Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 15  |  Issue : 3  |  Page : 504--511

Improvement of dose distribution in ocular brachytherapy with 125I seeds 20-mm COMS plaque followed to loading of choroidal tumor by gold nanoparticles


Mansour Zabihzadeh1, Hadi Rezaee2, Seyed Mohammad Hosseini3, Mostafa Feghhi4, Amir Danyaei2, Mojtaba Hoseini-Ghahfarokhi5,  
1 Department of Medical Physics, School of Medicine; Department of Clinical Oncology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Department of Medical Physics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3 Department of Clinical Oncology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4 Department of Ophthalmology, Ophthalmic Research Center, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
5 Department of Radiology and Nuclear Medicine, School of Para Medical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran

Correspondence Address:
Dr. Mansour Zabihzadeh
Department of Medical Physics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Golestan Blvd, Ahvaz
Iran

Abstract

Aims and Objectives: Brachytherapy using removable ophthalmic plaques loaded with suitable small sealed radioactive seeds adjacent to the ocular's tumor has been widely used as an effective treatment. The aim of this study was to investigate the dose distribution in a modeled eyeball followed to loading of an ocular melanoma tumor with different concentrations of gold nanoparticles (GNPs) as dose enhancement agent by Monte Carlo (MC) calculations. Materials and Methods: The MC code of MCNPX 2.6.0 was used to modeling of COMS standard eye plaque loaded with 24 125I sources (6711 model) located on the sclera of modeled eyeball with detailed structures and materials. A choroidal melanoma tumor was simulated and loaded with different concentrations of spherical gold GNPs (50 nm in diameter). Dose enhancement factors (DEFs) of ocular components were calculated. Results: The dosimetric properties of 125I source (6711 model) and dose distribution of COMS standard eye plaque were calculated successfully as recommended by TG-43U1; AAPM. Loading of tumor with GNPs increased dose to the tumor and decreased dose to the normal tissues; the DEF was increased up to 2.280 and 2.030 for tumor apex, while it was decreased to 0.760 and 0.892 for macula and for gold-tumor mixture and nanolattice distributions, respectively. Conclusion: Loading the choroidal tumor volume with GNPs improves the dose distribution by increasing dose to the tumor and decreasing dose to the health components in ocular brachytherapy with 125I seeds 20-mm COMS plaque.



How to cite this article:
Zabihzadeh M, Rezaee H, Hosseini SM, Feghhi M, Danyaei A, Hoseini-Ghahfarokhi M. Improvement of dose distribution in ocular brachytherapy with 125I seeds 20-mm COMS plaque followed to loading of choroidal tumor by gold nanoparticles.J Can Res Ther 2019;15:504-511


How to cite this URL:
Zabihzadeh M, Rezaee H, Hosseini SM, Feghhi M, Danyaei A, Hoseini-Ghahfarokhi M. Improvement of dose distribution in ocular brachytherapy with 125I seeds 20-mm COMS plaque followed to loading of choroidal tumor by gold nanoparticles. J Can Res Ther [serial online] 2019 [cited 2019 Oct 17 ];15:504-511
Available from: http://www.cancerjournal.net/text.asp?2019/15/3/504/244484


Full Text



 Introduction



Delivering of killing dose to the tumor volume and minimum dose to the peripheral health tissues is the major challenge in radiation therapy. The therapeutic radiation dose prescription is depending to the type and stage of tumor and the required dose is delivered by determination of radiation time for different modalities and techniques.[1]

Compliance of normal components of the eye due to their anatomical localization and radiation sensitivity has been remained as a concerning obstacle in teletherapy treatments.[2],[3] The potential of rapid dose falloff and positioning of small sealed radioactive seeds adjacent and/or inside the tumor volume introduce brachytherapy as an effective radiation treatment.[3],[4] Brachytherapy using removable ophthalmic plaques loaded with suitable number of small sealed radioactive seeds adjacent to the eye's tumor has been widely used as a high therapeutic gain modality with the potential of vision saving in contrast to enucleation.[5]

