Proton and ion beams are radiotherapy modalities of increasing importance and interest. Because of the different biological dose response of these radiations as compared with high-energy photon beams, the current approach of treatment prescription is based on the product of the absorbed dose to water and a biological weighting factor, but this is found to be insufficient for providing a generic method to quantify the biological outcome of radiation. It is therefore suggested to define new dosimetric quantities that allow a transparent separation of the physical processes from the biological ones. Given the complexity of the initiation and occurrence of biological processes on various time and length scales, and given that neither microdosimetry nor nanodosimetry on their own can fully describe the biological effects as a function of the distribution of energy deposition or ionization, a multiscale approach is needed to lay the foundation for the aforementioned new physical quantities relating track structure to relative biological effectiveness in proton and ion beam therapy. This article reviews the state-of-the-art microdosimetry, nanodosimetry, track structure simulations, quantification of reactive species, reference radiobiological data, cross-section data and multiscale models of biological response in the context of realizing the new quantities. It also introduces the European metrology project, Biologically Weighted Quantities in Radiotherapy, which aims to investigate the feasibility of establishing a multiscale model as the basis of the new quantities. A tentative generic expression of how the weighting of physical quantities at different length scales could be carried out is presented.

The biological action of ionizing charged particles is initiated at the DNA level, and the effectiveness with which the initial physical effect changes into measurable biological damage is likely ruled by the stochastics of ionizations produced by the incident ions in subcellular nanometric volumes. Based on this hypothesis, experimental nanodosimetry aims at establishing a new concept of radiation quality that builds on measurable characteristics of the particle track structure at the nanometer scale. Three different nanodosimetric detection systems have been developed to date that allow measurements of the number of ionizations produced by the passage of a primary particle in a nanometer-size gas volume (in unit density scale). Within the Italian project MITRA (MIcrodosimetry and TRAck structure), funded by the Italian Istituto Nazionale di Fisica Nucleare (INFN) and the EMRP Joint Research Project 'BioQuaRT' (Biologically Weighted Quantities in Radiotherapy), experiments have been carried out, in which the frequency distribution of ionizations produced by proton and carbon ion beams of given energy was measured with the three nanodosimetric detectors. Descriptors of the track structure can be derived from these distributions. In particular, the first moment M1, representing the mean number of ionizations produced in the target volume, and the cumulative probability Fk of measuring a number ν ≥ k of ionizations. The correlation between measured nanodosimetric quantities and experimental radiobiological data available in the literature is here presented and discussed.

After a short overview on the latest developments in nanodosimetry, measured frequency distributions of ionisation cluster size caused by 4.6 MeV alpha-particles or low-energy electrons in 'nanometric' volumes of nitrogen are compared with cluster-size distributions for liquid water cylinders that are equal in size to segments of DNA of 10 base-pairs length. Such frequency distributions are, to a greater part, governed by the same basic physical interaction data as those to be expected, if charged particles interact with DNA segments. Quantities derived from ionisation cluster-size distributions should, therefore, behave as a function of radiation quality similarly to the yields of single or double strand breaks in the DNA. To test this assumption, extensive Monte Carlo simulations were performed for electrons in the energy range between 12.5 eV and 100 keV for protons at energies between 0.7 MeV and 250 MeV and for alpha-particles in the energy range between 2 MeV and 100 MeV. The results are then compared with the yields of single- or double-strand breaks in the DNA, taken from the literature.

Probability distributions of the size of ion clusters created in "nanometric" volumes of nitrogen by single alpha-particles of a gold-plated 241Am source, were measured and compared with those calculated by Monte Carlo methods in the same geometry. The diameter of the sensitive volumes had a mass per area of between 0.015 microgram/cm2 and 1.3 micrograms/cm2 which, for a material at unit density, corresponds to a nanometric target volume 0.15-13 nm in diameter. These nanometre sizes were simulated experimentally in a device called the Jet Counter. This consists of a pulse-operated valve which injects into an interaction chamber an expansion jet of molecular nitrogen gas, which is crossed by a narrow beam of alpha-particles. The resulting ions are counted and analyzed from the point of view of ionization cluster formation. The measured or calculated cluster size probabilities prove that the formation of ionization clusters along a "nanometre" track is governed by Poisson's law only in the case of very small target volumes, due to the contributions by secondary electrons. The present ionization cluster probabilities produced in "nanometric" volumes 0.15-13 nm in diameter, are the first ever determined experimentally and confirmed by Monte Carlo simulation.

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