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Microdosimetry spectra and relative biological effectiveness of 15 and 30 MeV proton beams
Applied Radiation and Isotopes 97 (2015) 101–105
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Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Microdosimetry spectra and relative biological effectiveness of 15 and 30 MeV proton beams C.Y. Pan a, Y.W. Huang a, K.H. Cheng a, T.C. Chao a, C.J. Tung a,b,n a b
Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Kweishan 333, Taiwan Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital at Linkou, Kweishan 333, Taiwan
H I G H L I G H T S
There is lack of data on microdosimetry parameters of low-energy ( o40 MeV) protons. TEPC was built to measure lineal energy spectra of protons from TR 30/15 cyclotron. Monte Carlo FLUKA code was used to simulate lineal energy spectra of these protons. RBE was estimated for several biological endpoints using the lineal energy spectra.
art ic l e i nf o
a b s t r a c t
Article history: Received 14 July 2014 Received in revised form 16 November 2014 Accepted 18 December 2014 Available online 20 December 2014
The relative biological effectiveness (RBE) of high-energy protons has been well investigated, but estimates of RBE for lower-energy (o 40 MeV) protons are scarce. In the present work, measurements were made of the lineal energy spectra using a home-made miniature tissue-equivalent proportional counter for 15 and 30 MeV protons from the TR 30/15 cyclotron. Monte Carlo simulations were made for the same spectra using the FLUKA code. These spectra were coupled to several biological models to evaluate the RBE for various biological endpoints. & 2014 Elsevier Ltd. All rights reserved.
Keywords: Lineal energy Relative biological effectiveness Tissue equivalent proportional counter FLUKA code TR 30/15 cyclotron
1. Introduction The relative biological effectiveness (RBE) of high energy proton beams used in radiotherapy is reasonably well investigated (ICRU, 2007). The study of RBE for lower energy proton beams with higher linear energy transfer (LET) is scarce. This study, however, helps to increase the understanding of biophysical actions at the subcellular level, providing information that is required for radiobiological applications, and is relevant in the assessment of biological effectiveness of secondary particles produced by neutrons or ions. For example, an enhanced biological effectiveness has been found for 20 MeV protons in a submicrometer irradiation field (Schmid et al., 2012). The lineal energy distribution in a microscopic volume has been determined in n Corresponding author at: Department of Medical Imaging and Radiological Sciences, Chang Gung University, Kweishan Taoyuan 333, Taiwan. Fax: þ886 3 2118620. E-mail address: [email protected] (C.J. Tung).
http://dx.doi.org/10.1016/j.apradiso.2014.12.019 0969-8043/& 2014 Elsevier Ltd. All rights reserved.
order to analyze the in vitro biological data of low-energy protons (Folkard et al., 1989). Also, microdosimetric characteristics of 9.6 to 30 MeV proton beams have been examined with respect to secondary particles generated through nuclear reactions (Ghergherehchi et al., 2011). Measurements of microdosimetric lineal energy distributions have been previously performed using a spherical tissue-equivalent proportional counter (TEPC) for protons with energies ranging from 50–200 MeV (Borak et al., 2004). These protons were obtained by applying polycarbonate absorbers of different thicknesses to 194 MeV proton beams extracted from a synchrotron. The same experiments have not been made for proton energies below 50 MeV because of the large energy straggling as proton beams pass through thicker absorbers. In order to perform such experiments, it is necessary to use low-energy extracted proton beams. The TR 30/15 cyclotron at the Institute of Nuclear Energy Research (Shen et al., 2004), mainly used for the production of radioisotopes applied in nuclear medicine, is planned to be used for the biological experiments. Therefore, the RBE of TR 30/15
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proton beams should be assessed. Based on the microdosimety approach, RBE values can be determined from the lineal energy spectra using the biological models (Scholz, 2006). A simplified model makes use of the dose-mean lineal energies of the lineal energy spectra. A more comprehensive model applies the biological weighting functions for the various biological endpoints, e.g. the intestinal crypt cell regeneration (Pihet et al., 1990) and the induction of DNA double-strand break (DSB) (Semenenko and Stewart, 2006; Stewart et al., 2011). The biological weighting function for the intestinal crypt regeneration was derived using neutron measurements of the lineal energy spectra for a sensitive volume of 2 μm diameter. The biological weighting function for the induction of DSB was calculated using the Monte Carlo (MC) damage simulation code, MCDS. The lineal energy spectra of a micrometer sensitive volume are of considerable value in predicting the long-term biological effects (Hugtenburg, 2012). The individual DNA strands in a sub-micrometer sensitive volume are of particular interest in dictating the short-term biological effects such as radiation induced apoptosis of tumor cells (Carlson et al., 2008). In the present work, measurements of the lineal energy spectra were made using a home-made miniature TEPC (mini-TEPC) for 15 and 30 MeV protons extracted directly from a dual-energy compact cyclotron TR 30/15. To compare with measured data, MC simulations were also performed using the FLUKA code to compute the same spectra. It is found that the measured lineal energy spectra are generally reproduced by the MC simulated results. RBE values of 15 and 30 MeV protons are found in the range 1.00–1.25, depending on the biological endpoints.
