Fada Guan

Spatial mapping of the biologic effectiveness of scanned particle beams: towards biologically optimized particle therapy

The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE.

Analysis of the track- and dose-averaged LET and LET spectra in proton therapy using the GEANT4 Monte Carlo code

PURPOSE The motivation of this study was to find and eliminate the cause of errors in dose-averaged linear energy transfer (LET) calculations from therapeutic protons in small targets, such as biological cell layers, calculated using the geant 4 Monte Carlo code. Furthermore, the purpose was also to provide a recommendation to select an appropriate LET quantity from geant 4 simulations to correlate with biological effectiveness of therapeutic protons. METHODS The authors developed a particle tracking step based strategy to calculate the average LET quantities (track-averaged LET, LETt and dose-averaged LET, LETd) using geant 4 for different tracking step size limits. A step size limit refers to the maximally allowable tracking step length. The authors investigated how the tracking step size limit influenced the calculated LETt and LETd of protons with six different step limits ranging from 1 to 500 μm in a water phantom irradiated by a 79.7-MeV clinical proton beam. In addition, the authors analyzed the detailed stochastic energy deposition information including fluence spectra and dose spectra of the energy-deposition-per-step of protons. As a reference, the authors also calculated the averaged LET and analyzed the LET spectra combining the Monte Carlo method and the deterministic method. Relative biological effectiveness (RBE) calculations were performed to illustrate the impact of different LET calculation methods on the RBE-weighted dose. RESULTS Simulation results showed that the step limit effect was small for LETt but significant for LETd. This resulted from differences in the energy-deposition-per-step between the fluence spectra and dose spectra at different depths in the phantom. Using the Monte Carlo particle tracking method in geant 4 can result in incorrect LETd calculation results in the dose plateau region for small step limits. The erroneous LETd results can be attributed to the algorithm to determine fluctuations in energy deposition along the tracking step in geant 4. The incorrect LETd values lead to substantial differences in the calculated RBE. CONCLUSIONS When the geant 4 particle tracking method is used to calculate the average LET values within targets with a small step limit, such as smaller than 500 μm, the authors recommend the use of LETt in the dose plateau region and LETd around the Bragg peak. For a large step limit, i.e., 500 μm, LETd is recommended along the whole Bragg curve. The transition point depends on beam parameters and can be found by determining the location where the gradient of the ratio of LETd and LETt becomes positive.

Radiobiological issues in proton therapy

Abstract Background: The relative biological effectiveness (RBE) for particle therapy is a complex function of particle type, radiation dose, linear energy transfer (LET), cell type, endpoint, etc. In the clinical practice of proton therapy, the RBE is assumed to have a fixed value of 1.1. This assumption, along with the effects of physical uncertainties, may mean that the biologically effective dose distributions received by the patient may be significantly different from what is seen on treatment plans. This may contribute to unforeseen toxicities and/or failure to control the disease. Variability of Proton RBE: It has been shown experimentally that proton RBE varies significantly along the beam path, especially near the end of the particle range. While there is now an increasing acceptance that proton RBE is variable, there is an ongoing debate about whether to change the current clinical practice. Clinical Evidence: A rationale against the change is the uncertainty in the models of variable RBE. Secondly, so far there is no clear clinical evidence of the harm of assuming proton RBE to be 1.1. It is conceivable, however, that the evidence is masked partially by physical uncertainties. It is, therefore, plausible that reduction in uncertainties and their incorporation in the estimation of dose actually delivered may isolate and reveal the variability of RBE in clinical practice. Nevertheless, clinical evidence of RBE variability is slowly emerging as more patients are treated with protons and their response data are analyzed. Modelling and Incorporation of RBE in the Optimization of Proton Therapy: The improvement in the knowledge of RBE could lead to better understanding of outcomes of proton therapy and in the improvement of models to predict RBE. Prospectively, the incorporation of such models in the optimization of intensity-modulated proton therapy could lead to improvements in the therapeutic ratio of proton therapy.

GEANT4 calculations of neutron dose in radiation protection using a homogeneous phantom and a Chinese hybrid male phantom

The purpose of this study is to verify the feasibility of applying GEANT4 (version 10.01) in neutron dose calculations in radiation protection by comparing the calculation results with MCNP5. The depth dose distributions are investigated in a homogeneous phantom, and the fluence-to-dose conversion coefficients are calculated for different organs in the Chinese hybrid male phantom for neutrons with energy ranging from 1 × 10(-9) to 10 MeV. By comparing the simulation results between GEANT4 and MCNP5, it is shown that using the high-precision (HP) neutron physics list, GEANT4 produces the closest simulation results to MCNP5. However, differences could be observed when the neutron energy is lower than 1 × 10(-6) MeV. Activating the thermal scattering with an S matrix correction in GEANT4 with HP and MCNP5 in thermal energy range can reduce the difference between these two codes.

