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ORIGINAL ARTICLE
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Super-selective intra-arterial platinum-based chemotherapy concurrent with low-dose-rate plaque brachytherapy in the treatment of retinoblastoma: A simulation study


1 Department of Biomedical Physics and Engineering, School of Medicine; Advanced Health Technologies Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Medical Physics, School of Medicine, Jiroft University of Medical Sciences, Jiroft; Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
3 Department of Medical Physics and Biomedical Engineering, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission17-May-2019
Date of Acceptance23-Oct-2019
Date of Web Publication26-Sep-2020

Correspondence Address:
Hadi Rezaei,
Department of Medical Physics and Biomedical Engineering, School of Medicine, Tehran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_340_19

 > Abstract 


Objective: Retinoblastoma is the most common cancer among children under 5 years of age. The common conventional methods for the treatment of retinoblastoma include chemotherapy and brachytherapy (BT). This study investigated the concurrent use of BT with125 I and103 Pd sources and chemotherapy with platinum-based chemotherapy drugs for retinoblastoma.
Materials and Methods: The absorbed doses in different parts of the eye were measured with and without platinum. Platinum concentrations of 5, 7.5, 10, and 15 mg/g were evaluated, and the dose enhancement factors (DEFs) were calculated for different cases.
Results: For the125 I source, the DEFs at the tumor apex were 1.49, 1.67, 1.81, and 1.97 at concentrations of 5, 7.5, 10, and 15 mg/g, respectively. The DEF decreased dramatically beyond the apex at 0.85 cm from tumor base and was 0.87, 0.82, 0.76, and 0.63 for the abovementioned concentrations, respectively. For the103 Pd source, the DEFs were 1.15, 1.24, 1.21, and 1.07, respectively, at the apex and 0.76, 0.65, 0.56, and 0.39, respectively, beyond the apex.
Conclusions: Our results showed that the concurrent use of low-dose-rate plaque BT and platinum-based chemotherapy significantly increased the tumor-absorbed dose and decreased the absorbed dose in areas outside the tumor and the treatment time.

Keywords: Concurrent chemo-brachytherapy, low-dose-rate plaque brachytherapy, Monte Carlo simulation, platinum-base chemotherapy, retinoblastoma



How to cite this URL:
Mostaghimi H, Ahmadabad FG, Rezaei H. Super-selective intra-arterial platinum-based chemotherapy concurrent with low-dose-rate plaque brachytherapy in the treatment of retinoblastoma: A simulation study. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=296268




 > Introduction Top


Retinoblastoma is the most common primary intraocular malignancy among children, mostly those under 3 years of age.[1],[2],[3],[4],[5] This cancer is responsible for more than 3000 annual deaths worldwide.[6] While the survival rate is more than 95% in developed countries, it is below 50% in developing countries.[7] The standard treatment modality for retinoblastoma has been enucleation, external beam therapy, or a combination of both.[8] However, in recent years, globe salvage and functional vision preservation are also considered in addition to saving lives.[9] In spite of its positive effects, the application of external beam therapy has decreased due to significant side effects, including visage deformation, cataract, retinopathy, and secondary malignancies.[10] Therefore, systemic chemotherapy (computed tomography [CT], also known as chemoreduction) coupled with appropriate focal therapy (e.g., plaque radiotherapy) became an alternative approach.[11] However, systemic CT has its own complications, including transient neutropenia, anemia, organ toxicity, and hepatotoxicity, particularly because most patients are growing children.[12] Moreover, drug delivery to the tumor is restricted. For these reasons, the innovative superselective intra-arterial (IA) CT method was developed and is now being performed in more than 30 countries,[13] and multiple studies have reported its high success rate.[8],[12],[13] The main idea behind this technique is to maximize drug delivery and minimize systemic negative effects that lead to high local dosage and very high rates of response.[14],[15],[16],[17],[18],[19],[20],[21],[22] Carboplatin is the most common platinum-based (Pt-based) CT drug used in superselective IA CT, separately or in combination with topotecan or melphalan.[8],[12],[21],[23] Carboplatin is administered in dosages ranging from 15 to 30 mg per eye, which is equivalent to 7.5–15 mg platinum with regard to the carboplatin: platinum molar mass ratio (371:195).[13],[21],[24] If this method is performed in combination with plaque brachytherapy (BT), this amount of platinum can significantly affect the tumor and overall ocular-absorbed dose. Consequently, it is necessary to evaluate dose changes caused by the concurrent use of super-selective IA Pt-based CT with low-dose-rate (LDR) plaque BT. Due to the impractical dosimetry of human eye tissue, we simulated the human eye, its tumor, and 20-mm COMS plaque including 24 LDR seeds, using Monte Carlo N-Particle eXtended (MCNPX) code and calculated the absorbed dose, dose rate, and dose enhancement factor (DEF) for different Pt concentrations.


