The Effect of the Trace Elements Concentrations on the Cancerous and Healthy Tissues in Radiotherapy

The study is aimed to investigate the effect of the trace element concentrations in healthy and cancerous prostate tissues on dose distributions in radiotherapy. In this work, the trace element compounds completely soluble in the water were used and their concentrations given in the literature were mixed homogeneously with pure water. This is the first time study in literature as far as we know. The percent depth dose (PDD) measurements were performed using Elekta Synergy Platform Linac device for 6 and 18 MV photon energies. We also obtained the PDDs results by choosing higher trace element concentrations than given in literature in cancerous prostate tissue to see the effect on radiotherapy. The experimental measurements were compared with the results obtained from the GATE simulation code. The TPR20/10 was calculated for 10 × 10 cm field size at 6/18 MV energies photons and compared with simulation results. The differences between simulation and measurement for 6 MV and 18 MV photons are 1.75% and 1.82% respectively. The experimental results and simulations were presented an uncertainty lower than 3%. Simulated dose values are in good agreement with less than 2% differences with the experimental results. We see that the trace element concentrations of healthy and cancerous tissues did not affect the dose distribution at high-energy photons. This is expected and well known result. We believe that this in vitro study is important for proving the reliability of the dose given in radiotherapy treatment once again.


Introduction
Cancer is considered as one of the most deadly diseases and the leading causes of death worldwide [1]. Cancer treatment is performed by various methods such as surgery, chemotherapy, brachytherapy and radiotherapy or the application of these methods together. Approximately 50% of all cancer patients undergo external radiotherapy (ER) using photons [2] [3] [4]. Linear accelerators used in external beam radiation therapy treatments enable patients to be irradiated at different dose rates. The main aim of radiotherapy is to give the highest dose to the tumor and to give the lowest dose to the healthy tissue around the tumor. It is important to confirm the accuracy of the dose given to the patient during treatment planning by using the dose distribution algorithms. The particle transport calculations in the presence of an internal or external source, and the energy stored in the tissue can be determined by Monte Carlo (MC) calculations.
In many studies, MC simulation packages have been used for radiation dosimeter calculations; such as OMEGA [5], MCNP4C [6] [7], EGS [8] [9]. In this research, the experimental results were simulated with the open-source code called Geant4 Application for Emission Tomography (GATE) MC simulation based on the GEANT4 toolkit (http://www.opengatecollaboration.org/). Geant4 is a software toolkit for the simulation of the interaction of particles with matter, and its application areas include high-energy physics experiments, astrophysics and astroparticle physics, nuclear physics, space science, medical physics and medical imaging, radiation protection [10] [11]. GATE plays a key role in the simulation of the radiotherapy experiments, PET, SPECT studies and design of new medical imaging devices [12] [13]. Recent studies have emphasized the importance of trace elements in the investigation about the possible causes of cancer [14] [15] [16] [17]. Trace elements have a significant effect as a component of many enzymes in all biological systems [18]. Although trace elements constitute a minor part of living tissues, they are important for vital processes. Trace element levels were determined to have deficiency or excess concerning the normal values in some diseases including cancer [19] [20]. Trace elements have different concentrations in healthy and cancerous tissues due to biological changes induced by the disease. The concentrations of trace elements in healthy and cancerous tissues or fluids have been recently obtained by using many experimental techniques such as particle-induced X-ray emission (PIXE), X-ray fluorescence analysis (XRF) and its total reflection geometry method (TRXRF), atomic absorption spectrometry (AAS) and neutron activation analysis (NAA) [21] [22] [23] [24] [25].
The concentration of trace elements has a noticeable effect on dose distributions at brachytherapy treatment (an internal radiation) which is used the low energy photon sources [26] [27]. In brachytherapy, the dosimetric impact of trace elements has been studied for normal and cancerous tissues using low energy photon sources with Monte Carlo (MC) calculations [28]. The results showed that in the presence of trace elements, dose distributions varied depend-T. Sahmaran, A. Kaskas ing on the atomic number and fraction of the elements in tissue.
The effect of the tissue composition on dose distribution was also investigated by using electron beams in radiotherapy [29]. Ghorbani et al. [29] showed that differences in dose distribution were not significant in various soft tissues and tissue-equivalent materials. However, due to the differences in the composition of the materials, it has been proposed to be investigated the uncertainties in the calculations.
This study aimed to determine the effect of the trace elements concentrations on dose distribution in healthy and cancerous prostatic tissues in radiotherapy.
The trace elements concentrations given in the literature were mixed homogeneously inside the water phantom. Here, we used the trace element compounds completely soluble in the water. The experiment was performed for 6 MV photon beams of the Elekta Synergy Platform Linear Accelerator. The percent depth-dose distributions (PDD) of the concentration of each element were measured, and the results were compared with the simulations using GATE/GEANT4 code.  Table 1. Measurements were carried out with an electrometer, CC13 and FC65P ion chambers (IBA Dosimetry, Nuremberg, Germany). Ion chambers were calibrated by Turkey Atomic Energy Agency Secondary Standard Dosimetry Laboratory (ISDL). tons. The source to surface distance was 100 cm and the irradiation field sizes were 10 × 10 cm 2 and 20 × 20 cm 2 . FC65P ion chamber was placed in a solid water phantom (RW3, IBA; Schwarzenbruck, Germany). Then, the water tank was located at the top of the solid water phantoms. Pure water and all chemical elements used in the measurements were obtained from Ankara University Chemistry Department Central Warehouse.