2. Materials and methods
TEPC
Rexolite
hole
A 150 A-150
A-150 Rexolite
1
0 3 mm Al housing 0.3 0.01 mm anode wire
2.1. Mini-TEPC measurements TEPC is a primary instrument used to measure the single-event energy deposition of ionizing radiation in a biologically sensitive volume resembling the subcellular target. The deduced quantity of measurements is the microdosimetric lineal energy, y (ICRU, 1983). Biological damages induced by an ionizing radiation in the sensitive volume depend on its featured distribution of lineal energy for all primary and secondary particles. The difference in lineal energy distributions of various radiations can be used to explain the difference in their biological effects under equal absorbed doses (ICRU, 2007). Since both the gas and the wall of TEPC are made of tissue equivalent materials, the biological site in the tissue is then simulated according to the Fano theorem (Fano, 1954), i.e. the flux of secondary radiation is independent of the density of a medium with given composition. The TEPC should be operated under a low pressure and the voltage must be applied in the proportional counter region. Measuring and analyzing the pulse heights of all individual ionizing events, the TEPC is capable to determine the absorbed dose as a function of lineal energy, i.e. D(y). TEPC is particularly useful for applications in mixed field and particle beam dosimetry (Hsu et al., 2003, Kase et al., 2011), where each component of radiations (primary or secondary) makes its separate contribution to the absorbed dose. A typical TEPC has a spherical cavity of 25.4 mm in diameter. In the measurements of high intensity particle beams, TEPC easily undergoes the pile-up effect because of its large cavity volume. In such a case, a miniature TEPC is needed to facilitate the measurements. (De Nardo et al., 2004) In the present work, a home-made mini-TEPC with a cylindrical cavity of 1 mm in both diameter and height was constructed to measure the lineal energy spectra of low-energy proton beams emitted from the TR 30/15 cyclotron. All measurements were
Fig. 1. Photographs of the home-made mini-TEPC. Panel (a) shows the complete mini-TEPC, with the detector (at the left end) enclosed in an aluminum housing. Panel (b) shows the mini-TEPC detector, made of two Rexolite cylinders and a A-150 cylinder. The hole through the wall is to allow alpha particles (during calibrations) and protons (during measurements) to pass through it and reach the cavity. Panel (c) is the perspective view of the mini-TEPC with components and dimensions.
performed using the propane-based tissue-equivalent gas mixture, i.e. 55% C3H8, 39.6% CO2 and 5.4% N2 by partial pressures. The gas pressure of 422 Torr was used for the measurements of lineal energies in a 1 μm diameter site. Fig. 1 shows the photographs of this mini-TEPC. Panel (a) is the complete mini-TEPC, with the detector (at the left end) enclosed in an aluminum housing of 0.3 mm thickness that provides the electrostatic shielding and serves as a vacuum tight container. Removing the housing, Panel (b) shows the mini-TEPC detector consisting of two insulating Rexolite R cylinders and a conducting A-150 cylinder. The central hole through the wall is to allow alpha particles from an internal source to pass into the sensitive volume during TEPC calibrations. This hole is aligned along the central axis of the proton beam to allow 15 and 30 MeV protons reaching the cavity during measurements. Panel (c) shows the perspective view of the mini-TEPC with all components and dimensions. The 1 1 mm (height diameter) cylindrical cavity in the 13 13 mm A-150 plastic is the sensitive volume that actually detects the ionization signal. This volume is defined by the cylindrical extrusions of the Rexolite cylinders that enter the cavity. The anode is a 10 μm goldplated tungsten wire stretched by a spring. Before measurements, the mini-TEPC was filled with tissue equivalent gas by a predetermined pressure in order to simulate the microscopic site. The filling procedure included repeated runs of pumping out the gas down to 1 10 3 Torr and then filling up
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the tissue equivalent gas up to 500 Torr. After several runs, the final gas filling was set to the predetermined pressure. During measurements, the pulse height analysis system was used to examine the signals. This system included the high voltage supply (ORTEC 556), low-noise preamplifier (ORTEC 142PC), linear amplifier (ORTEC 572A), and multi-channel analyzer (Canberra ASA100 Board 5031820C). To avoid radiation damage and signal pileup, a reduced current (in the range 0.03–0.5 nA) was applied to the TR 30/15 cyclotron. 2.2. Monte Carlo simulations MC transport codes have extensively been employed to simulate the response of a detector for photon and neutron sources (Rollet et al., 2004). Recent studies demonstrated that MC FLUKA code (Battistoni et al., 2007; Ferrari et al., 2005) was able to predict the TEPC response under irradiation of proton beams (Rollet et al., 2010) and heavy-ion beams (Böhlen et al., 2012). To compare with the measured lineal energy spectra, FLUKA was used here to simulate the same spectra for proton beams ejected from the TR 30/ 15 cyclotron. Simulations were performed using a circular proton beam of 1.5 mm diameter by uniform irradiation. A Gaussian distribution for the energy spread was implemented with a standard deviation of 3.3%. The distance from the cyclotron beam exit to the detector (chamber) center was 50 mm. All experimental conditions, including detector geometry and materials, were simulated as closely as possible in FLUKA. In each simulation, 5 106 particles were executed. The energy losses, energy loss straggling, scattering, and nuclear interactions of all primary and secondary particles were included. The code was configured in a way that ensured the production and transport of all essential radiation particles. Descriptions of the experimental setup in FLUKA included dimensions and materials of the detector, the proton beam, and the irradiation geometry. To treat delta-electrons entering and leaving the mini-TEPC cavity, a threshold energy of electromagnetic particles was set to 1 keV, the minimum possible value in FLUKA. All simulations were made using FLUKA 2011 version.