 > Materials and Methods Top


In this study, MCNPX code version 2.6.0 (Los Alamos National Laboratory, New Mexico, USA) was used to simulate the human eye and its tumor (with 0–15 mg Pt), 20-mm COMS plaque loaded with 24125 I (Amersham, model 6711) and103 Pd (Theragenics, model 200) BT seeds. The absorbed dose, dose rate, and DEF were obtained from the MCNPX outputs for different Pt concentrations (equivalent to 15–30 mg carboplatin) in different parts of the eye.

Platinum concentrations

Several recent studies have used carboplatin alone or in association with other antineoplastic agents (e.g., melphalan, topotecan) in superselective IA CT for retinoblastoma. Gobin et al.[21] reported 15 mg carboplatin to be the minimally effective dose, while a 50 mg dose resulted in inflammatory reactions. The authors have also reported the administration of 30 mg carboplatin as a standard dose for a 3-year-old child. Klufas et al.[13] presented a comprehensive article on the management of retinoblastoma, suggesting the administration of 15–30 mg carboplatin by IA CT. The chemical formula of carboplatin is C6H12N2O4 Pt, with a molar mass of 371 g/mol. Carbon, hydrogen, nitrogen, and oxygen are the organic elements comprising human body and ocular tissues [Table 1]. Therefore, these elements cannot significantly affect the eye or the tumor-absorbed dose. However, the heavy metal Pt, with a high atomic number that constitutes about half of the carboplatin molar mass, can significantly affect the eye and its tumor-absorbed dose. Therefore, the administration of 15–30 mg carboplatin is approximately equivalent to the accumulation of 7.5–15 mg Pt that is distributed in ocular tissues, including the tumor. In this study, 5, 7.5, 10, and 15 mg Pt were considered in our simulations in order to calculate the absorbed dose, dose rate, and DEF in the tumor and in different parts of the eye in the case of concurrent superselective IA CT and plaque BT with LDR seeds. Considering the similar mean energy of various125 I and103 Pd seeds models and the molar mass of other Pt-based CT drugs, this evaluation can also be considered for other125 I and103 Pd models and Pt-based CT drugs.
Table 1: Elemental composition and mass densities of human eye tissues

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Human eye

Using some mathematical equations, the human eye and its components were simulated using MCNPX code. The ocular body is made of three main concentric spherical shells, namely, the sclera, choroid, and retina, each with the thickness of 1 mm (and defined by follow equation).

([Ri–0.1) ≤ [x]2+ [y + 1.6)]+ [z]2)

The inner radii of these shells were R1 =1.23, R2 =1.13, and R3 =1.03 cm, respectively. The vitreous body was defined as the inner surface of the retina, which was a sphere with a 0.935 cm radius. The shells were centered in the middle of the eye (The vitreous body equation is below):

([x]2+ [y + 1.6]2+ [z]2 ≤ 0.935)

The cornea is an elliptical shell made of two ovals and the outer surface of the sclera.

(The following equations are defined the cornea that made of two ovals and the outer surface of the sclera):

(1.56 [x]2 + 1.62 (y + 1.6)2 + 1.66 [z − 0.73]2 ≥ 1)

(1.29 [x]2 + 1.39 (y + 1.6)2 + 1.52 (z − 0.73]2 ≤ 1)

([x]2+ [y + 1.6]2+ [z]2≥ [1.22]2)

The ocular lens (as below equations) was formed by an oval surface and the spherical surface of the choroid:

(2.98 [x]2 + 2.98 [y + 1.6]2 + 9.15 [z − 0.73]2 ≤ 1)

([x]2+ [y + 1.6]2+ [z]2≥ [1.22]2)

The inner surface of the cornea and outer surface of the sclera constituted the anterior chamber.

