- Email: [email protected]
Measurement of dose distribution from treatment of shallow brain tumors in BNCT by NIPAM polymer gel
Progress in Nuclear Energy 100 (2017) 292e296
Contents lists available at ScienceDirect
Progress in Nuclear Energy journal homepage: www.elsevier.com/locate/pnucene
Measurement of dose distribution from treatment of shallow brain tumors in BNCT by NIPAM polymer gel Azim Khajeali c, d, Roghayeh Khodadadi b, c, f, Yaser Kasesaz e, Mark Horsfield g, Ali Reza Farajollahi a, b, c, * a
Medical Education Research Center, Tabriz, Iran Imam Reza Teaching Hospital, Radiotherapy Department, Tabriz University of Medical Sciences, Tabriz, Iran Faculty of Medicine, Department of Medical Physics, Tabriz University of Medical Sciences, Tabriz, Iran d Incubator Center of Health Technology, Shahrekord University of Medical Science, Shahrekord, Iran e Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran f Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran g Xinapse Systems Ltd, West Bergholt, Essex, CO6 3BW, UK b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 January 2017 Received in revised form 27 May 2017 Accepted 7 July 2017
Because of the unique characteristics of polymer gel dosimeters, it appears that these gels might offer a reliable method for measuring absorbed radiation dose from various radiotherapy techniques, such as BNCT. In this study, the ability of NIPAM polymer gel to record the dose distribution from the BNCT treatment modality was evaluated by simulating the clinical conditions for treatment of shallow tumors. In this regards, two polymethyl methacrylate (PMMA) cylinder phantoms, measuring 8 cm in diameter and 6 cm in height with a wall thickness of 5 mm, were used for irradiating the gel in front of the BNCT beam of the Tehran Research Reactor (TRR). One of the phantoms was filled by only NIPAM gel prepared by standard formulation and the other one containing about 20 cc NIPAM gel with 30 ppm of 10B which was embedded inside the standard gel, with no separating layer, at a depth of 1 cm from the phantom wall. From the results, 18% increased dose was recorded in the area that was loaded the 10B doped gel in comparison with the pure NIPAM gel. It can be concluded that NIPAM gel has the potential to be used in verification of BNCT treatment planning. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Gel dosimetry NIPAM polymer gel BNCT dosimetry
1. Introduction Radiation-sensitive gels have achieved prominence in different radiotherapy techniques as a reliable tool to determine the absorbed radiation dose. The unique ability of the gel dosimeters in recording the radiation dose in three dimensions (3D) with high spatial resolution, as well as, their tissue-equivalence, has resulted in many researchers using them for dosimetry in many radiotherapy techniques utilizing different types of ionizing radiation such as x-rays, neutrons, protons, gamma rays and heavy ion radiation (Boni, 1961; De Deene et al., 2006; Farajollahi et al., 2000b; Jirasek and Duzenli, 2002; Ramm et al., 2000). One of the radiotherapy techniques in which the gel dosimeters play an important role, is Boron Neutron Capture Therapy (BNCT) (Khajeali et al.,
* Corresponding author. Medical Education Research Center, Tabriz, Iran. E-mail address: [email protected] (A.R. Farajollahi). http://dx.doi.org/10.1016/j.pnucene.2017.07.004 0149-1970/© 2017 Elsevier Ltd. All rights reserved.
2015a). This treatment modality is based on the high capture cross-section of the stable isotope 10B for thermal neutrons. In this technique, the patient is irradiated by a neutron beam following accumulation of 10B in the cancerous cells after receiving an injection of the boron-containing compound. The energy of the neutron beam used in BNCT is adjusted so that the neutrons will have thermal energy (<0.1 eV) when they reach the 10B-labelled cells. Therefore, thermal neutron beams are used for shallow and superficial tumors like melanoma, and epithermal neutron beams are used for deep tumors such a glioblastoma multiforme (Sauerwein et al., 2012). Epithermal neutron beams used in BNCT are thermalized after passing through the patient's tissues, increasing the possibility of a capture reaction by 10B when the beam reaches the cancerous cells. During this reaction, high-energy alpha and lithium particles are produced that have a very high LET and release their energy at a distance comparable to the diameter of the cell (5e9 mm), resulting in the death of cancerous cells. Since, in addition to 10B, the
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296
nitrogen in the tissue is able to absorb thermal neutrons, another part of the dose reaching the patient results from the reaction of this element with thermal neutronsð14 Nðnth ; pÞ14 CÞ. In routine dosimetry of the BNCT technique, the dose resulting from the reaction of thermal neutrons and boron and nitrogen is not measured directly. Instead, first the neutron flux is determined through neutron activation technique and then the dose given to the patient is determined through the use of flux-to-dose conversion factors (International Atomic Energy Agency, 2001). In general, indirect determination of the dose resulting from the thermal neutrons is one of the disadvantages of dosimetry in BNCT, and several studies have been undertaken to evaluate the possibility of using gel dosimeters to measure this dose component directly. In this context, Fricke gel dosimeters have been frequently studied in BNCT (Bartesaghi et al., 2009; Gambarini et al., 1994, 2000). The results of these studies have shown that Fricke gels can not only record the dose resulting from the interaction of thermal neutrons, but they also have the ability to map the dose distribution in 3D. Although studies carried out using Fricke gel dosimeters in BNCT have shown their unique ability for dosimetry of this treatment modality, there are also major limitations, including the diffusion of ferrous and ferric ions after irradiation, resulting in poor stability of the recorded 3D dose distribution. Therefore, another group of gel dosimeters that depend on radiation-induced polymerization have attracted the attention of researchers. Polymeric dosimeters were first suggested by Alexander et al. for the dosimetry of ionizing