C Peeler

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.

Monte Carlo study of radial energy deposition from primary and secondary particles for narrow and large proton beamlet source models

In spot-scanning intensity-modulated proton therapy, numerous unmodulated proton beam spots are delivered over a target volume to produce a prescribed dose distribution. To accurately model field size-dependent output factors for beam spots, the energy deposition at positions radial to the central axis of the beam must be characterized. In this study, we determined the difference in the central axis dose for spot-scanned fields that results from secondary particle doses by investigating energy deposition radial to the proton beam central axis resulting from primary protons and secondary particles for mathematical point source and distributed source models. The largest difference in the central axis dose from secondary particles resulting from the use of a mathematical point source and a distributed source model was approximately 0.43%. Thus, we conclude that the central axis dose for a spot-scanned field is effectively independent of the source model used to calculate the secondary particle dose.

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.

A model for relative biological effectiveness of therapeutic proton beams based on a global fit of cell survival data

We introduce an approach for global fitting of the recently published high-throughput and high accuracy clonogenic cell-survival data for therapeutic scanned proton beams. Our fitting procedure accounts for the correlation between the cell-survival, the absorbed (physical) dose and the proton linear energy transfer (LET). The fitting polynomials and constraints have been constructed upon generalization of the microdosimetric kinetic model (gMKM) adapted to account for the low energy and high lineal-energy spectrum of the beam where the current radiobiological models may underestimate the reported relative biological effectiveness (RBE). The parameters (α, β) of the linear-quadratic (LQ) model calculated by the presented method reveal a smooth transition from low to high LETs which is an advantage of the current method over methods previously employed to fit the same clonogenic data. Finally, the presented approach provides insight into underlying microscopic mechanisms which, with future study, may help to elucidate radiobiological responses along the Bragg curve and resolve discrepancies between experimental data and current RBE models.

SU‐F‐T‐122: 4Dand 5D Proton Dose Evaluation with Monte Carlo

PURPOSE We evaluated uncertainties in therapeutic proton doses of a lung treatment, taking into account intra-fractional geometry changes, such as breathing, and inter-fractional changes, such as tumor shrinkage and weight loss. METHODS A Monte Carlo study was performed using four dimensional CT image sets (4DCTs) and weekly repeat imaging (5DCTs) to compute fixed RBE (1.1) and variable RBE weighted dose in an actual lung treatment geometry. The MC2 Monte Carlo system was employed to simulate proton energy deposition and LET distributions according to a thoracic cancer treatment plan developed with a 3D-CT in a commercial treatment planning system, as well as in each of the phases of 4DCT sets which were recorded weekly throughout the course of the treatment. A cumulative dose distribution in relevant structures was computed and compared to the predictions of the treatment planning system. RESULTS Using the Monte Carlo method, dose deposition estimates with the lowest possible uncertainties were produced. Comparison with treatment planning predictions indicates that significant uncertainties may be associated with therapeutic lung dose prediction from treatment planning systems, depending on the magnitude of inter- and intra-fractional geometry changes. CONCLUSION As this is just a case study, a more systematic investigation accounting for a cohort of patients is warranted; however, this is less practical because Monte Carlo simulations of such cases require enormous computational resources. Hence our study and any future case studies may serve as validation/benchmarking data for faster dose prediction engines, such as the track repeating algorithm, FDC.

WE‐H‐BRA‐05: Investigation of LET Spectral Dependence of the Biological Effects of Therapeutic Protons

PURPOSE To investigate the dependence of biologic effect (BE) of therapeutic protons on LET spectra by comparing BEs with equal dose-averaged LET (LETd) derived from different LET spectra using high-throughput in vitro clonogenic survival assays. METHODS We used Geant4 to design the relevant experimental setups and perform the dose, LETd, and LET spectra calculations for spot-scanning protons. The clonogenic assay was performed using the H460 lung cancer cell line cultured in 96-well plates. In the first experimental setup (S1), cells were irradiated using 127.4 MeV protons with a 93.22 mm Lucite buildup resulting in a LETd value of 3.4 keV/µm in the cell layer. In the second experimental setup (S2), cells were irradiated by a combination of 127.4 MeV and 136.4 MeV protons with a 96.61 mm Lucite buildup. The LETd values in the cell layer were 11.4 keV/µm and 1.5 keV/µm respectively, but an average LETd of 3.4 keV/µm was obtained by adjusting the relative fluence of each beam. Ten discrete dose levels with 0.5 Gy increments were delivered. RESULTS In the two setups, the energies or LET spectra were different but resulted in identical LETd values. We quantified the dose contributions from high-LET (≥10 keV/µm, threshold determined by previous experiments) events in the LET spectra separately for these two setups as 3.2% and 10.5%. The biologic effects at each identical dose level yielded statistically significant different survival curves (extra sum-of-squares F-test, P<0.0001). The second setup with a higher contribution from high-LET events exhibited the higher biologic effect with a dose enhancement factor of 1.17±0.03 at 0.10 surviving fraction. CONCLUSION The dose-averaged LET may not be an accurate indicator of the biological effects of protons. Detailed LET spectra may need to be considered explicitly to accurately quantify the biologic effects of protons. Funding Support: U19 CA021239-35, R21 CA187484-01 and MDACC-IRG.