Although brachytherapy has been used to treat intraocular tumors since 1930[6] and several plaque sources such as 60 Co,90 Sr,103 Pd,106 Ru,125 I, and 131 Cs have been reported,[7],[8],[9],[10]125 I plaque brachytherapy has become the selected treatment for medium-sized choroidal melanoma. However, beside of elaborate efforts for redesign and optimization of 125 I plaque brachytherapy, there are some posttreatment complications in relevance to the ocular oncologist.[2]

Recently, the nanotechnology has been rapidly used in various scientific fields; instantly in the medical diagnostic and therapeutic fields such as infrared activated thermal therapy,[11] diagnostic imaging,[12] targeted drug and gene delivery, and molecular labeling [13],[14] due to their high penetration and retention properties into the interested regions. Currently, loading of tumor volume with high-Z nanoparticles (NPs) as radiosensitizer agent was suggested to enhance tumor dose during radiation therapy.[15],[16],[17],[18],[19],[20] From the investigated NPs as radiation dose enhancement agent, gold NPs (GNPs) have been more interested due to the nontoxicity, acceptable biocompatibility, and high atomic number (Z = 79).

As an experimental study, Ngwa et al.[21] examined the effect of GNPs on HeLa cells which were irradiated by a plaque containing 125 I seeds. They reported that residual dose enhancement factor (rDEF) is dependent on deposited dose and as well dose rate. The rDEF had ranges from 1.7 to 2.3 for 2.1–4.5 cGy/h dose rates. In a Monte Carlo (MC) study,[22] enhancement of deposited dose in 1 cm from the center of the 125 I source was calculated as 116 and 68% for 18 and 7 mg Au/g, respectively. The effect of GNPs on radiosensitivity of BAEC cells was explored in combination with 80 kVp X-rays where yielded a high DEF (about 20) in comparison to 150 kVp.[23] In addition, an in vivo study proved HER2 conjugated GNPs can lead to a significant inhibition in tumor growth of breast tumor-bearing mice.[24] Hainfeld et al.[25] showed that 1.9-nm GNPs plus 100 kVp radiation result in 56% long-term survival versus 18% for those of irradiation alone. According to the literature, X-rays with low keV energies are able to more sensitizing tumor cells to the radiation. It can be explained by occurrence of photoelectric interaction in keV energy range more than MeV energies. This interaction yields photoelectrons and Auger electrons which mainly deposited their energies locally and have a key role in produced radiosensitivity by GNPs.[1]

In summary, to applying GNPs as radiation dose enhancer in an optimized proposed ocular brachytherapy by ocular plaque, a full detailed dosimetry data is needed to implantation in treatment planning system. To this end, in this study, improvement of dose distribution in a modeled eyeball followed to loading of an ocular melanoma tumor with different concentrations of GNPs was investigated by MC calculations. In addition, two models of GNPs distribution (mixture and uniform dispersion by lattice option of the code) were considered for all calculations.

 Materials and Methods



In this study, the MC code of MCNPX 2.6.0[26] was used to modeling of 20-mm COMS standard ocular plaque loaded with 24 125 I sources (6711 model), in which located frontally on the modeled eyeball with detailed structures and materials. All physics aspects were implanted in programs to transport of photon and electrons within plaque and ocular structures. The f6, *f8, and mesh tallies were used to calculate dosimetric properties of kerma and absorbed dose. The photon and electron transport energy cutoff was set to 1 keV in all input programs. No variance reduction technique was used. The maximum error in calculating and reporting of data was <3%.

125I brachytherapy source (6711 model)

The 125 I brachytherapy source (6711 model) has an average energy of 28.37 keV and half-lifetime of 59.4 days that makes it suitable for radiation treatment of choroidal melanomas. The energy spectrum of 125 I source recommended by TG-43U1; AAPM [27] was implemented in MC programs; only X-ray emitted spectrum of source was used. A silver cylindrical marker (with radius of 0.254 mm, length of 2.8 mm, and density of 10.5 g/cm 3) coated by bromide iodine, Br5I2(density of 6.245 g/cm 3 with a thickness of 2 μm) was centered in it. The effective length of source with convex angle of 45° and radius of 0.045 mm is 2.8 mm. This assembly is encapsulated by a titanium cover (density of 4.54 g/cm 3) with hemisphere end limits and filled by argon gas with density of 1.784 g/cm 3 [Figure 1].{Figure 1}