radiation in 1954 (Alexander et al., 1954). In these hydrogels, water free radicals led to polymerization of the monomers existed in the gel composition as a function of the absorbed radiation dose (Baldock et al., 2010). Later in 1992 Maryanski et al. introduce a new formulation of gel dosimeter consisting of N, N0 -Methylenebisacrylamide (BIS), acrylamide (AAm), nitrous oxide and agarose, known as BNANA, based on polymerization and cross linking of AAm and BIS monomers in the agarose gel matrix. This gel did not have the diffusion problem associated with Fricke gel and spatial dose distribution remained stable after irradiation (Baldock et al., 2010). In 1994, they replaced agarose with gelatin in gel composition and gave the acronym BANG polymer gel because of its chemical ingredients (BIS, AAm, nitrogen and gelatin) (Maryanski et al., 1994). Subsequently different polymer gel dosimeters which denoted by BANG-2 and BANG-3 were manufactured by replacing AAM with acrylic acid and methacrylic acid respectively (Maryanski, 1999; Maryanski et al., 1996). The BANG gel was first evaluated by Farajollahi et al. in 2000 for their use in BNCT dosimetry. 10B was incorporated into the gel and they showed that this gel can properly record an increase in dose resulting from the interaction between thermal neutrons and 10B (Farajollahi et al., 2000b). Uusi-Simola et al. also evaluated and confirmed the potential of BANG-3 and MAGIC polymer gels in BNCT dosimetry (Uusi-Simola et al., 2003b, 2007). Although polymer gels overcome some of the problems of Fricke gels, there are disadvantages that prevent their widespread use, including the use of toxic ingredients in their formulation such as acrylamide, and inhibitory effect of oxygen on polymerization process. To overcome the oxygen problem, a new type of the polymer gels, known as MAGIC, was developed by Fong et al., in 2001, which could be prepared in normal room atmospheric conditions. Moreover, in 2006, Senden et al. replaced acrylamide with N-isopropylacrylamide (NIPAM) in PAGAT polymer gel and introduced a new formulation of gel dosimeters, referred to as NIPAM, which has very low toxicity compared to other polymer gels (Senden et al., 2006). Subsequently, evaluation of the dosimetric properties of NIPAM gel showed that this gel is tissue-equivalent in terms of its electron and mass density, and its response is independent of the energy and dose rate, in addition to its
293
reproducibility (Farajollahi et al., 2014; Khodadadi et al., 2015a, 2015b). Considering these characteristics and other properties of polymer gel dosimeters such as their ability in recording dose distribution in 3D with high spatial resolution and tissueequivalency, it appears that NIPAM gel can be considered a reliable dosimetric tool and is capable of being used with various radiotherapy techniques to measure the absorbed dose. Therefore, in the present study, in addition to the evaluation of the response of the NIPAM gel to neutron irradiation, the possibility of using this gel to achieve dose distribution in BNCT treatment modality was evaluated. By embedding the NIPAM gel containing 10B, without any separating layer, within a cylindrical gel phantom, the conditions for the treatment of tumors at a depth of 1 cm were simulated. Thus, we evaluated both of the capabilities of the thermal neutron beam of TRR in the treatment of shallow tumors, and also the potential of NIPAM gel for verification of treatment planning in BNCT. 2. Materials and methods In the current study, preparation of NIPAM gel was based on the formulation originally proposed by Senden et al. (2006), according to which 89% of the gel volume consists of deionized water. In order to make the required amount volume of gel, gelatin (300 Bloom Type A) was added to 80% of the water, and heated up to 50 C. Once the gelatin was completely melted, the solution was cooled down to 37 C and N, N0 -Methylenebisacrylamide (BIS) was added to it as a cross-linker. After BIS was dissolved (within 15 min), N-isopropylacrylamide (NIPAM) was added to the solution at the same temperature. Once the monomers were completely dissolved, a solution of the antioxidant (hydroxymethyl) phosphonium chloride (THPC) was prepared with the remaining 20% of water and added to the gel solution at 35 C. The weight percentages of the materials used, all of which are products of Sigma-Aldrich, are given in Table 1. Following preparation, the NIPAM gel was poured into polymethyl methacrylate (PMMA) cylinder phantom, measuring 8 cm in diameter and 6 cm in height with a wall thickness of 5 mm (Fig. 1). Subsequently, the phantom containing the gel was irradiated in front of the thermal neutron column of the Tehran Research Reactor (TRR) to obtain the depth dose distribution resulting from the neutron beam. The thermal neutron column of TRR was designed and constructed to be employed in BNCT for treating superficial and relatively shallow tumors (Kasesaz et al., 2014a, 2014b, 2014c, 2016). This beam was already optimized in terms of gamma contamination (Khajeali et al., 2015b). In order to investigate the capability of the TRR BNCT beam line in treating relatively shallow tumors, the clinical condition was simulated by embedding the gel with 30 ppm of 10B inside the identical PMMA phantom containing the gel, with no separating layer, at a depth of 1 cm from the phantom wall. The phantom was then irradiated by thermal neutrons from TRR BNCT beam. Fig. 2 shows a schematic representation of the phantom with a simulated tumor. The phantoms were imaged 24 h after irradiation using a 1.5 T S MRI scanner. Since temperature fluctuation is known to affect Table 1 Different components and their percentage weight in the gel preparation. Component
Weight percent
Water Gelatin 300 Bloom Type A N-Isopropylacrylamide (NIPAM) N, N0 -Methylenebisacrylamide (BIS) Tetrakis (hydroxymethyl) phosphonium chloride (THPC)
89 wt% 5 wt% 3 wt% 3 wt% 10 mM
294
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296 Table 2 MRI protocol used for scanning the gel dosimeters. Pulse sequence Matrix Size (mm) Slice Thickness (mm) Repetition Time (TR) (ms) Echo Time (TE) (ms) Inter Echo Time Spacing (ms) Number of Slices Number of Echoes Number of acquisitions
Fig. 1. The polymethyl methacrylate (PMMA) cylinder phantom.
