Inverse treatment planning in intensity modulated particle therapy (IMPT) with scanned carbon-ion beams is currently based on the optimization of RBE-weighted dose to satisfy requirements of target coverage and limited toxicity to organs-at-risk (OARs) and healthy tissues. There are many feasible IMPT plans that meet these requirements, which allows the introduction of further criteria to narrow the selection of a biologically optimal treatment plan. We propose a novel treatment planning strategy based on the simultaneous optimization of RBE-weighted dose and nanometric ionization details (ID) as a new physical characteristic of the delivered plan beyond LET. In particular, we focus on the distribution of large ionization clusters (more than 3 ionizations) to enhance the biological effect across the target volume while minimizing biological effect in normal tissues. Carbon-ion treatment plans for different patient geometries and beam configurations generated with the simultaneous optimization strategy were compared against reference plans obtained with RBE-weighted dose optimization alone. Quality indicators, inhomogeneity index and planning volume histograms of RBE-weighted dose and large ionization clusters were used to evaluate the treatment plans. We show that with simultaneous optimization, ID distributions can be optimized in carbon-ion radiotherapy without compromising the RBE-weighted dose distributions. This strategy can potentially be used to account for optimization of endpoints closely related to radiation quality to achieve better tumor control and reduce risks of complications.

Details of the pattern of ionization formed by particle tracks extends knowledge of dose effects on the nanometer scale. Ionization detail (ID), frequently characterized by ionization cluster size distributions (ICSD), is obtained through time-consuming Monte Carlo (MC) track-structure simulations. In this work, TOPAS-nBio was used to generate a highly precise database of biologically significant ID quantities, sampled with randomly oriented 2.3 nm diameter cylinders, 3.4 nm (10 base pairs) long, inside a chromatin-size cylinder, irradiated by 1-1000 MeV/u ions of Z  =  1-8. A macroscopic method developed to utilize the database using condensed-history MC was used to calculate distributions of the ICSD first moment [Formula: see text] and cumulative probability [Formula: see text] in a 20  ×  20  ×  40 cm³ water phantom irradiated with proton and carbon spread-out Bragg peak (SOBP) of 10.5 cm range, 2 cm width. Results were verified against detailed MC track-structure simulations using phase space scored at several depths. ID distributions were then obtained for intensity modulated proton and carbon radiotherapy plans in a digitized anthropomorphic phantom of a base of skull tumor to demonstrate clinical application of this approach. The database statistical uncertainties were 0.5% (3 standard deviations). Fluence-averaged ID as implemented proved unsuitable for macroscopic calculation. E _dep-averaged ID agreed with track-structure results within 0.8% for protons. For carbon, maximum absolute differences of 2.9%  ±  1.6% and 5.6%  ±  1.9% for [Formula: see text], 1.7%  ±  0.8% and 1.9%  ±  0.4% (1 standard deviation) for [Formula: see text], were found in the plateau and SOBP, respectively, up to 11.5%  ±  5.6% in the tail region. Macroscopic ID calculation was demonstrated for a realistic treatment plan. Computation times with or without ID calculation were comparable in all cases. Pre-calculated nanodosimetric data may be used for condensed-history MC for nanodosimetric ID-based treatment planning in ion radiotherapy in the future. The macroscopic approach developed has the calculation speed of condensed-history MC while approaching the accuracy of full track structure simulations.

Microdosimetric energy depositions have been suggested as a key variable for the modeling of the relative biological effectiveness (RBE) in proton and ion radiation therapy. However, microdosimetry has been underutilized in radiation therapy. Recent advances in detector technology allow the design of new mico- and nano-dosimeters. At the same time Monte Carlo (MC) simulations have become more widely used in radiation therapy. In order to address the growing interest in the field, a microdosimetric extension was developed in TOPAS. The extension provides users with the functionality to simulate microdosimetric spectra as well as the contribution of secondary particles to the spectra, calculate microdosimetric parameters, and determine RBE with a biological weighting function approach or with the microdosimetric kinetic (MK) model. Simulations were conducted with the extension and the results were compared with published experimental data and other simulation results for three types of microdosimeters, a spherical tissue equivalent proportional counter (TEPC), a cylindrical TEPC and a solid state microdosimeter. The corresponding microdosimetric spectra obtained with TOPAS from the plateau region to the distal tail of the Bragg curve generally show good agreement with the published data.