# Publications

^{90}Y-microsphere radioembolization using the TOPAS Monte Carlo toolkit.” Physics in Medicine and Biology, In press. Publisher's VersionAbstract

The spatial distribution of energy deposition events is an essential aspect in the determination of the radiobiological effects of ionizing radiation at the cellular level. Microdosimetry provides a theoretical framework for the description of these events, and has been used in several studies to address problems such as the characterization of Linear Energy Transfer (LET) and Relative Biological Effectiveness (RBE) of ion beams for proton therapy applications. Microdosimetry quantities and their distributions can be obtained by means of Monte Carlo simulations. In this work, we present a track structure Monte Carlo (MC) application, based on Geant4-DNA, for the computation of microdosimetric distributions of protons in liquid water. This application provides two sampling methods uniform and weighted , for the scoring of the quantities of interest in spherical sites, with diameters ranging from 1 to 10 μm. As an element of novelty, the work shows the approach followed to calculate, without resorting to dedicated simulations, the distribution of energy imparted to the site per electronic collision of the proton, which can be used to obtain the macroscopic dose-averaged LET as proposed by Kellerer. Furthermore, in this work the concept of effective mean chord length is proposed to take into account δ-ray influx and escape in the calculation of macroscopic dose-averaged LET for proton track segments and retrieve the agreement predicted by Kellerer’s formula. Finally, the results obtained demonstrate that our MC application is reliable and computational-efficient to perform calculations of microdosimetric distributions and dose-averaged LET of proton track segments in liquid water.

### Purpose

To investigate the correlation between imaging changes in brain normal tissue and the spatial distribution of linear energy transfer (LET) for a cohort of meningioma patients treated with scanned proton beams. Then, assuming imaging changes are induced by cell lethality, to study the correlation between normal tissue complication probability and LET.

### Methods

MRI T2/FLAIR acquired at different intervals after proton radiation were co-registered with the planning CT images from 26 patients diagnosed with meningioma with abnormalities after proton radiotherapy. For this purpose, the T2/FLAIR areas not on the original MRIs were contoured and LET values for each voxel in the patient geometry were calculated to investigate the correlation between the position of imaging changes and LET at those positions. To separate the effect of dose as inductor of these changes, we compared LET in these areas with a sample of voxels matching the dose distributions across the image change areas. Patients with higher LET in image change areas were grouped to verify whether they shared common characteristics.

### Results

11 of the patients showed higher LETd in imaging change regions than in group of voxels with the same dose. This group of patients had significantly shallower targets for their treatment than the other 15 and used fewer beams and angles.

### Conclusion

This study points towards the possibility of areas with imaging change are more likely to occur in regions with high dose or in those areas with lower dose but increased LETd. The effect of LETd on imaging changes seems to be more relevant when treating superficial lesions with few non opposed beams. However, most of the patients did not show spatial correlation between their image changes and the LETd values, limiting the cases for the possible role of high LET as a toxicity inductor.

### Purpose

To implement RBE calculations in treatment planning systems based on the Microdosimetric Kinetic Model (MKM) upon analytical calculations of dose-mean lineal energy (yD). MKM relies on the patterns of energy deposition in sub-nuclear structures called domains, whose radii are cell-specific and need to be determined.

### Methods and material

The radius of a domain (rd) can be determined from the linear-quadratic (LQ) curves from clonogenic experiments for different cell lines exposed to X-ray and proton beams with known yD. In this work, LQ parameters for two different human lung cell lines (H1299 and H460) are used, and yD among cells is calculated through an analytical algorithm. Once rd is determined, MKM-based calculations of RBE are implemented in a treatment planning system (TPS). Results are compared to those produced by phenomenological models of RBE, such as Carabe and McNamara.

### Results

Differences between model-based predictions and experimentally determined RBE are analyzed for yD=5 keV/μm. For the H1299 line, mean differences in RBE are 0.13, −0.29 and −0.27 for our MKM-based calculation, Carabe and McNamara models, respectively. For the H460 line, differences become −0.044, −0.091 and −0.048, respectively. RBE is computed for these models in a simple plan, showing MKM the best agreement with the experimentally obtained RBE, keeping deviations below 0.08.

### Conclusions

Microdosimetry calculations at the TPS-level provide tools to improve predictions of RBE using the MKM with actual values of yD instead of LET. The radius of the characteristic domain needs to be determined to tailor the RBE prediction for each cell or tissue.

### Purpose

There is a growing trend towards the adoption of model-based calculation algorithms (MBDCAs) for brachytherapy dose calculations which can properly handle media and source/applicator heterogeneities. However, most of dose calculations in ocular plaque therapy are based on homogeneous water media and standard in-silico ocular phantoms, ignoring non-water equivalency of the anatomic tissues and heterogeneities in applicators and patient anatomy. In this work, we introduce *EyeMC*, a Monte Carlo (MC) model-based calculation algorithm for ophthalmic plaque brachytherapy using realistic and adaptable patient-specific eye geometries and materials.

### Methods

We used the MC code PENELOPE in *EyeMC* to model Bebig IsoSeed I25.S16 seeds in COMS plaques and ^{106}Ru/^{106}Rh applicators that are coupled onto a customizable eye model with realistic geometry and composition. To significantly reduce calculation times, we integrated *EyeMC* with *CloudMC*, a cloud computing platform for radiation therapy calculations. *EyeMC* is equipped with an evaluation module that allows the generation of isodose distributions, dose–volume histograms, and comparisons with *Plaque Simulator* three-dimensional dose distribution. We selected a sample of patients treated with ^{125}I and ^{106}Ru isotopes in our institution, covering a variety of different type of plaques, tumor sizes, and locations. Results from *EyeMC* were compared to the original plan calculated by the TPS *Plaque Simulation*, studying the influence of heterogeneous media composition as well.