The tumor was simulated by cutting the inner surface of the retina and a semi-ellipsoid with an apex with a 0.55 cm height:

(0.444 [x]2 + 0.04 [y + 3.6]2 + 0.444 [z − 0.73]2 ≤ 1)

([x]2+ [y + 1.6]2+ [z]2≤ [1.22]2)

The surfaces were defined using quadratic equations as reported by Yoriyaz et al.{Yoriyaz, 2005 #29}[25] The elemental compositions and mass densities of different parts of the human eye are listed in [Table 1].[26],[27] (The modeled eye was placed in a spherical water phantom with 5 cm radius).

2.3125I and103Pd sources

Both125 I and103 Pd seeds were simulated based on actual three-dimensional seeds and benchmarked in our previous studies.[28],[29],[30],[31] The125 I seed (Amersham, model 6711) (with a mean photon energy of 28.37 keV) is a titanium capsule filled with Argon gas and included a silver cylindrical marker coated with a 2-μm layer of Br5I2[Figure 1]a. The103 Pd (Theragenics, model 200) seed (with mean photon energy of 20.74 keV) was a titanium capsule that included two cylindrical graphite rods covered by a thin layer of radioactive palladium; the rods were separated by a lead marker [Figure 1]b. All details related to these seeds, including their dimensions, densities, energies, and mean lifetime, are described in detail in our previous studies.[28],[29],[30],[31] The dosimetric parameters of the seeds were obtained based on the Task Group No. 43 (TG-43) protocol and validated sources were loaded in the COMS plaque.[32]
Figure 1: (a) 125I brachytherapy source model 6711, (b) 103Pd brachytherapy source model 200

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COMS plaque

The 20-mm COMS plaque was simulated based on TG-129 protocol,[33] including LDR seeds. The plaque was loaded with 24125 I seeds one time and with 24103 Pd seeds another time. The standard COMS plaques are generally made of gold alloy and a silastic seed carrier. The gold alloy has a mass density of 15.8 g/cm3 with 77% Au, 14% Ag, 8% Cu, and 1% Pd. The silastic carrier has density of 1.12 g/cm3, effective atomic number of 11.0, and elemental composition of Si (39.9%), O (28.9%), C (24.9%), H (6.3%), and Pt (0.005%). [Figure 2] shows this plaque that was loaded with 24 seeds and pinned with the eye phantom. The voxels, in this study, were considered along the plaque's central axis, from the tumor base to the opposite side at the sclera.
Figure 2: Eye model pinned with 20-mm COMS plaque loaded with brachytherapy seeds

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Calculation of task group no. 43 parameters

The dosimetry parameters of both seeds were calculated using the MCNPX code according to the AAPM TG-43U1 protocol[34] included in the following equation:

Ḋ (r, θ) = SkΛ (G [r, θ]/G [r0, θ0]) g (r) F (r, θ)(1)

Where Ḋ (r, θ) and Sk are dose rate and air-kerma strength of the source, respectively; Λ is the dose rate constant at the reference point (1 cm, π/2); and G (r, θ), g (r), and F (r, θ) are the geometry function, radial dose function, and anisotropy function, respectively.

Absorbed dose, dose rate, and dose enhancement factor

The purpose of placing the COMS plaque, including LDR BT seeds, was to deliver an 85-Gy dose to the prescription point (tumor apex). In simulation studies, the absorbed dose and dose rate were calculated as the product of the dose per source particle (dose per history) according to the coefficient conversion factor, source strength, and treatment time. Since our goal was to compare two cases (with and without Pt) and not the calculation of the absolute dose, the dose per history was adequate due to the similarity of the other coefficients between the cases. Considering the energy range of125 I and103 Pd seeds and the voxel size, there was electron equilibrium, and the collision kerma was a good estimation of the absorbed dose. An F6 track-length estimator was used to obtain the dose per history. In addition, the dose rate per source strength (U) was calculated as the product of the F6 tally ([the tally that results energy deposition averaged in a cell]) outputs by the air-kerma strength per history and a conversion factor coefficient. Cutoff energy for photons and electrons was 5 and 10 keV, respectively. The default cross-section of the MCNPX was used, and the particle interactions were treated by ENDF/B library. All programs were implemented to obtain acceptable accuracy (<5%).