Calculation the TG-43U1; AAPM dosimetric parameters of 125 I brachytherapy source (6711 model)

The dosimetric parameters recommended by TG-43U1; AAPM [27] were calculated for the 125 I brachytherapy source (6711 model) and compared with reported data in literature to validate the modeled source. As recommended by the TG-43U1; AAPM,[27] the dose rate at a given point (r, θ) around the cylindrical symmetry source relative to its geometric center is given by equation 1:

[INLINE:1]

where r is the radial distance from the source center to the point of interest, θ is polar angle with respect to the longitudinal axis of the source, Sk is the air-kerma strength in unit of U = cGycm2h–1, Λ is the dose rate constant in unit of cGy h–1U–1, G(r, θ) is the geometry factor that accounts for the spatial distribution of the radioactive material, g(r) is the radial dose function that accounts for radial dependence of photon absorption and scatter in the medium along the source longitudinal axis, F(r, θ) is the anisotropy factor that accounts for the radial and angular dependence of photon absorption and scatter in the medium, and the reference point (r0, θ0) is located on the transversal axis at r0= 1 cm and θ0= π/2. The needed parameters to calculated equation 1 followed by equations 2, 3, 4, and 5.

To calculate source air-kerma strength, Sk, the 103 I source was centered in a vacuum sphere with radius of 150 cm and surrounded by an air ring detectors of 1 cm height and 1 cm thickness. To minimize the fluctuation, the inner radius of the air ring detector was changed from 10 to 100 cm with interval of 10 cm in separate programs and average of calculated air-kerma rates was reported.

[INLINE:2]

[INLINE:3]

To calculate the radial dose function, g(r), the 103 I source was centered in a large enough cubic water phantom with dimensions of 30 cm 3 (to mimic the full scatter conditions) and the absorbed doses were scored in concentric rings with thickness of 0.5, 1, 5, and 10 mm for r < 0.3 cm, 0.3 < r < 1 cm, 1 < r < 10 cm, and r > 10 cm, respectively. The rings were bonded by 88° and 92° conics along the transversal axis of the source to compromise between the desired accuracy and the spatial resolution of the calculated doses.

[INLINE:4]

To calculate F(r, θ), the phantom was divided only in one quarter, due to symmetry of source geometry to minimization of calculating errors, by concentric rings with thickness of 0.5 mm on the included plan of longitudinal axis of source. The rings were bounded with two oblique cones (with interval angle of 1°) from 0° to 90°.

[INLINE:5]

To minimize statistical uncertainties, 1×108 and 1×109 photon histories were simulated to calculate Sk and g(r) or F(r,θ), respectively. The statistical uncertainties were <1% for r < 5 cm, <2% for 5 < r < 10 cm, and 3% for 10 < r < 20 cm.

Modeling of orbit with a choroidal melanoma tumor

Choroidal melanoma is one of the uvea melanoma as the malignant primary intraocular tumor that originates from the blood vessel layer of the orbit. Due to anatomical orbit's location, adjacent of its radiosensitive components and importance of vision saving, design an optimized brachytherapy plan to treat the intraocular tumors is highly depends on its size and apical height. As recommended by literature, the plaque brachytherapy is an optional procedure to treat the intraocular tumor (with the apical height of 2.5–10 mm and the basal diameter of ≤16 mm) associated to saving of orbit. An adult orbit globe was modeled by intersection of suitable surfaces. The sclera, choroid, and retina were simulated as concentric spheres, each with thickness of 1 mm, by equation 6:

[INLINE:6]

where Ri of 1.2, 1.1, and 1.01 was considered for the sclera, choroid, and retina, respectively. A choroidal melanoma tumor located on the equator temporal to the orbit was modeled by intersection of an ellipsoid, equation 7, with the interior spherical surface of the sclera. The cornea was built by two concentric ellipsoidal surfaces, equation 8, that intersected by the external surface of sclera. The lens was modeled by intersection of the interior spherical surface of sclera by an ellipsoidal surface with equation 9. The aqueous humor was modeled by intersection of the interior surface of the cornea with the exterior surface of the sclera. The vitreous body was modeled as the volume encapsulated by the interior surface of the retina. The schematic view of the modeled eye was shown in [Figure 1].