A Monte Carlo-based radiation safety assessment for astronauts in an environment with confined magnetic field shielding

The active shielding technique has great potential for radiation protection in space exploration because it has the advantage of a significant mass saving compared with the passive shielding technique. This paper demonstrates a Monte Carlo-based approach to evaluating the shielding effectiveness of the active shielding technique using confined magnetic fields (CMFs). The International Commission on Radiological Protection reference anthropomorphic phantom, as well as the toroidal CMF, was modeled using the Monte Carlo toolkit Geant4. The penetrating primary particle fluence, organ-specific dose equivalent, and male effective dose were calculated for particles in galactic cosmic radiation (GCR) and solar particle events (SPEs). Results show that the SPE protons can be easily shielded against, even almost completely deflected, by the toroidal magnetic field. GCR particles can also be more effectively shielded against by increasing the magnetic field strength. Our results also show that the introduction of a structural Al wall in the CMF did not provide additional shielding for GCR; in fact it can weaken the total shielding effect of the CMF. This study demonstrated the feasibility of accurately determining the radiation field inside the environment and evaluating the organ dose equivalents for astronauts under active shielding using the CMF.

Optimization of Monte Carlo particle transport parameters and validation of a novel high throughput experimental setup to measure the biological effects of particle beams

Purpose: Accurate modeling of the relative biological effectiveness (RBE) of particle beams requires increased systematic in vitro studies with human cell lines with care towards minimizing uncertainties in biologic assays as well as physical parameters. In this study, we describe a novel high‐throughput experimental setup and an optimized parameterization of the Monte Carlo (MC) simulation technique that is universally applicable for accurate determination of RBE of clinical ion beams. Clonogenic cell‐survival measurements on a human lung cancer cell line (H460) are presented using proton irradiation. Methods: Experiments were performed at the Heidelberg Ion Therapy Center (HIT) with support from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg, Germany using a mono‐energetic horizontal proton beam. A custom‐made variable range selector was designed for the horizontal beam line using the Geant4 MC toolkit. This unique setup enabled a high‐throughput clonogenic assay investigation of multiple, well defined dose and linear energy transfer (LETs) per irradiation for human lung cancer cells (H460) cultured in a 96‐well plate. Sensitivity studies based on application of different physics lists in conjunction with different electromagnetic constructors and production threshold values to the MC simulations were undertaken for accurate assessment of the calculated dose and the dose‐averaged LET (LETd). These studies were extended to helium and carbon ion beams. Results: Sensitivity analysis of the MC parameterization revealed substantial dependence of the dose and LETd values on both the choice of physics list and the production threshold values. While the dose and LETd calculations using FTFP_BERT_LIV, FTFP_BERT_EMZ, FTFP_BERT_PEN and QGSP_BIC_EMY physics lists agree well with each other for all three ions, they show large differences when compared to the FTFP_BERT physics list with the default electromagnetic constructor. For carbon ions, the dose corresponding to the largest LETd value is observed to differ by as much as 78% between FTFP_BERT and FTFP_BERT_LIV. Furthermore, between the production threshold of 700 μm and 5 μm, proton dose varies by as much as 19% corresponding to the largest LETd value sampled in the current investigation. Based on the sensitivity studies, the FTFP_BERT physics list with the low energy Livermore electromagnetic constructor and a production threshold of 5 μm was employed for determining accurate dose and LETd. The optimized MC parameterization results in a different LETd dependence of the RBE curve for 10% SF of the H460 cell line irradiated with proton beam when compared with the results from a previous study using the same cell line. When the MC parameters are kept consistent between the studies, the proton RBE results agree well with each other within the experimental uncertainties. Conclusions: A custom high‐throughput, high‐accuracy experimental design for accurate in vitro cell survival measurements was employed at a horizontal beam line. High sensitivity of the physics‐based optimization establishes the importance of accurate MC parameterization and hence the conditioning of the MC system on a case‐by‐case basis. The proton RBE results from current investigations are observed to agree with a previous measurement made under different experimental conditions. This establishes the consistency of our experimental findings across different experiments and institutions.

Calculations of S values and effective dose for the radioiodine carrier and surrounding individuals based on Chinese hybrid reference phantoms using the Monte Carlo technique.

The S values for the thyroid as the radioiodine source organ to other target organs were investigated using Chinese hybrid reference phantoms and the Monte Carlo code MCNP5. Two radioiodine isotopes (125)I and (131)I uniformly distributed in the thyroid were investigated separately. We compared our S values for (131)I in Chinese phantoms with previous studies using other types of phantoms: Oak Ridge National Laboratory (ORNL) stylized phantoms, International Commission on Radiological Protection (ICRP) voxel phantoms, and University of Florida (UF) phantoms. Our results are much closer to the UF phantoms. For each specific target organ, the S value for (131)I is larger than for (125)I in both male and female phantoms. In addition, the S values and effective dose to surrounding face-to-face exposed individuals, including different genders and ages (10- and 15-year-old juniors, and adults) from an adult male radioiodine carrier were also investigated. The target organ S values and effective dose for surrounding individuals obey the inverse square law with the distance between source and target phantoms. The obtained effective dose data in Chinese phantoms are comparable to the results in a previous study using the UF phantoms. The data generated in this study can serve as the reference to make recommendations for radiation protection of the Chinese patients or nuclear workers.