dosimeter responses, the gels were isothermal at room temperature. T2-weighted images were then obtained using a multiple spin-echo pulse sequence and analyzed using software written using MATLAB (2014) to achieve transverse relaxation rate (R2) maps. The protocol used in MR imaging is shown in Table 2. 3. Results and discussion It has been shown that NIPAM gel is tissue-equivalent in terms of electron and mass density in photon irradiation (Farajollahi et al., 2014). The elemental composition of a dosimeter is an important factor in being tissue-equivalent and in the accuracy of the absorbed dose measurements in all radiotherapy modalities especially in neutron therapy techniques such as BNCT. Since BNCT has traditionally been introduced for treating glioblastoma multiforme, in the Khajeali et al. study conducted in 2015, the elemental composition of NIPAM gel was evaluated and compared with brain tissue, and it was found that the gel could be considered a good choice for use in BNCT dosimetry as a brain tissue-equivalent phantom. In this study, in order to measure the depth dose distribution resulting from the TRR BNCT beam, the cylindrical phantom containing the gel was irradiated and after MR imaging, R2 maps were
T2 weighted multiple spin echo 512 5 4000 20 20 1 32 2
calculated from the T2-weighted images. Fig. 3 shows the relative dose distribution maps obtained from the irradiated phantom containing the gel in 2D and 3D view after normalization R2 values to the maximum. As can be seen from the figure, NIPAM polymer gel as a homogeneous tissue equivalent medium depicted dose distribution from neutron beam in passing through the phantom. Therefore, the gel could be a useful dosimetric tool for verification of dose distribution resulted from BNCT treatment planning system (TPS) in clinical ground. The amount of energy deposed in pass length of radiation inside the body is one of the important factors in calculating the absorbed dose received by the patient. Therefore, to evaluate the percentage change in the absorbed dose with increase in phantom depth, the depth profile was measured parallel to the neutron beam (Fig. 4). As shown in the Figure, there is an approximately 50% difference in the absorbed dose between the start and end points of the phantom. In general, we have demonstrated that NIPAM gel can record dose data resulting from thermal neutrons and shown its use in neutron therapy techniques, such as BNCT, as an accurate dosimetric tool with the capacity to measure the dose in three dimensions with high resolution. These results are consistent with those of other studies using polymer gels in the dosimetry of the BNCT treatment modality, carried out by Farajollahi et al. and UusiSimola et al. (Farajollahi et al., 2000a; Uusi-Simola et al., 2006; Uusi-Simola et al., 2003a). Although these studies showed the capabilities of BANG, BANG-3 and MAGIC polymer gels for use in the dosimetry of BNCT technique, the toxic constituents of these gels has prevented their widespread use. Therefore, since NIPAM, which has a composition with lower toxicity, is stable, and is able to record dose resulting from neutron radiation, it is expected that this gel could be useful in neutron dosimetry as a 3D dosimeter with high spatial resolution in BNCT clinics. In this context, in order to simulate the tumor under clinical conditions, gel containing 30 ppm of 10B was embedded within a cylindrical phantom containing NIPAM gel without any separating layer at a depth of 1 cm and irradiated by the neutron beam. Fig. 5 shows the 2D and 3D view of the dose distribution obtained from this phantom.
Fig. 2. Schematic of the PMMA phantom with a tumor inside.
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296
295
Fig. 3. Dose map obtained from the gel irradiated by the TRR BNCT beam in 2D (left) and 3D (right).
As shown in Fig. 5, NIPAM gel was able to record the increase in dose resulting from the interaction between the thermal neutrons and 10B in the tumor region and around it. Comparison of the dose profiles through the phantom with and without the simulated tumor confirmed an increase of 18% in dose in the area with 10B compared to that without 10B (Fig. 6). More accurate evaluation of Fig. 6 shows that as well as a significant increase in dose in the simulated tumor, there is a minor increase in dose in other areas, too, with the profiles completely overlapping each other at the end of the phantom. This increase in dose might be attributed to the gamma rays resulting from the interaction between thermal neutrons and 10B. 4. Conclusion It has been shown that NIPAM polymer gel can be used as a tissue equivalent dosimeter not only for providing basic calculation dose data but also can apply to dose verification in neutron therapy clinics for modalities such as BNCT because of its basic nature to record dose information in 3D with high spatial resolution. In addition, the present preliminary study evaluated the potential of the thermal neutron beam of the TRR to be applied in the BNCT
Fig. 4. Depth dose profile along the BNCT beam line.
Fig. 5. Dose distribution in the phantom containing the gel with 30 ppm
10
B (simulated tumor) embedded in the gel without
10
B, in 2D (left) and 3D (right).
296
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296
Fig. 6. Dose profiles obtained from the phantoms with and without the simulated tumor.