[INLINE:7]

[INLINE:8]

[INLINE:9]

The elements and density (g/cm 3) of different components of the modeled eye were collected in [Table 1].{Table 1}

Modeling of 20-mm COMS ocular plaque

In this study, a 20-mm COMS ocular plaque including of 24 seed of 125 I (6711 model) was used [Figure 1]. This standard COMS plaque was made of an outer gold alloy modular (composed of 77% Au, 14% Ag, 8% Cu, and 1% Pd with density of 15.8 g/cm 3) and an inner plastic seed career (composed of 39.9% Si, 28.9% O, 24.9% C, 3.6% H, and 0.005% Pt with density of 1.12 g/cm 3 and an effective atomic number of 11). The inner radius of plaque is 12.3 mm and the outer radius of gold alloy (with thickness of 0.5 mm) is 15.05 mm. The 24 validated 125 I sources (6711 model) were arranged simultaneously in the defined slits (with full detailed coordinates) on the 20-mm COMS eye plaque by setting the proper parameters implemented on the SDEF option of MCNPX 2.6.0[26] code. To avoid of hotspots, a separation distance of 1 mm between the outer front surface of plaque and the outer layer of eye is recommended.

Loading of tumor with gold nanoparticles (gold-tumor mixture or real nanolattice distribution)

GNPs with concentration of 5, 15, and 30 mgr Au/gr of tumor tissue were distributed in the tumor volume. Two models as the gold-tumor mixture distribution (simple model that needs no long time to run) and nanolattice distribution (real model that is accurate but is time-consuming to run) were simulated to loading of tumor with gold spheres of 50 nm in diameter. This size was selected because the overall particle's size, in clinical practice, must be large enough to avoid renal clearance but small enough to penetrate into the cell volume.[28],[29] For the gold-tumor mixture distribution, the mass of tumor loaded by GNPs was defined by tumor components and their weighted factors which modified in the presence of known concentration of GNPs. In the case of real nanolattice distribution, lattice option of MCNPX code was used to voxelized the tumor volume with different grid sizes depend on the used GNPs concentrations. For example, the grid size for concentration of 5 mgr 79 Au/gr was 1.13 × 10−4 cm. More details of such these GNPs distribution models could be found in our previous study.[15] Finally, the effect of GNPs presence in tumor volume on dose profile was investigated. The DEF was defined as ratio of the dose calculated in the presence of GNPs to the dose calculated in the absence of GNPs by equation 10:

[INLINE:10]

 Results



Benchmark of 125 I brachytherapy source (6711 model)

The dosimetric parameters recommended by AAPM report TG-43U1[27] were calculated for 125 I brachytherapy source (6711 model). The relative errors of the calculated air-kerma rates were <0.02% for all radial distances and the resulted fluctuations of the air-kerma strengths (SK) were within 0.3%. The calculated air-kerma strength and air-kerma constant (averaged on all air-kerma strengths) were 0.557 cGycm2h-1mCi−1 and 0.887 cGyh−1U−1, respectively.

The calculated radial dose function, g (r), compared to the data reported by Rivard [30] and Rodríguez et al.[31] was depicted in [Figure 2]. The fitted curve on our data was a forth degree equation of g (r) = −0.0002r 4 + 0.0046r 3 – 0.025r 2 – 0.093r + 1.0918 with correlation coefficient of 0.9987.{Figure 2}

The calculated anisotropy functions, F(r, θ), were in good agreement with the reported data by Rivard [30] and Rodríguez et al.[31] as shown in [Figure 3]. Only data for r = 3 cm is depicted.{Figure 3}

The isodose curves for the 20-mm COMS eye plaque loaded with 24 125 I brachytherapy sources (6711 model) are shown in [Figure 4]. All calculated doses were normalized to dose at the apex of the tumor.{Figure 4}

Absorbed dose in an eyeball with choroidal melanoma tumor loaded with gold nanoparticles