SU‐E‐T‐502: In Search of the Optimum Ion for Radiotherapy

Purpose: To investigate the physical and biological properties and the clinical potential of several different ions through computer simulations. Methods: Using the Geant4 Monte Carlo toolkit, we calculated spatial dose and LET distributions in a water phantom for monoenergetic beams for four candidate ions with the same range (28 cm in water): 207 MeV/u protons, 244 MeV/u 3He ions, 206 MeV/u 4He ions, and 400 MeV/u 12C ions. An ideal broad beam of 6 cm in diameter was used in the simulations. The scoring voxel volume was set to 1 cubic millimeter. We also recorded the dose contributions from several major nuclear fragments. Furthermore, data for a 5‐cm RBE‐weighted dose SOBP for 12C ions with a range of 30 cm were analyzed. Results: Simulation results showed advantages and disadvantages of each ion. For instance, a 12C ion beam produces the sharpest and narrowest Bragg peak, and the smallest penumbra, but it has the highest entrance to peak dose ratio, and highest and longest nuclear fragmentation tail. Furthermore, the lateral dose halo effect of 12C is substantially greater than other ions. For the same range in water, 3He and 4He ions show very similar features. They have smaller lateral penumbrae than protons, and much smaller fragmentation tails compared with 12C ions. Although protons have the largest lateral penumbra and widest Bragg peak, they do not have an observable fragmentation tail. For a pristine beam of 400 MeV/u 12C ions, the fragmentation tail dose is 15% of the peak dose. In the case of 5‐cm SOBP with 30‐cm range of 12C ions, the fragmentation tail dose can be as high as 30% of the maximum dose. Conclusion: Each type of ion has special advantages and disadvantages. Further research is needed to consider additional factors such as energy dependence, cost effectiveness and RBE. NCI grant P01CA021239

SU‐E‐T‐535: On the Out‐Of‐Field‐Doses Caused by Secondary Particles From Light Ion Beams in Charged Particle Therapy

PURPOSE Charged ion therapy in the United States consists mainly of proton therapy, which may deposit a larger than necessary lateral dose to healthy tissues. Application of heavier particles may Result in an improvement, i.e., lowering the dose bath to the patient. The purpose of this study is to evaluate the secondary halo dose of therapeutic light ion beams. METHODS Monte Carlo simulations have been performed to evaluate lateral dose distributions (halo dose) caused by scattered primary particles as well as by secondary particles, in therapeutic ion beams. Primary particles included Protons, Helium ions, Lithium ions as well as 12C-ions. Energy deposition profiles in a water phantom from various particle species were evaluated and compared. The secondaries included heavy ions (heavier than alphas), alphas, protons, as well as neutrons and photons. The study provides estimates of out of field doses from secondary particles for a variety of beam parameters such as range in water, field size, modulation width, and the source particle type. RESULTS Preliminary data indicates, that with increasing Z of the source particles, lateral dose profiles, including scattered primary and secondary particles from nuclear reactions, decrease significantly. CONCLUSION Further studies are indicated to evaluate any possible improvement in lateral dose deposition versus increased doses to tissues distal to the Bragg peaks, caused by source particle and target fragmentation.

Physical parameter optimization scheme for radiobiological studies of charged particle therapy

We have developed an easy-to-implement method to optimize the spatial distribution of a desired physical quantity for charged particle therapy. The basic methodology requires finding the optimal solutions for the weights of the constituent particle beams that together form the desired spatial distribution of the specified physical quantity, e.g., dose or dose-averaged linear energy transfer (LETd), within the target region. We selected proton, 4He ion, and 12C ion beams to demonstrate the feasibility and flexibility of our method. The pristine dose Bragg curves in water for all ion beams and the LETd for proton beams were generated from Geant4 Monte Carlo simulations. The optimization algorithms were implemented using the Python programming language. High-accuracy optimization results of the spatial distribution of the desired physical quantity were then obtained for different cases. The relative difference between the real value and the expected value of a given quantity was approximately within ±1.0% in the whole target region. The optimization examples include a flat dose spread-out Bragg peak (SOBP) for the three selected ions, an upslope dose SOBP for protons, and a downslope dose SOBP for protons. The relative difference was approximately within ±2.0% for the case with a flat LETd (target value = 4 keV/µm) distribution for protons. These one-dimensional optimization algorithms can be extended to two or three dimensions if the corresponding physical data are available. In addition, this physical quantity optimization strategy can be conveniently extended to encompass biological dose optimization if appropriate biophysical models are invoked.