treatment modality, which showed promising results in the treatment of shallow tumors. Further study is necessary to compare plan produced by TPS and dose distribution provided by NIPAM polymer gel. References Alexander, P., Charlesby, A., Ross, M., 1954. The degradation of solid polymethylmethacrylate by ionizing radiation. Proc. Roy. Soc. Lond. Ser. A. Math. Phys. Sci. 223, 392e404. Baldock, C., Deene, Y.D., Doran, S., Ibbott, G., Jirasek, A., Lepage, M., McAuley, K.B., Oldham, M., Schreiner, L.J., 2010. Polymer gel dosimetry. Phys. Med. Biol. 55, R1. Bartesaghi, G., Burian, J., Gambarini, G., Marek, M., Negri, A., Viererbl, L., 2009. Evaluation of all dose components in the LVR-15 reactor epithermal neutron beam using Fricke gel dosimeter layers. Appl. Radiat. Isot. 67, S199eS201. Boni, A.L., 1961. A polyacrylamide gamma dosimeter. Radiat. Res. 14, 374e380. De Deene, Y., Vergote, K., Claeys, C., De Wagter, C., 2006. The fundamental radiation properties of normoxic polymer gel dosimeters: a comparison between a methacrylic acid based gel and acrylamide based gels. Phys. Med. Biol. 51, 653e673. Farajollahi, A., Bonnett, D., Tattam, D., Green, S., 2000a. The potential use of polymer gel dosimetry in boron neutron capture therapy. Phys. Med. Biol. 45, N9. Farajollahi, A.R., Bonnett, D.E., Tattam, D., Green, S., 2000b. The potential use of polymer gel dosimetry in boron neutron capture therapy. Phys. Med. Biol. 45, N9eN14. Farajollahi, A.R., Pak, F., Horsfield, M., Myabi, Z., 2014. The basic radiation properties of the N-isopropylacrylamide based polymer gel dosimeter. Int. J. Radiat. Res. 12, 347e354. Gambarini, G., Agosteo, S., Marchesi, P., Nava, E., Palazzi, P., Pecci, A., Rosi, G., Tinti, R., 2000. Discrimination of various contributions to the absorbed dose in BNCT: Fricke-gel imaging and intercomparison with other experimental results. Appl. Radiat. Isot. 53, 765e772. Gambarini, G., Arrigoni, S., Cantone, M.C., Molho, N., Facchielli, L., Sichirollo, A.E., 1994. Dose-response curve slope improvement and result reproducibility of
ferrous-sulphate-doped gels analysed by NMR imaging. Phys. Med. Biol. 39, 703. International Atomic Energy Agency, 2001. Current Status of Neutron Capture Therapy. International Atomic Energy Agency, Austria. Jirasek, A., Duzenli, C., 2002. Relative effectiveness of polyacrylamide gel dosimeters applied to proton beams: fourier transform Raman observations and track structure calculations. Med. Phys. 29, 569e577. Kasesaz, Y., Khalafi, H., Rahmani, F., 2014a. Design of an epithermal neutron beam for BNCT in thermal column of Tehran Research Reactor. Ann. Nucl. Energy 68, 234e238. Kasesaz, Y., Khalafi, H., Rahmani, F., Ezati, A., Keyvani, M., Hossnirokh, A., Shamami, M.A., Monshizadeh, M., 2014b. A feasibility study of the Tehran Research Reactor as a neutron source for BNCT. Appl. Radiat. Isot. 90, 132e137. Kasesaz, Y., Khalafi, H., Rahmani, F., Ezzati, A., Keyvani, M., Hossnirokh, A., Shamami, M.A., Amini, S., 2014c. Design and construction of a thermal neutron beam for BNCT at Tehran Research Reactor. Appl. Radiat. Isot. 94, 149e151. Kasesaz, Y., Bavarnegin, E., Golshanian, M., Khajeali, A., Jarahi, H., Mirvakili, S., Khalafi, H., 2016. BNCT project at Tehran Research Reactor: Current and prospective plans. Progr. Nucl. Energ. 91, 107e115. Khajeali, A., Farajollahi, A.R., Khodadadi, R., Kasesaz, Y., Khalili, A., 2015a. Role of gel dosimeters in boron neutron capture therapy. Appl. Radiat. Isot. 103, 72e81. Khajeali, A., Reza, F.A., Kasesaz, Y., Khodadadi, R., Khalili, A., Naseri, A., 2015b. Capability of NIPAM polymer gel in recording dose from the interaction of (10) B and thermal neutron in BNCT. Appl. Radiat. Isot. Incl. Data Instrum. Meth. Use Agric. Ind. Med. 105, 257e263. Khodadadi, R., Khajeali, A., Farajollahi, A.R., Hajalioghli, P., Raeisi, N., 2015a. Comparison of non-electrophoresis grade with electrophoresis grade BIS in NIPAM polymer gel preparation. Biolmpacts 5. Khodadadi, R., Khajeali, A., Farajollahi, A.R., Ziaei, J.E., Hajalioghli, P., 2015b. Dosimetric properties of N-isopropylacrylamide polymer gel using nonelectrophoresis grade BIS in preparation. J. Cancer Res. Ther. 11. Maryanski, M., 1999. Radiation-sensitive polymer gels: properties and manufacturing. In: Proceedings of the First Workshop on Radiation Therapy Gel Dosimetry, pp. 65e76. Lexington, KY. Maryanski, M., Ibbott, G., Eastman, P., Schulz, R., Gore, J., 1996. Radiation therapy dosimetry using magnetic resonance imaging of polymer gels. Med. Phys. 23, 699e705. Maryanski, M.J., Schulz, R.J., Ibbott, G.S., Gatenby, J.C., Xie, J., Horton, D., Gore, J.C., 1994. Magnetic resonance imaging of radiation dose distributions using a polymer-gel dosimeter. Phys. Med. Biol. 39, 1437. Ramm, U., Weber, U., Bock, M., Kramer, M., Bankamp, A., Damrau, M., Thilmann, C., Bottcher, H.D., Schad, L.R., Kraft, G., 2000. Three-dimensional BANG gel dosimetry in conformal carbon ion radiotherapy. Phys. Med. Biol. 45, N95eN102. Sauerwein, W.A.G., Wittig, A., Moss, R., Nakagawa, Y., 2012. Neutron Capture Therapy: Principles and Applications. Springer, Berlin Heidelberg. Senden, R.J., Jean, P.D., McAuley, K.B., Schreiner, L.J., 2006. Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical doseeresponse using different monomers. Phys. Med. Biol. 51, 3301. Uusi-Simola, J., Heikkinen, S., Kotiluoto, P., Seren, T., Seppala, T., Auterinen, I., Savolainen, S., 2007. MAGIC polymer gel for dosimetric verification in boron neutron capture therapy. J. Appl. Clin. Med. Phys. 8, 114e123. n, T., Seppa €la €, T., Auterinen, I., Uusi-Simola, J., Heikkinen, S., Kotiluoto, P., Sere Savolainen, S., 2006. MAGIC polymer gel for dosimetric verification in boron neutron capture therapy. J. Appl. Clin. Med. Phys. Am. Coll. Med. Phys. 8, 114e123. €ki, A., Heikkinen, S., Perkio €, J., Uusi-Simola, J., Savolainen, S., Kangasma €l€ Ramadan, U.A., Seppa a, T., Karila, J., Seren, T., Kotiluoto, P., 2003a. Study of the ® relative dose-response of BANG-3 polymer gel dosimeters in epithermal neutron irradiation. Phys. Med. Biol. 48, 2895. €ki, A., Heikkinen, S., Perkio €, J., Uusi-Simola, J., Savolainen, S., Kangasma €, T., Karila, J., Sere n, T., Kotiluoto, P., Sorvari, P., Ramadan, U.A., Sepp€ ala ® Auterinen, I., 2003b. Study of the relative dose-response of BANG-3 polymer gel dosimeters in epithermal neutron irradiation. Phys. Med. Biol. 48, 2895.