Total absorbed dose rate is governed by equation 2 as follows:

Total absorbed dose rate (cGy/h) = MC output (MeV/g per photon) × 1/sk(cm2·MeV/g per photon)−1 × Sk(U/seed) × Ns(2)

Where MC output is the F6 tally output (dose per history), sk is the air-kerma strength per history obtained from the Monte Carlo calculations, Sk is the initial air-kerma strength of each source in the treatment, and Ns is the total number of seeds.


 > Results Top


AAPM TG-43U1 dosimetric parameters were considered in order to simulate and validate the LDR125 I and103 Pd seeds. These seeds have been simulated, and their dosimetric parameters are reported in our previous studies.[28],[29],[30],[31] The validated sources were loaded in the 20-mm COMS plaque to obtain the expected results. [Figure 3] shows the calculated absorbed dose rates as functions of the distance along the central axis of the plaque for different Pt concentrations in the BT plaques with125 I and103 Pd seeds, respectively. [Figure 4] shows the DEF per distance for various Pt concentrations, respectively. [Table 2] shows the DEFs in different parts of the eye according to the Pt concentrations.
Figure 3: Dose rate (cGy.h-1.U-1) versus distance at plaque's central axis for various Platinum concentrations for (a) 125I source and (b) 103Pd source

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Figure 4: Dose enhancement factor at plaque's central axis versus distance for various Platinum concentrations for (a) 125I source and (b) 103Pd source

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Table 2: Dose enhancement factor at different parts of the eye for different platinum concentrations and brachytherapy seeds

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 > Discussion Top


This study evaluated the change in ocular dose following the concurrent use of super-selective IA Pt-based CT and LDR plaque BT with125 I and103 Pd sources. Based on child eye dimensions, a human eye and tumor with different Pt concentrations and a 20-mm COMS plaque loaded with 24 LDR seeds were simulated. The tumor was defined to have an oval base with a 2-cm diameter and 0.65 cm height, originating from the retina. The BT seeds –125 I (Amersham, model 6711) and103 Pd (Theragenics, model 200) – were completely simulated and benchmarked in our previous studies, with acceptable dosimetric parameters in good agreement with other studies.[27],[32],[33] (For example the results of radial dose function in comparison with TG-43U1[34] report indicated that in small distances than 1 cm maximum discrepancy for103 Pd and125 I was 1.5% and 1.8%, and for higher than 1 cm distances was 5% and 1.4%, respectively).

Using Equation 2, the dose rate per source strength (cGy/h/U) was calculated along the central axis of the plaque [Figure 3] and in some critical parts of the eye [Table 2]. The initial composition of the eye and its tumor was considered water equivalent (Pt concentration = 0 mg); its dose rate functions are indicated As purple lines in [Figure 3]a and [Figure 3]b. These functions indicate a reverse correlation (reduction) according to the distance squared. Based on multiple references, 5, 7.5, 10, and 15 mg Pt (equivalent to 10, 15, 20, and 30 mg carboplatin) are generally used in superselective IA CT. Therefore, we used these Pt concentrations in our simulations. The dose rate functions related to these doses are shown in [Figure 3]a and [Figure 3]b for125 I and103 Pd sources, respectively. The results indicated that Pt-based CT resulted in an increased tumor dose rate and a steep reduction outside the tumor.125 I and103 Pd seeds are LDR sources with mean photon energies of 0.028 and 0.021 MeV, respectively. Due to the low energy of the emitted photons and high atomic number of Pt, the probability of a photoelectric effect increases with Pt. Various Pt concentrations (5, 7.5, 10, and 15 mg) were added to the tumor and the dose rate was calculated at different points within and outside of the tumor. As shown in [Figure 3]a and [Figure 3]b, the dose rate decreased with increasing depth at the first voxels of the sclera and suddenly increased on entering the tumor (with Pt) area. The dose enhancement at this area was due to the photoelectric effect, which was increased by the presence of Pt. The dose rate reduced dramatically as it entered the area beyond the tumor (d = 0.85 cm). The high atomic number of Pt leads to significant photon absorption and reduced photon fluence, which leads to dose reduction in areas beyond the tumor. The enhancement and reduction in the absorbed dose rates were compared to those in simulations without Pt. In addition, the dose rate increased in the tumor and decreased in areas beyond the tumor with increasing Pt concentration.