Percentage Depth Dose Measurements
Firstly, the tissue phantom ratio for depths of 20 and 10 cm (TPR 20/10 ) was obtained for 10 × 10 cm 2 field size to validate the simulation for 6 and 18 MV photon energies [30]. The beam quality is specified by TPR 20  [23] [31] [32] [33] [34]. The PDD measurements were at first performed with pure water, which is a tissue-equivalent material. The concentrations for each trace element were calculated according to water phantom volume.
The trace element concentrations of healthy and cancerous prostate tissues given in the literature were used to obtain a mixture of water [35]. Then, the PDD measurements were carried out for each trace element compound.

GATE Simulations
For dosimetry related applications in radiation therapy, the GATE v8.  statistical uncertainty in any volume [10]. We determined the Standard physics list with option 3 for photons, e− and e+ [36].

Results and Discussion
First, the flatness and symmetry of the instrument were determined by using the IBA Blue Phantom 2 water phantom. In Linac, the flatness value should be less than 3% and the symmetry value should be less than 2%. These values can be obtained in the largest field size at 100 cm SSD and 10 cm depth [37]. TPR 20/10 was calculated for 10 × 10 cm 2 field size at 6/18 MV energies photons and compared with simulation results. The differences between simulation and measurement for 6 MV and 18 MV photons are 1.75% and 1.82% respectively, as shown by the values in Table 3 Table 4.
Teixeira et al. [38] created the phase space of the Novalis Classic linear accelerator at 6 MV energy performed the GATE simulation program and compared PDD and dose profiles with experimental data for 10 × 10 cm 2 and 3 × 3 cm 2 radiation field. They found that the TPR 20/10 difference between simulation and measurement was about 1.5% for 6 MV. In our study, the difference between simulation and experiment was calculated at 1.75%. In Figure 3 and Figure 4 the experimental measurements performed for pure water were compared with the simulated results at 6/18 MV photons, at 10 × 10 cm 2 and 20 × 20 cm 2 field sizes. The PDD distributions for the concentrations of trace elements in healthy and cancerous prostate tissues were measured by using the trace element mass fraction as indicated in Table 2. The same conditions were defined and then simulated in GATE. ICRU 24 [39] recommends that the uncertainty in the dose given in radiotherapy should not exceed ± 5%. In this study, the difference between measured and simulated results for the pure water measurement did not exceed ±2%.
Grevillot et al. [40] measured PDD and dose profiles at 6 MV photons by using Elekta Precise Linac device and simulated with GATE program. They also found the dose differences between simulation and measurements approximately   Ghorbani et al. [29] studied the effect of the tissue composition on dose distribution for 8/12/14 MeV electron beams in radiotherapy. The various soft tissues and tissue-equivalent materials were simulated using MCNPX MC code for a Siemens Primus linear accelerator. There were no differences in dose distributions in various soft tissues and tissue-equivalent materials. Ghorbani et al. [45] T. Sahmaran, A. Kaskas           White et al. [28] determined the dose distribution for the trace element concentrations at healthy or cancerous human tissues with low energy photon sources in brachytherapy. They simulated the dose distribution with Geant4 v9.3 and found that the different trace element concentration between healthy and cancerous prostate tissues affected the dose distribution and it should not be ignored.
In Figure 14, the experimental data performed with pure water and mixture of nine elements (CTCx4) for 6 MV photons, at 10 × 10 cm 2 and 20 × 20 cm 2 field sizes were compared with the simulation.

Conclusion
To investigate the effect of trace element concentrations in tissue on dose distribution, the experimental and simulated PDD values for pure water, healthy and cancerous prostate tissues were obtained at 6 MV photon energy. The experimental values of PDD were in a good agreement with the simulated data using GATE simulation code. There is a difference of less than 2% between the meas-T. Sahmaran, A. Kaskas ured and simulated results. The experimental results and simulations were presented an uncertainty lower than 3%. As expected, it is seen that the difference between the trace element concentrations of healthy and cancerous tissues did not affect the dose distribution at high-energy photons. This is expected and well known result. We believe that this in vitro study is important for proving the reliability of the dose given in radiotherapy treatment once again.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.