Contents lists available at ScienceDirect
Progress in Nuclear Energy journal homepage: www.elsevier.com/locate/pnucene
Measurement of dose distribution from treatment of shallow brain tumors in BNCT by NIPAM polymer gel Azim Khajeali c, d, Roghayeh Khodadadi b, c, f, Yaser Kasesaz e, Mark Horsfield g, Ali Reza Farajollahi a, b, c, * a
Medical Education Research Center, Tabriz, Iran Imam Reza Teaching Hospital, Radiotherapy Department, Tabriz University of Medical Sciences, Tabriz, Iran Faculty of Medicine, Department of Medical Physics, Tabriz University of Medical Sciences, Tabriz, Iran d Incubator Center of Health Technology, Shahrekord University of Medical Science, Shahrekord, Iran e Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran f Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran g Xinapse Systems Ltd, West Bergholt, Essex, CO6 3BW, UK b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 January 2017 Received in revised form 27 May 2017 Accepted 7 July 2017
Because of the unique characteristics of polymer gel dosimeters, it appears that these gels might offer a reliable method for measuring absorbed radiation dose from various radiotherapy techniques, such as BNCT. In this study, the ability of NIPAM polymer gel to record the dose distribution from the BNCT treatment modality was evaluated by simulating the clinical conditions for treatment of shallow tumors. In this regards, two polymethyl methacrylate (PMMA) cylinder phantoms, measuring 8 cm in diameter and 6 cm in height with a wall thickness of 5 mm, were used for irradiating the gel in front of the BNCT beam of the Tehran Research Reactor (TRR). One of the phantoms was filled by only NIPAM gel prepared by standard formulation and the other one containing about 20 cc NIPAM gel with 30 ppm of 10B which was embedded inside the standard gel, with no separating layer, at a depth of 1 cm from the phantom wall. From the results, 18% increased dose was recorded in the area that was loaded the 10B doped gel in comparison with the pure NIPAM gel. It can be concluded that NIPAM gel has the potential to be used in verification of BNCT treatment planning. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Gel dosimetry NIPAM polymer gel BNCT dosimetry
1. Introduction Radiation-sensitive gels have achieved prominence in different radiotherapy techniques as a reliable tool to determine the absorbed radiation dose. The unique ability of the gel dosimeters in recording the radiation dose in three dimensions (3D) with high spatial resolution, as well as, their tissue-equivalence, has resulted in many researchers using them for dosimetry in many radiotherapy techniques utilizing different types of ionizing radiation such as x-rays, neutrons, protons, gamma rays and heavy ion radiation (Boni, 1961; De Deene et al., 2006; Farajollahi et al., 2000b; Jirasek and Duzenli, 2002; Ramm et al., 2000). One of the radiotherapy techniques in which the gel dosimeters play an important role, is Boron Neutron Capture Therapy (BNCT) (Khajeali et al.,
* Corresponding author. Medical Education Research Center, Tabriz, Iran. E-mail address: [email protected] (A.R. Farajollahi). http://dx.doi.org/10.1016/j.pnucene.2017.07.004 0149-1970/© 2017 Elsevier Ltd. All rights reserved.
2015a). This treatment modality is based on the high capture cross-section of the stable isotope 10B for thermal neutrons. In this technique, the patient is irradiated by a neutron beam following accumulation of 10B in the cancerous cells after receiving an injection of the boron-containing compound. The energy of the neutron beam used in BNCT is adjusted so that the neutrons will have thermal energy (<0.1 eV) when they reach the 10B-labelled cells. Therefore, thermal neutron beams are used for shallow and superficial tumors like melanoma, and epithermal neutron beams are used for deep tumors such a glioblastoma multiforme (Sauerwein et al., 2012). Epithermal neutron beams used in BNCT are thermalized after passing through the patient's tissues, increasing the possibility of a capture reaction by 10B when the beam reaches the cancerous cells. During this reaction, high-energy alpha and lithium particles are produced that have a very high LET and release their energy at a distance comparable to the diameter of the cell (5e9 mm), resulting in the death of cancerous cells. Since, in addition to 10B, the
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296
nitrogen in the tissue is able to absorb thermal neutrons, another part of the dose reaching the patient results from the reaction of this element with thermal neutronsð14 Nðnth ; pÞ14 CÞ. In routine dosimetry of the BNCT technique, the dose resulting from the reaction of thermal neutrons and boron and nitrogen is not measured directly. Instead, first the neutron flux is determined through neutron activation technique and then the dose given to the patient is determined through the use of flux-to-dose conversion factors (International Atomic Energy Agency, 2001). In general, indirect determination of the dose resulting from the thermal neutrons is one of the disadvantages of dosimetry in BNCT, and several studies have been undertaken to evaluate the possibility of using gel dosimeters to measure this dose component directly. In this context, Fricke gel dosimeters have been frequently studied in BNCT (Bartesaghi et al., 2009; Gambarini et al., 1994, 2000). The results of these studies have shown that Fricke gels can not only record the dose resulting from the interaction of thermal neutrons, but they also have the ability to map the dose distribution in 3D. Although studies carried out using Fricke gel dosimeters in BNCT have shown their unique ability for dosimetry of this treatment modality, there are also major limitations, including the diffusion of ferrous and ferric ions after irradiation, resulting in poor stability of the recorded 3D dose distribution. Therefore, another group of gel dosimeters that depend on radiation-induced polymerization have attracted the attention of researchers. Polymeric dosimeters were first suggested by Alexander et al. for the dosimetry of ionizing radiation in 1954 (Alexander et al., 1954). In these hydrogels, water free radicals led to