TH-CD-209-12: Spatial Mapping of Scanned Proton Biologic Effect Using the High-Throughput Technique, Continued

PURPOSE To investigate the biologic effects of scanned protons by evenly sampling dose-averaged LET (LETd) values. METHODS Our previous high-throughput clonogenic study demonstrated a distinct relationship between RBE and LETd. However, our initial experimental design resulted in over-sampling the low LETd values in the plateau region of the Bragg curve while under-sampling in the region proximal to the Bragg peak as well as the high LETd values in the distal edge of the Bragg curve. To further examine the relationship between RBE and LETd, we refined the experimental design to more evenly sample proton LETd values from 1 to 20 keV/µm by optimizing the thicknesses of the irradiation jig steps. We used the clonogenic survival as the biological endpoint for the H460 lung cancer cell line cultured in 96-well plates (12 columns by 8 rows). In the irradiation, the 8 wells in each column received a uniform dose-LETd pair. The dose-LETd pairs of the 12 different columns were sampled along the Bragg curve of 81.4 MeV scanned protons. Five peak dose levels from 1.5 Gy to 7.5 Gy were delivered with an increment of 1.5 Gy in the preliminary test. Two 96-well plates were irradiated simultaneously to decrease the statistical uncertainties. RESULTS In the proximal region, for LETd = 5 keV/µm and 8 keV/µm, we did not observe any distinct differential biologic effects between the survival curves. At the Bragg peak (LETd = 9.5 keV/µm) and in the distal edge, irradiation with increasing LET values resulted in decreasing cell survival. CONCLUSION The survival curves from the new experimental design support our previous findings that below 10 keV/µm, the LET effect in cell kill is obscured, but above 10 keV/µm, the biologic effects increase with LETd. Funding Support: U19 CA021239-35 and R21 CA187484-01.

WE-H-BRA-06: Experimental Investigation of RBE for Lung Cancer Cell Lines as a Function of Dose and LET in Proton, Helium and Carbon Beams

PURPOSE Investigate and quantify the effect of dose and LET on the RBE of protons, helium and carbon ions. METHODS High throughput, high accuracy experimental setups were custom designed to investigate the Relative Biological Effectiveness (RBE) dependence on the dose and Linear Energy Transfer (LET) values for proton, helium and carbon ion beams. The experiment was conducted at the HIT facility in collaboration with the DKFZ in Heidelberg/Germany. Clonogenic assays of two human lung cancer cell lines, H460 and H1437, were investigated in this study. γH2AX foci staining on the H460 cell line was also undertaken to facilitate the study of differential DNA double-strand break induction and repair between low-design available at the HIT facility. Specific points along the Bragg curve corresponding to well-defined doses and LET values were chosen by appropriate selection of the pre-absorber thicknesses. With a setup design for horizontal beam lines we were able to minimize ion scattering in the cell plate, resulting in narrower energy spectra and hence LET distributions in the Bragg peak and in the distal falloff regions, compared to the earlier experiments. RESULTS Approximately 16,000 samples of cancer cells were irradiated during 23 hours of beam time. The preliminary results of the survival curves for both cell lines show a distinct dependence on LET for a given dose with decreased survival fractions at increasing LET values, encountered at the Bragg peak and in the distal falloff. CONCLUSION Our preliminary findings are indicative of the importance of novel variable-RBE models for proton therapy and provide insight into the RBE of heavy ions for possible future heavy ion therapy facilities in the US. Funding support: SINF 2015/16.