The absorbed dose curves on the central axis of plaque inside the eyeball followed to loading of tumor with GNPs concentrations of 5, 15, and 30 mgr 79 Au/gr are depicted in [Figure 5]. The related curve without GNPs is shown to the comparison. All doses were averaged on each voxel and normalized to per emitted photon from all 24 sources. The outputs of *f8 tally in unit of MeV/g were converted to Gray (J/kg). The maximum uncertainty to calculate absorbed dose was <2.5%. Without loading of GNPs, the absorbed dose (Gy) on central axis has a maximum value at the entrance surface of sclera and decrease slowly with depth (d, cm) inside the eyeball by a 4° polynomial equation as dose (Gy) = 1E-17d 4-7E-16d 3 + 1E-14d 2-2E-13d + 8E-13; R2 = 0.9987. Loading of tumor volume with GNPs significantly increases the absorbed dose of tumor as depend to concentration of GNPs. The calculated doses are slightly higher for gold-tumor mixture distribution of GNPs compared to the nanolattice distribution.{Figure 5}

In addition, the DEFs for both mixture [Figure 6]a and lattice [Figure 6]b conditions were obtained for voxels located on the central axis of the beam. For all concentrations, the DEFs were >1 inside the tumor and <1 for extra-tumoral regions. The calculated DEFs also showed a dependency manner to GNPs concentration. Furthermore, the DEFs for all parts of the eye were calculated for concentrations of 5, 15, and 30 mgr Au/gr [Table 1]. Increasing of GNPs concentration in tumor volume result higher dose to the tumor and lower dose to the normal components; for example, the DEF increase up to 2.280 and 2.030 for tumor apex while it decreases to 0.760 and 0.892 for macula and gold-tumor mixture and nanolattice distributions, respectively. From the table, as expected, the maximum of DEFs was for the tumor base region, highest concentration, and mixture condition. The DEFs of the mixture distribution were slightly higher than those of nanolattice distribution. For comparison, the average of difference between mixture and lattice distribution have been also indicated in the table.{Figure 6}

 Discussion



In this study, the effect of the presence of the GNPs on radiation dose distribution in combination to an ocular 125 I radioactive source was assessed for a tumor-contained eyeball model. The calculations were carried out for two different types of distributions of the GNPs (mixture and nanolattice) into the tumor.

Our data for dose rate constant, radial dose function [Figure 2], and anisotropy function [Figure 3] are in good agreement with the data reported in literature [30],[31] where the dose distribution of 125 I radioactive source is calculated as recommended by TG-43U1.[27] Rodríguez et al.[31] and Rivard [30] calculated the air-kerma constant as 0.867 cGyh−1U−1 and 0.887 cGyh−1U−1 that are in good agreement with our results.

However, the treatment of choroidal melanoma in the eyeball by the 20-mm COMS eye plaque loaded with 24 125 I radioactive seeds (6711 model) was modeled successfully. The prescribed dose was normalized to the tumor apex. As illustrated in [Figure 4], dose values decrease rapidly with increase of distance from plaque so that the prescribed therapeutic dose could be delivered to the whole tumor volume. The tumor volume (with apex of 0.55 cm and base of 1 cm) is covered relatively well by isodose curve of 100%.

Loading of tumor with high-Z GNPs increase dose in depths inside the tumor volume while decrease dose in depths beyond the tumor [Figure 5]. These results were expected as photoelectric interaction probability is proportional to Z 3/E 3, where Z and E are atomic number of the irradiated mass and energy of emitted photon, respectively.[1] For the low-energy emitted from 125 I sources, the increased effective atomic number of tumor volume due to the presence of high-Z GNPs could shift a considerable amount of interactions to the photoelectric interaction that was Compton interaction in the case of no GNPs loading. As well known, the rapid dose falloff with depth is one of the main advantages of low energy brachytherapy sources to protect of the deeper health tissues that could be enriched by loading of tumor with GNPs.