polymerization of the monomers existed in the gel composition as a function of the absorbed radiation dose (Baldock et al., 2010). Later in 1992 Maryanski et al. introduce a new formulation of gel dosimeter consisting of N, N0 -Methylenebisacrylamide (BIS), acrylamide (AAm), nitrous oxide and agarose, known as BNANA, based on polymerization and cross linking of AAm and BIS monomers in the agarose gel matrix. This gel did not have the diffusion problem associated with Fricke gel and spatial dose distribution remained stable after irradiation (Baldock et al., 2010). In 1994, they replaced agarose with gelatin in gel composition and gave the acronym BANG polymer gel because of its chemical ingredients (BIS, AAm, nitrogen and gelatin) (Maryanski et al., 1994). Subsequently different polymer gel dosimeters which denoted by BANG-2 and BANG-3 were manufactured by replacing AAM with acrylic acid and methacrylic acid respectively (Maryanski, 1999; Maryanski et al., 1996). The BANG gel was first evaluated by Farajollahi et al. in 2000 for their use in BNCT dosimetry. 10B was incorporated into the gel and they showed that this gel can properly record an increase in dose resulting from the interaction between thermal neutrons and 10B (Farajollahi et al., 2000b). Uusi-Simola et al. also evaluated and confirmed the potential of BANG-3 and MAGIC polymer gels in BNCT dosimetry (Uusi-Simola et al., 2003b, 2007). Although polymer gels overcome some of the problems of Fricke gels, there are disadvantages that prevent their widespread use, including the use of toxic ingredients in their formulation such as acrylamide, and inhibitory effect of oxygen on polymerization process. To overcome the oxygen problem, a new type of the polymer gels, known as MAGIC, was developed by Fong et al., in 2001, which could be prepared in normal room atmospheric conditions. Moreover, in 2006, Senden et al. replaced acrylamide with N-isopropylacrylamide (NIPAM) in PAGAT polymer gel and introduced a new formulation of gel dosimeters, referred to as NIPAM, which has very low toxicity compared to other polymer gels (Senden et al., 2006). Subsequently, evaluation of the dosimetric properties of NIPAM gel showed that this gel is tissue-equivalent in terms of its electron and mass density, and its response is independent of the energy and dose rate, in addition to its
293
reproducibility (Farajollahi et al., 2014; Khodadadi et al., 2015a, 2015b). Considering these characteristics and other properties of polymer gel dosimeters such as their ability in recording dose distribution in 3D with high spatial resolution and tissueequivalency, it appears that NIPAM gel can be considered a reliable dosimetric tool and is capable of being used with various radiotherapy techniques to measure the absorbed dose. Therefore, in the present study, in addition to the evaluation of the response of the NIPAM gel to neutron irradiation, the possibility of using this gel to achieve dose distribution in BNCT treatment modality was evaluated. By embedding the NIPAM gel containing 10B, without any separating layer, within a cylindrical gel phantom, the conditions for the treatment of tumors at a depth of 1 cm were simulated. Thus, we evaluated both of the capabilities of the thermal neutron beam of TRR in the treatment of shallow tumors, and also the potential of NIPAM gel for verification of treatment planning in BNCT. 2. Materials and methods In the current study, preparation of NIPAM gel was based on the formulation originally proposed by Senden et al. (2006), according to which 89% of the gel volume consists of deionized water. In order to make the required amount volume of gel, gelatin (300 Bloom Type A) was added to 80% of the water, and heated up to 50 C. Once the gelatin was completely melted, the solution was cooled down to 37 C and N, N0 -Methylenebisacrylamide (BIS) was added to it as a cross-linker. After BIS was dissolved (within 15 min), N-isopropylacrylamide (NIPAM) was added to the solution at the same temperature. Once the monomers were completely dissolved, a solution of the antioxidant (hydroxymethyl) phosphonium chloride (THPC) was prepared with the remaining 20% of water and added to the gel solution at 35 C. The weight percentages of the materials used, all of which are products of Sigma-Aldrich, are given in Table 1. Following preparation, the NIPAM gel was poured into polymethyl methacrylate (PMMA) cylinder phantom, measuring 8 cm in diameter and 6 cm in height with a wall thickness of 5 mm (Fig. 1). Subsequently, the phantom containing the gel was irradiated in front of the thermal neutron column of the Tehran Research Reactor (TRR) to obtain the depth dose distribution resulting from the neutron beam. The thermal neutron column of TRR was designed and constructed to be employed in BNCT for treating superficial and relatively shallow tumors (Kasesaz et al., 2014a, 2014b, 2014c, 2016). This beam was already optimized in terms of gamma contamination (Khajeali et al., 2015b). In order to investigate the capability of the TRR BNCT beam line in treating relatively shallow tumors, the clinical condition was simulated by embedding the gel with 30 ppm of 10B inside the identical PMMA phantom containing the gel, with no separating layer, at a depth of 1 cm from the phantom wall. The phantom was then irradiated by thermal neutrons from TRR BNCT beam. Fig. 2 shows a schematic representation of the phantom with a simulated tumor. The phantoms were imaged 24 h after irradiation using a 1.5 T S MRI scanner. Since temperature fluctuation is known to affect Table 1 Different components and their percentage weight in the gel preparation. Component
Weight percent
Water Gelatin 300 Bloom Type A N-Isopropylacrylamide (NIPAM) N, N0 -Methylenebisacrylamide (BIS) Tetrakis (hydroxymethyl) phosphonium chloride (THPC)
89 wt% 5 wt% 3 wt% 3 wt% 10 mM
294
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296 Table 2 MRI protocol used for scanning the gel dosimeters. Pulse sequence Matrix Size (mm) Slice Thickness (mm) Repetition Time (TR) (ms) Echo Time (TE) (ms) Inter Echo Time Spacing (ms) Number of Slices Number of Echoes Number of acquisitions
Fig. 1. The polymethyl methacrylate (PMMA) cylinder phantom.
