Multiscale approach predictions for biological outcomes in ion-beam cancer therapy.

Ion-beam therapy provides advances in cancer treatment, offering the possibility of excellent dose localization and thus maximising cell-killing within the tumour. The full potential of such therapy can only be realised if the fundamental mechanisms leading to lethal cell damage under ion irradiation are well understood. The key question is whether it is possible to quantitatively predict macroscopic biological effects caused by ion radiation on the basis of physical and chemical effects related to the ion-medium interactions on a nanometre scale. We demonstrate that the phenomenon-based MultiScale Approach to the assessment of radiation damage with ions gives a positive answer to this question. We apply this approach to numerous experiments where survival curves were obtained for different cell lines and conditions. Contrary to other, in essence empirical methods for evaluation of macroscopic effects of ionising radiation, the MultiScale Approach predicts the biodamage based on the physical effects related to ionisation of the medium, transport of secondary particles, chemical interactions, thermo-mechanical pathways of biodamage, and heuristic biological criteria for cell survival. We anticipate this method to give great impetus to the practical improvement of ion-beam cancer therapy and the development of more efficient treatment protocols.

Thermomechanical effects caused by heavy ions propagating in tissue.

The thermomechanical effects caused by ions propagating in tissue are discussed. Large energy densities in small regions surrounding ion paths cause shock waves propagating in tissue. The strength of the shock waves depends on the linear energy transfer. Molecular dynamics simulations help in determining the necessary strength of shock waves in order for the stresses caused by them to directly produce DNA strand breaks. At much smaller values of linear energy transfer, the shock waves may be instrumental in propagating reactive species formed close to the ion's path to large distances, successfully competing with diffusion.

Multiscale physics of ion-induced radiation damage.

This is a review of a multiscale approach to the physics of ion-beam cancer therapy, an approach suggested in order to understand the interplay of a large number of phenomena involved in the radiation damage scenario occurring on a range of temporal, spatial, and energy scales. We describe different effects that take place on different scales and play major roles in the scenario of interaction of ions with tissue. The understanding of these effects allows an assessment of relative biological effectiveness that relates the physical quantities, such as dose, to the biological values, such as the probability of cell survival.

Biodamage via shock waves initiated by irradiation with ions.

Radiation damage following the ionising radiation of tissue has different scenarios and mechanisms depending on the projectiles or radiation modality. We investigate the radiation damage effects due to shock waves produced by ions. We analyse the strength of the shock wave capable of directly producing DNA strand breaks and, depending on the ion's linear energy transfer, estimate the radius from the ion's path, within which DNA damage by the shock wave mechanism is dominant. At much smaller values of linear energy transfer, the shock waves turn out to be instrumental in propagating reactive species formed close to the ion's path to large distances, successfully competing with diffusion.

Calculation of complex DNA damage induced by ions.

This paper is devoted to the analysis of the complex damage of DNA irradiated by ions. The assessment of complex damage is important because cells in which it occurs are less likely to survive because the DNA repair mechanisms may not be sufficiently effective. We study the flux of secondary electrons through the surface of nucleosomes and calculate the radial dose and the distribution of clustered damage around the ion's path. The calculated radial dose distribution is compared to simulations. The radial distribution of the complex damage is found to be different from that of the dose. A comparison with experiments may solve the question of what is more lethal for the cell, damage complexity or absorbed energy. We suggest a way to calculate the probability of cell death based on the complexity of the damage. This work is done within the framework of the phenomenon-based multiscale approach to radiation damage by ions.

Spectra of secondary electrons generated in water by energetic ions.

The energy distributions of secondary electrons produced by energetic carbon ions (in the energy range used, e.g., in hadron therapy), incident on liquid water, are discussed. For low-energy ions, a parametrization of the singly differential ionization cross sections is introduced, based on tuning the position of the Bragg peak. The resulting parametrization allows a fast calculation of the energy spectra of secondary electrons at different depths along the ion's trajectory, especially near the Bragg peak. At the same time, this parametrization provides penetration depths for a broad range of initial-ion energies within the therapeutically accepted error. For high-energy ions, the energy distribution is obtained with a use of the dielectric-response function approach. Different models are compared and discussed.

Ion-beam cancer therapy: news about a multiscale approach to radiation damage.

We report the present stage of development of our multiscale approach to the physics related to radiation damage caused by irradiation of a tissue with energetic ions. This approach is designed to quantify the most important physical, chemical, and biological phenomena taking place during and following such an irradiation in order to understand the scenario of the events leading to cell death and provide a better means for clinically necessary calculations with an adequate accuracy. On this stage, we overview the latest progress in calculating energy spectra of secondary electrons in liquid water and the results of an application of the inelastic thermal spike model to liquid water in order to calculate the heat transfer in the vicinity of the incident-ion track. The dependence of energy distributions of secondary electrons, resulting from ionization of the liquid water, on the energy of primary ions is studied in two regimes. For slow ions, a new parameterization of energy spectra in liquid water is suggested. For fast ions, different dispersion schemes on the basis of a dielectric response function approach are used and compared. Thermal spike calculations indicate a very large temperature increase in the vicinity of ion tracks near the Bragg peak during the time interval from 10(-15) to 10(-9)s after the ion's passage. An increase of pressure, as large as tens of MPa, can also be induced during that time. These effects suggest a possibility of thermo-mechanical pathways to disruption of irradiated DNA. A combination of a temperature spike and electron/hole interactions may be a dominant pathway of DNA damage.

Shock wave initiated by an ion passing through liquid water.

We investigate the shock wave produced by an energetic ion in liquid water. This wave is initiated by a rapid energy loss when the ion moves through the Bragg peak. The energy is transferred from the ion to secondary electrons, which then transfer it to the water molecules. The pressure in the overheated water increases by several orders of magnitude and drives a cylindrical shock wave on a nanometer scale. This wave eventually weakens as the front expands further; but before that, it may contribute to DNA damage due to large pressure gradients developed within a few nanometers from the ion's trajectory. This mechanism of DNA damage may be a very important contribution to the direct chemical effects of low-energy electrons and holes.

Temperature and pressure spikes in ion-beam cancer therapy.

The inelastic thermal spike model is applied to liquid water in relation to high-energy 12C6+ beams (hundreds of MeV/u) used for cancer therapy. The goal of this project is to calculate the heat transfer in the vicinity of the incident-ion track. Thermal spike calculations indicate a very large temperature increase in the vicinity of ion tracks near the Bragg peak during the time interval from 10(-15) to 10(-9) s after the ion's passage and an increase in pressure, as large as tens of MPa, can be induced during that time. These effects suggest a possibility of thermomechanical pathways to disruption of irradiated DNA. An extension of the model for hydrogen, beryllium, argon, krypton, xenon, and uranium ions around the Bragg peak is presented as well.

Physics of ion beam cancer therapy: a multiscale approach.

We propose a multiscale approach to understand the physics related to ion-beam cancer therapy. It allows the calculation of the probability of DNA damage as a result of irradiation of tissues with energetic ions, up to 430 MeV/u. This approach covers different scales, starting from the large scale, defined by the ion stopping, followed by a smaller scale, defined by secondary electrons and radicals, and ending with the shortest scale, defined by interactions of secondaries with the DNA. We present calculations of the probabilities of single and double strand breaks of DNA, suggest a way to further expand such calculations, and also make some estimates for glial cells exposed to radiation.