As shown in [Figure 6], the calculated DEFs versus depths, DEF >1 is limited to the tumor depths and its magnitude depends to the concentration of GNPs. Obviously, increasing the GNPs concentration increases the probability of photon interaction with gold and results more photoelectric phenomena; however, loading of tumor by GNPs is limited by their toxicity in high concentrations. In consistency with our results, the dependency of the dose enhancement due to the presence of GNPs has been reported by other researchers. Rahman et al.[23] utilized GNPs as a radiosensitizer factor plus irradiation of a superficial X-ray therapy unit and concluded higher concentration could lead to a more killing effect on BEAC cells. In a MC study by Cho et al.,[22] a high DEF was achieved for 18 mgAu rather than 7 mgAu. Moreover, it has been demonstrated that survival fraction of the HeLa cells has a direct relation to the GNPs concentration.[32] On the other hand, it has been shown that dose enhancement and radiosensitization of NPs are influenced by the beam's quality, diameter, and coating materials, etc.[33]

In comparison to a study by Cho et al.,[22] the calculated DEF (2.16) for concentration of 18 mgAu/g and 125 I as a source, our calculated DEF for concentration of 15 mgAu/g have a good consistency with their results. Moreover, Lechtman et al.[34] showed that among the various keV and MeV radiation sources,125 I requires to lowest concentration of the 1.9 nm GNPs to double the prescription dose. In another MC study,[35] the maximum DEF was achieved for 125 I source as 3.43 which is concordant with our calculated DEF at the tumor base. Recently, Brivio et al.[36] implemented three plans for treatment of prostate by GNPs plus 125 I radioactive sources. They found that for mixture condition, the calculated DEF is >2. The differences in calculated DEFs could be attributed to the GNPs size and concentration and variety in the distribution of them into the tumors.

From [Figure 6], DEF <1 for the presence of GNPs in the tumor volume means dose would be decreased in shadow depths behind the tumor volume compared to the absenence of GNPs; the DEF is high in the entrance depth of tumor and decrease with depth inside the tumor and then decrease rapidly at depths behind the tumor volume that could be interested to obtain the better therapeutic gain in brachytherapy. After iodine brachytherapy (IBT) of choroidal melanoma, there are frequent side effects related to radiation damage to ocular tissues uninvolved by the tumor.[3] These decreased doses to the health ocular structures interested to decrease of such complications. Considering the real model for the distribution of GNPs (nanolattice distribution) to mimic loaded tumor with GNPs is more accurate to calculate absorbed dose; from [Figure 6], however, there is no significant difference between the DEFs calculated from two models in clinical usage, but nanolattice model needs more running time for MC calculations.

The usual tumoricidal dose is 80–100 Gy at the tumor apex, while it is recommended that a 1500-Gy scleral dose should not be exceeded.[37] Puusaari et al. reported major complications and vision loss after IBT and redesigned brachytherapy protocol to reduce these complications and vision loss after IBT of uveal melanoma.[3] From [Table 2], followed to loading of tumor with GNPs, the calculated DEFs for different components of modeled ocular are less than unity that means better protection of nontargeted tissues compared to conventional brachytherapy.{Table 2}

Our results indicate that loading of tumor with optimized concentration of GNPs associated by the conformal positioning of 125 I seeds and proper selecting of collimating plaque design have potential to increase dose delivered to the tumor with minimum complications to the health ocular components due to lower received doses. Considering the potential ability of the GNPs on radiation enhancement of the ocular tumors in combination with low-energy brachytherapy sources, utilizing targeting strategies such as conjugating the GNPs with tumor-specified antibodies or aptamers could lead to higher accumulation of the GNPs into the target volume and consequently cause an intensive damage to the tumor. In fact, GNPs-treated tumors need a lower dosage of radiation to achieve a given radiobiological end-point compared to untreated ones.

 Conclusion



In this study, a full detailed model of ocular brachytherapy treatment for choroidal melanoma tumor by 125 I radioactive seeds 20-mm COMS eye plaque was simulated successfully with and without GNPs. Loading the target volume with high-Z GNPs followed to irradiate with low-energy photons of radioactive sources have potential to improve the dose distribution of ocular brachytherapy as increased dose to the tumor volume and decreased dose to the health tissues. However, for clinical application, use of nontoxic concentration of GNPs and apply of targeting strategies to limit of GNPs uptake only by tumor volume needs further in vitro and in vivo studies.

Acknowledgment

This report was extracted from Hadi Rezaee's Msc thesis results. The thesis was financially supported by Vice-Chancellor for Research Affairs of Ahvaz Jundishapur University of Medical Sciences (Grant number: IORC-9201).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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