, where the treatment planning are optimized on the bases of the RBE-weighted dose, a constant RBE value of 1.1 is currently used in proton therapy. Assuming a uniform value can lead to under-or over-dosage, not just to the tumor but also to the surrounding normal tissue. In this study, we take advantage of an existing methodology for assessing cell survival RBE from measured physical quantities and exploited it to assess potential toxicity regions both inside and outside the irradiation field. We used microdosimetry to measure lineal energy y spectra in a water phantom irradiated with a 152 MeV clinical proton beam. This approach provided a simultaneous characterization of the radiation field quality as well as an estimate of the deposited dose. Taking advantage of the Linear Quadratic (LQ) and a modified version of the Microdosimetric Kinetic (MKM) models, the microdosimetric data were combined with radiobiological parameters (α and β) characteristics of Human Salivary Gland (HSG) tumor cells for assessing cell survival RBE and RBE-weighted dose at several depths in-beam and at out-of-field. For a full treatment of 60 Gy delivered to the tumor, the overall dose received by the normal tissue is as high as 4 Gy at the field edge, 10 −2 Gy in the close-out-of-field region and 5*10 −4 Gy in the far-outof-field region. The RBE measured in-beam shows large variations, ranging from Microdosimetric evaluation of protons RBE 2 0.98±0.18 at the plateau to 2.68±0.10 at the tail. Out-of-field, the values are always higher than 1.1 independently of the depth and reach their maximum value of approximately 2.6 at the Bragg peak depth. The approach presented in this study provides a characterization of the radiation field in-beam and out-of-field from which the RBE for cell survival can be calculated. The results can point to normal tissue regions at potential higher risk of toxicities.