[Figure 4]a and [Figure 4]b show DEF as a function of depth along the central axis of the tumor for various Pt concentrations (equivalent to Pt-based CT drugs) for125 I and103 Pd sources, respectively. Increasing Pt concentration resulted in increased DEF in the tumor and reduced DEF in areas outside the tumor. The DEFs in the tumor base were 1.70, 2.04, 2.37, and 3.0 for125 I seeds and 1.58, 1.86, 2.11, and 2.60 for103 Pd seeds for Pt concentrations of 5, 7.5, 10, and 15 mg, respectively. The DEFs at the tumor apex were 1.49, 1.67, 1.81, and 1.97 for125 I seeds and 1.15, 1.24, 1.21, and 1.07 for103 Pd seeds for Pt concentrations of 5, 7.5, 10, and 15 mg Pt, respectively. For the103 Pd seeds, the Pt concentration higher than 10 mg/g leads to DEF reduction at tumor apex. As shown in [Figure 4]b and [Table 2], the DEFs at the tumor apex were 1.21 and 1.24 for 10 mg and 7.5 mg concentrations, respectively. Comparison of the DEFs for 10 and 15 mg showed the same trend. The reason for this trend is that103 Pd is a low-energy source (lower than that of125 I) and its photon fluence decreases as Pt increases; thus, the DEF reduces dramatically at further distances for Pt concentrations above 10 mg/g eye tissue.

When using antineoplastic agents including high atomic number elements (Pt) concurrent with radiation therapy, it is also necessary to consider source energy and CT drug concentration. The DEF was also calculated for areas beyond the tumor, starting from the sclera (d = 0.85 cm). For Pt concentrations of 5, 7.5, 10, and 15 mg, the DEFs were 0.88, 0.82, 0.76, and 0.63 for125 I seeds and 0.76, 0.65, 0.56, and 0.39 for103 Pd seeds, respectively. These results indicate a significant dose reduction in areas beyond the tumor, which decreased more with increasing Pt concentration. Since the goal of radiotherapy is to maximize the tumor dose and minimize the healthy tissues dose, the concurrent use of LDR plaque BT with Pt-based super-selective IA CT fulfills this desire.

The influence of Pt was also evaluated by calculating the DEF in other parts of the eye, as shown in [Table 2]. For instance, the DEFs at the lens were 0.94, 0.91, 0.88, and 0.83 for125 I and 0.91, 0.87, 0.83, and 0.76 for103 Pd for Pt concentrations of 5, 7.5, 10, and 15 mg, respectively. The DEF in the cornea, anterior chamber, and center of the vitreous body (center of the eye) was reduced due to the presence of Pt. Comparison of the relative deviation (RD) in DEF between125 I and103 Pd sources indicated that the DEF would increase with Pt concentration in the tumor. The mean RD in the calculation of the DEFs (for125 I and103 Pd) for different Pt concentrations was 11% and 48% at the tumor base and apex, respectively. This difference is due to the higher average energy of125 I compared to that of103 Pd, which leads to a higher photon absorption. In addition, [Table 2] and [Figure 4]a and [Figure 4]b show increased DEF reduction in areas beyond the tumor for103 Pd compared to that of125 I. Therefore, both sources can be used with respect to tumor size.

The results of this study indicate that the concurrent use of super-selective IA CT with LDR plaque BT sources resulted in increased tumor dose, reduced dose to healthy parts, and reduced treatment time. Concurrent chemo-radiotherapy has recently been performed in clinical settings; therefore, concurrent chemo-BT may be also performed for the treatment of retinoblastoma following comprehensive studies and further simulations.


 > Conclusions Top


The results of this study illustrate that the concurrent use of super-selective IA Pt-based CT with LDR plaque BT significantly increases tumor dose and decreases the dose to healthy parts of the eye due to the high atomic number of Pt, which leads to higher photoelectric absorption. This advantage could reduce treatment time and assist in the preservation of functional vision. Considering ongoing clinical concurrent chemo-radiotherapy, further investigation and evaluation of concurrent chemo-BT with targeted Pt-based drug delivery and LDR plaque BT can lead to better treatment of children with minimal damage.

Acknowledgments

The authors would like to thank vice-chancellery for research and technology affairs of SUMS for supporting this research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

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