Calculating Variations in Biological Effectiveness for a 62 MeV Proton Beam

Abstract

A biophysical model of radiation-induced cell death and chromosome aberrations [called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA)] was further developed and applied to therapeutic protons. The model assumes a pivotal role of DNA cluster damage, which can lead to clonogenic cell death following three main steps: (i) a DNA “cluster lesion” (CL) produces two independent chromosome fragments; (ii) fragment mis-rejoining within a threshold distance d gives rise to chromosome aberrations; (iii) certain aberration types (dicentrics, rings, and large deletions) lead to clonogenic inactivation. The yield of CLs and the probability, f, that a chromosome fragment remains un-rejoined even if other fragment(s) are present within d, were adjustable parameters. The model, implemented as a MC code providing simulated dose–responses directly comparable with experimental data, was applied to pristine and modulated Bragg peaks of the proton beam used to treat eye melanoma at INFN-LNS in Catania, Italy. Experimental survival curves for AG01522 cells exposed to the Catania beam were reproduced, supporting the model assumptions. Furthermore, cell death and chromosome aberrations at different depths along a spread-out Bragg peak (SOBP) dose profile were predicted. Both endpoints showed an increase along the plateau, and high levels of damage were found also beyond the distal dose fall-off, due to low-energy protons. Cell death and chromosome aberrations were also predicted for V79 cells, in the same irradiation scenario as that used for AG01522 cells. In line with other studies, this work indicated that assuming a constant relative biological effectiveness (RBE) along a proton SOBP may be sub-optimal. Furthermore, it provided qualitative and quantitative evaluations of the dependence of the beam effectiveness on the considered endpoint and dose. More generally, this work represents an example of therapeutic beam characterization avoiding the use of experimental RBE values, which can be source of uncertainties.

Radiobiological quantities in proton-therapy: Estimation and validation using Geant4-based Monte Carlo simulations

“…Monte Carlo (MC) simulations are able to simulate hadronic elastic and inelastic processes when particles penetrate matter and the transport of secondaries produced in such interactions. Many MC codes are available today but only a few have the capability to evaluate proton RBE distributions [13][14][15]. In a recent publication, Mairani et al [16] discussed an approach to calculate the RBE-weighted dose in case of two opposed and superimposed 12 C ion beams.…”

New insights in the relative radiobiological effectiveness of proton irradiation

“…Also the number of unrepaired double-stranded DNA breaks, as assessed by the number of γ-H2AX foci assay 24 h after irradiation was higher for irradiation at the distal end of the SOBP. In a theoretical study of Carante and Ballarini, a biophysical model of radiation-induced cell death and chromosome aberrations called Biophysical Analysis of Cell death and chromosome Aberrations (BIANCA) was used in order to predict the cell death and the yield of dicentric chromosomes at different depth positions along a SOBP dose profile of therapeutic protons [ 53 ]. These simulation data are consistent with the experimental cell survival data as reported in Chaudhary et al [ 11 ] and for both investigating endpoints an increased beam effectiveness was shown along the plateau, implying that the assumption of a constant RBE along a proton SOBP may be sub-optimal [ 53 ].…”

“…In a theoretical study of Carante and Ballarini, a biophysical model of radiation-induced cell death and chromosome aberrations called Biophysical Analysis of Cell death and chromosome Aberrations (BIANCA) was used in order to predict the cell death and the yield of dicentric chromosomes at different depth positions along a SOBP dose profile of therapeutic protons [ 53 ]. These simulation data are consistent with the experimental cell survival data as reported in Chaudhary et al [ 11 ] and for both investigating endpoints an increased beam effectiveness was shown along the plateau, implying that the assumption of a constant RBE along a proton SOBP may be sub-optimal [ 53 ]. The results of an ex vivo study, where the intestine of mice was irradiated with 200 MeV clinical proton beam are consistent with in vitro data showing an increased proton RBE with depth in an SOBP for both investigated biological endpoints, the intestinal crypt regeneration and lethal dose 50% (LD 50 ) [ 54 ].…”

Study of the Influence of NanOx Parameters

“…Determining the value of RBE for every scenario is a challenging task that requires modeling to comply with the demands of a clinical environment. Several solutions have already been developed (also specifically for protons, e.g., [ 1 , 2 , 3 ]), and a few are currently used in treatment planning [ 4 , 5 , 6 , 7 ]. However, the latter present some shortcomings that may limit their improvement: in the modified microdosimetric kinetic model, the nanometric scale is disregarded, and the Poissonian distribution relating cell survival to the total number of lethal damages is corrected in a second instance, as it is not adapted for high-LET ions; in the local effect model, the stochastic nature of the dose deposition is not taken into account at the nanoscopic level, and the use of the amorphous track structure results in conceptual incongruities [ 8 , 9 ].…”