dosimeter responses, the gels were isothermal at room temperature. T2-weighted images were then obtained using a multiple spin-echo pulse sequence and analyzed using software written using MATLAB (2014) to achieve transverse relaxation rate (R2) maps. The protocol used in MR imaging is shown in Table 2. 3. Results and discussion It has been shown that NIPAM gel is tissue-equivalent in terms of electron and mass density in photon irradiation (Farajollahi et al., 2014). The elemental composition of a dosimeter is an important factor in being tissue-equivalent and in the accuracy of the absorbed dose measurements in all radiotherapy modalities especially in neutron therapy techniques such as BNCT. Since BNCT has traditionally been introduced for treating glioblastoma multiforme, in the Khajeali et al. study conducted in 2015, the elemental composition of NIPAM gel was evaluated and compared with brain tissue, and it was found that the gel could be considered a good choice for use in BNCT dosimetry as a brain tissue-equivalent phantom. In this study, in order to measure the depth dose distribution resulting from the TRR BNCT beam, the cylindrical phantom containing the gel was irradiated and after MR imaging, R2 maps were
T2 weighted multiple spin echo 512 5 4000 20 20 1 32 2
calculated from the T2-weighted images. Fig. 3 shows the relative dose distribution maps obtained from the irradiated phantom containing the gel in 2D and 3D view after normalization R2 values to the maximum. As can be seen from the figure, NIPAM polymer gel as a homogeneous tissue equivalent medium depicted dose distribution from neutron beam in passing through the phantom. Therefore, the gel could be a useful dosimetric tool for verification of dose distribution resulted from BNCT treatment planning system (TPS) in clinical ground. The amount of energy deposed in pass length of radiation inside the body is one of the important factors in calculating the absorbed dose received by the patient. Therefore, to evaluate the percentage change in the absorbed dose with increase in phantom depth, the depth profile was measured parallel to the neutron beam (Fig. 4). As shown in the Figure, there is an approximately 50% difference in the absorbed dose between the start and end points of the phantom. In general, we have demonstrated that NIPAM gel can record dose data resulting from thermal neutrons and shown its use in neutron therapy techniques, such as BNCT, as an accurate dosimetric tool with the capacity to measure the dose in three dimensions with high resolution. These results are consistent with those of other studies using polymer gels in the dosimetry of the BNCT treatment modality, carried out by Farajollahi et al. and UusiSimola et al. (Farajollahi et al., 2000a; Uusi-Simola et al., 2006; Uusi-Simola et al., 2003a). Although these studies showed the capabilities of BANG, BANG-3 and MAGIC polymer gels for use in the dosimetry of BNCT technique, the toxic constituents of these gels has prevented their widespread use. Therefore, since NIPAM, which has a composition with lower toxicity, is stable, and is able to record dose resulting from neutron radiation, it is expected that this gel could be useful in neutron dosimetry as a 3D dosimeter with high spatial resolution in BNCT clinics. In this context, in order to simulate the tumor under clinical conditions, gel containing 30 ppm of 10B was embedded within a cylindrical phantom containing NIPAM gel without any separating layer at a depth of 1 cm and irradiated by the neutron beam. Fig. 5 shows the 2D and 3D view of the dose distribution obtained from this phantom.
Fig. 2. Schematic of the PMMA phantom with a tumor inside.
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296
295
Fig. 3. Dose map obtained from the gel irradiated by the TRR BNCT beam in 2D (left) and 3D (right).
As shown in Fig. 5, NIPAM gel was able to record the increase in dose resulting from the interaction between the thermal neutrons and 10B in the tumor region and around it. Comparison of the dose profiles through the phantom with and without the simulated tumor confirmed an increase of 18% in dose in the area with 10B compared to that without 10B (Fig. 6). More accurate evaluation of Fig. 6 shows that as well as a significant increase in dose in the simulated tumor, there is a minor increase in dose in other areas, too, with the profiles completely overlapping each other at the end of the phantom. This increase in dose might be attributed to the gamma rays resulting from the interaction between thermal neutrons and 10B. 4. Conclusion It has been shown that NIPAM polymer gel can be used as a tissue equivalent dosimeter not only for providing basic calculation dose data but also can apply to dose verification in neutron therapy clinics for modalities such as BNCT because of its basic nature to record dose information in 3D with high spatial resolution. In addition, the present preliminary study evaluated the potential of the thermal neutron beam of the TRR to be applied in the BNCT
Fig. 4. Depth dose profile along the BNCT beam line.
Fig. 5. Dose distribution in the phantom containing the gel with 30 ppm
10
B (simulated tumor) embedded in the gel without
10
B, in 2D (left) and 3D (right).
296
A. Khajeali et al. / Progress in Nuclear Energy 100 (2017) 292e296
Fig. 6. Dose profiles obtained from the phantoms with and without the simulated tumor.