### Results

*EyeMC* calculations for Ru plaques agreed well with manufacturer’s reference data and data of MC simulations from Hermida et al. (2013). Significant deviations, up to 20%, were only found in lateral profiles for notched plaques. As expected, media composition significantly affected estimated doses to different eye structures, especially in the ^{125}I cases evaluated. Dose to sclera and lens were found to be about 12% lower when considering real media, while average dose to tumor was 9% higher. ^{106}Ru cases presented a 1%–3% dose reduction in all structures using real media for calculation, except for the lens, which showed an average dose 7.6% lower than water-based calculations. Comparisons with *Plaque Simulator* calculations showed large differences in dose to critical structures for ^{106}Ru notched plaques. ^{125}I cases presented significant and systematic dose deviations when using the default calculation parameters from *Plaque Simulator* version 5.3.8., which were corrected when using calculation parameters from a custom physics model for *carrier*-*attenuation* and *air*-*interface* correction functions.

### Conclusions

*EyeMC* is a MC calculation system for ophthalmic brachytherapy based on a realistic and customizable eye-tumor model which includes the main eye structures with their real composition. Integrating this tool into a cloud computing environment allows to perform high-precision MC calculations of ocular plaque treatments in short times. The observed variability in eye anatomy among the selected cases justifies the use of patient-specific models.

In radiopharmaceutical treatments α-particles are employed to treat tumor cells. However, the mechanism that drives the biological effect induced is not well known. Being ionizing radiation, α- particles can affect biological organisms by producing damage to the DNA, either directly or indirectly. Following the principle that microdosimetry theoryaccounts for the stochastic wayin which radiation deposits energy in sub-cellular sized volumes via physical collisions, we postulate that microdosimetry represents a reasonable framework to characterize the statistical nature of direct damage induction by α-particles to DNA. We used the TOPAS-nBio Monte Carlo package to simulate direct damage produced bymonoenergetic alpha particles to different DNAstructures. In separate simulations, we obtained the frequency-mean lineal energy (yF) and dose-mean lineal energy (yD) of microdosimetric distributions sampled with spherical sites ofdifferent sizes. The total number of DNA strand breaks, double strand breaks (DSBs) and complex strand breaks per track were quantified and presented as a function of either yF or yD. The probability ofinteraction between a track and the DNA depends on how the base pairs are compacted. To characterize this variability on compactness, spherical sites of different size were used to match these probabilities ofinteraction, correlating the size-dependent specific energy (z) with the damage induced. The total number of DNA strand breaks per track was found to linearly correlate with yF and zF when using what we defined an effective volume as microdosimetric site, while the yield of DSB per unit dose linearly correlated with yD or zD, being larger for compacted than for unfolded DNA structures. The yield ofcomplex breaks per unit dose exhibited a quadratic behavior with respect to yD and a greater difference among DNA compactness levels. Microdosimetric quantities correlate with the direct damage imparted on DNA.

^{211}At, an alpha emitter, with a spherical target representing the nucleus, placed at the center of the cell. We compare the results of our analytical method with calculations using Geant4-DNA of this specific setup for three nucleus sizes corresponding to our three functions. For nuclei with diameter of 1 µm and 5 µm, all mean and dose-mean quantities for y and z were in an agreement within 4% to Geant4-DNA calculations. This agreement improves to approximately 1% for dose-mean lineal energy and dose-mean specific energy. For the 10-µm-diameter case, discrepancies scale to approximately 9% for mean values and 3% for dose-mean values. Dose-mean values are within Geant4-DNA uncertainties in all cases. Our method provides accurate analytical calculations of dose-mean quantities that may be further employed to characterize radiobiological effectiveness of targeted radiotherapy. The spatial distributions of sources and targets are required to calculate microdosimetric-relevant quantities.

### Purpose

To study the agreement between proton microdosimetric distributions measured with a silicon-based cylindrical microdosimeter and a previously published analytical microdosimetric model based on Geant4-DNA in-water Monte Carlo simulations for low energy proton beams.

### Methods and material

Distributions for lineal energy (y) are measured for four proton monoenergetic beams with nominal energies from 2.0 MeV to 4.5 MeV, with a tissue equivalent proportional counter (TEPC) and a silicon-based microdosimeter. The actual energy for protons traversing the silicon-based microdosimeter is simulated with SRIM. Monoenergetic beams with these energies are simulated with Geant4-DNA code by simulating a water cylinder site of dimensions equal to those of the microdosimeter. The microdosimeter response is calibrated by using the distribution peaks obtained from the TEPC. Analytical calculations for y‾F and y‾D using our methodology based on spherical sites are also performed choosing the equivalent sphere to be checked against experimental results.

### Results

Distributions for y at silicon are converted into tissue equivalent and compared to the Geant4-DNA simulated, yielding maximum deviations of 1.03% for y‾F and 1.17% for y‾D. Our analytical method generates maximum deviations of 1.29% and 3.33%, respectively, with respect to experimental results.

### Conclusion

Simulations in Geant4-DNA with ideal cylindrical sites in liquid water produce similar results to the measurements in an actual silicon-based cylindrical microdosimeter properly calibrated. The found agreement suggests the possibility to experimentally verify the calculated clinical y‾D with our analytical method.

Proton arc therapy (PAT) has been proposed as a possible evolution for proton therapy. This commentary uses dosimetric and cancer risk evaluations from earlier studies to compare PAT with intensity modulated proton therapy. It is concluded that, although PAT may not produce better physical dose distributions than intensity modulated proton therapy, the radiobiological considerations associated with particular PAT techniques could offer the possibility of an increased therapeutic index.