treatment modality, which showed promising results in the treatment of shallow tumors. Further study is necessary to compare plan produced by TPS and dose distribution provided by NIPAM polymer gel. References Alexander, P., Charlesby, A., Ross, M., 1954. The degradation of solid polymethylmethacrylate by ionizing radiation. Proc. Roy. Soc. Lond. Ser. A. Math. Phys. Sci. 223, 392e404. Baldock, C., Deene, Y.D., Doran, S., Ibbott, G., Jirasek, A., Lepage, M., McAuley, K.B., Oldham, M., Schreiner, L.J., 2010. Polymer gel dosimetry. Phys. Med. Biol. 55, R1. Bartesaghi, G., Burian, J., Gambarini, G., Marek, M., Negri, A., Viererbl, L., 2009. Evaluation of all dose components in the LVR-15 reactor epithermal neutron beam using Fricke gel dosimeter layers. Appl. Radiat. Isot. 67, S199eS201. Boni, A.L., 1961. A polyacrylamide gamma dosimeter. Radiat. Res. 14, 374e380. De Deene, Y., Vergote, K., Claeys, C., De Wagter, C., 2006. The fundamental radiation properties of normoxic polymer gel dosimeters: a comparison between a methacrylic acid based gel and acrylamide based gels. Phys. Med. Biol. 51, 653e673. Farajollahi, A., Bonnett, D., Tattam, D., Green, S., 2000a. The potential use of polymer gel dosimetry in boron neutron capture therapy. Phys. Med. Biol. 45, N9. Farajollahi, A.R., Bonnett, D.E., Tattam, D., Green, S., 2000b. The potential use of polymer gel dosimetry in boron neutron capture therapy. Phys. Med. Biol. 45, N9eN14. Farajollahi, A.R., Pak, F., Horsfield, M., Myabi, Z., 2014. The basic radiation properties of the N-isopropylacrylamide based polymer gel dosimeter. Int. J. Radiat. Res. 12, 347e354. Gambarini, G., Agosteo, S., Marchesi, P., Nava, E., Palazzi, P., Pecci, A., Rosi, G., Tinti, R., 2000. Discrimination of various contributions to the absorbed dose in BNCT: Fricke-gel imaging and intercomparison with other experimental results. Appl. Radiat. Isot. 53, 765e772. Gambarini, G., Arrigoni, S., Cantone, M.C., Molho, N., Facchielli, L., Sichirollo, A.E., 1994. Dose-response curve slope improvement and result reproducibility of
ferrous-sulphate-doped gels analysed by NMR imaging. Phys. Med. Biol. 39, 703. International Atomic Energy Agency, 2001. Current Status of Neutron Capture Therapy. International Atomic Energy Agency, Austria. Jirasek, A., Duzenli, C., 2002. Relative effectiveness of polyacrylamide gel dosimeters applied to proton beams: fourier transform Raman observations and track structure calculations. Med. Phys. 29, 569e577. Kasesaz, Y., Khalafi, H., Rahmani, F., 2014a. Design of an epithermal neutron beam for BNCT in thermal column of Tehran Research Reactor. Ann. Nucl. Energy 68, 234e238. Kasesaz, Y., Khalafi, H., Rahmani, F., Ezati, A., Keyvani, M., Hossnirokh, A., Shamami, M.A., Monshizadeh, M., 2014b. A feasibility study of the Tehran Research Reactor as a neutron source for BNCT. Appl. Radiat. Isot. 90, 132e137. Kasesaz, Y., Khalafi, H., Rahmani, F., Ezzati, A., Keyvani, M., Hossnirokh, A., Shamami, M.A., Amini, S., 2014c. Design and construction of a thermal neutron beam for BNCT at Tehran Research Reactor. Appl. Radiat. Isot. 94, 149e151. Kasesaz, Y., Bavarnegin, E., Golshanian, M., Khajeali, A., Jarahi, H., Mirvakili, S., Khalafi, H., 2016. BNCT project at Tehran Research Reactor: Current and prospective plans. Progr. Nucl. Energ. 91, 107e115. Khajeali, A., Farajollahi, A.R., Khodadadi, R., Kasesaz, Y., Khalili, A., 2015a. Role of gel dosimeters in boron neutron capture therapy. Appl. Radiat. Isot. 103, 72e81. Khajeali, A., Reza, F.A., Kasesaz, Y., Khodadadi, R., Khalili, A., Naseri, A., 2015b. Capability of NIPAM polymer gel in recording dose from the interaction of (10) B and thermal neutron in BNCT. Appl. Radiat. Isot. Incl. Data Instrum. Meth. Use Agric. Ind. Med. 105, 257e263. Khodadadi, R., Khajeali, A., Farajollahi, A.R., Hajalioghli, P., Raeisi, N., 2015a. Comparison of non-electrophoresis grade with electrophoresis grade BIS in NIPAM polymer gel preparation. Biolmpacts 5. Khodadadi, R., Khajeali, A., Farajollahi, A.R., Ziaei, J.E., Hajalioghli, P., 2015b. Dosimetric properties of N-isopropylacrylamide polymer gel using nonelectrophoresis grade BIS in preparation. J. Cancer Res. Ther. 11. Maryanski, M., 1999. Radiation-sensitive polymer gels: properties and manufacturing. In: Proceedings of the First Workshop on Radiation Therapy Gel Dosimetry, pp. 65e76. Lexington, KY. Maryanski, M., Ibbott, G., Eastman, P., Schulz, R., Gore, J., 1996. Radiation therapy dosimetry using magnetic resonance imaging of polymer gels. Med. Phys. 23, 699e705. Maryanski, M.J., Schulz, R.J., Ibbott, G.S., Gatenby, J.C., Xie, J., Horton, D., Gore, J.C., 1994. Magnetic resonance imaging of radiation dose distributions using a polymer-gel dosimeter. Phys. Med. Biol. 39, 1437. Ramm, U., Weber, U., Bock, M., Kramer, M., Bankamp, A., Damrau, M., Thilmann, C., Bottcher, H.D., Schad, L.R., Kraft, G., 2000. Three-dimensional BANG gel dosimetry in conformal carbon ion radiotherapy. Phys. Med. Biol. 45, N95eN102. Sauerwein, W.A.G., Wittig, A., Moss, R., Nakagawa, Y., 2012. Neutron Capture Therapy: Principles and Applications. Springer, Berlin Heidelberg. Senden, R.J., Jean, P.D., McAuley, K.B., Schreiner, L.J., 2006. Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical doseeresponse using different monomers. Phys. Med. Biol. 51, 3301. Uusi-Simola, J., Heikkinen, S., Kotiluoto, P., Seren, T., Seppala, T., Auterinen, I., Savolainen, S., 2007. MAGIC polymer gel for dosimetric verification in boron neutron capture therapy. J. Appl. Clin. Med. Phys. 8, 114e123. n, T., Seppa €la €, T., Auterinen, I., Uusi-Simola, J., Heikkinen, S., Kotiluoto, P., Sere Savolainen, S., 2006. MAGIC polymer gel for dosimetric verification in boron neutron capture therapy. J. Appl. Clin. Med. Phys. Am. Coll. Med. Phys. 8, 114e123. €ki, A., Heikkinen, S., Perkio €, J., Uusi-Simola, J., Savolainen, S., Kangasma €l€ Ramadan, U.A., Seppa a, T., Karila, J., Seren, T., Kotiluoto, P., 2003a. Study of the ® relative dose-response of BANG-3 polymer gel dosimeters in epithermal neutron irradiation. Phys. Med. Biol. 48, 2895. €ki, A., Heikkinen, S., Perkio €, J., Uusi-Simola, J., Savolainen, S., Kangasma €, T., Karila, J., Sere n, T., Kotiluoto, P., Sorvari, P., Ramadan, U.A., Sepp€ ala ® Auterinen, I., 2003b. Study of the relative dose-response of BANG-3 polymer gel dosimeters in epithermal neutron irradiation. Phys. Med. Biol. 48, 2895.