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(Loncol et al., 1994). This function was obtained from experimental measurements using neutron therapy beams with different radiation qualities by the iterative procedure for the early effect of intestinal crypt regeneration (Pihet et al., 1990). Applying the biological weighing function, the RBE can be calculated from
RBE =
∫ d(y)⋅r(y)⋅dy.
(2)
Eq. (2) indicates the weighting of the single-event dose spectrum, d(y), by the y-dependent biological effectiveness function, r (y). Its validity was discussed previously by applying the unfolding calculations for different sets of RBE-d(y) data to high energy photons, protons and neutrons (Loncol et al., 1994). The model has been previously applied to boron neutron capture therapy (Hsu et al., 2003) and proton therapy (Coutrakon et al., 1997). More recently, the same method has been applied to heavy ion beams (Gerlach et al., 2002). In the present work, a similar biological weighting function for the DNA DSB derived using the MCDS code (Stewart et al., 2011) was also applied.
3. Results and discussion Fig. 2(a) shows a comparison of the dose-weighted lineal energy spectra, yd(y), measured using the mini-TEPC (solid curves) and simulated using the FLUKA code (dashed curves) for, nominally, 15 and 30 MeV protons emitted from the TR 30/15 cyclotron.
2.3. Biological models The lineal energy distribution can be coupled to a biological model to estimate the RBE of ionizing radiation. For example, a simple model involves the use of the dose-mean lineal energy defined by
y¯D =
∫ yd(y)dy,
(1)
where d(y) is the normalized dose probability density as a function of lineal energy. Based on this model, one can determine the RBE from the large database containing in-vitro and in-vivo data for a variety of biological effects (Loeffler and Durante, 2013, ICRU, 2007). Assuming y¼LET and adopting y¯D as the LET descriptor, one determines the RBE from measured RBE(LET) data. Note that LETΔ, a non-stochastic quantity, is the mean collisional (ionization and excitation) energy loss per unit path length by imposing an energy cutoff Δ (ICRU, 1970). On the other hand, y, a stochastic quantity, is the energy deposition per unit mean chord length subject to a geometric cutoff (e.g. a sphere) (ICRU, 1983). In general, these two quantities are different, however, it is common to assume y ELET for practical applications (Sabol and Weng, 1995). Due to the variation of measured RBE(LET) data, it was established previously the upper and lower bounds of measured data (Chu et al., 1993). Therefore, corresponding upper and lower limits of the RBE values can be determined. A more detailed model is based on the lineal energy spectrum, d(y), combining with the biological weighting function, r(y)
Fig. 2. Panel (a) shows a comparison of dose-weighted lineal energy spectra, yd(y), obtained from the mini-TEPC measurements (solid curves) and the MC simulations (dashed curves) for, nominally, 15 and 30 MeV proton beams from the TR 30/15 cyclotron. Also shown are the MC simulated results of 70 MeV protons and 60Co γrays (Rollet et al., 2010). Panel (b) is a similar comparison by plotting the same spectra with a logarithmic scale. Here the maximum attainable lineal energy 140 keV/μm, the so-called proton edge (ICRU, 1993), is indicated.
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It is seen that the general shapes of the measured spectra are reproduced by the MC simulations. It was noticed that for the purpose of simulating irradiated cells in the biological experiments, the aluminum housing of the mini-TEPC was removed in MC simulations. Thus the simulated lineal energy spectra represent results for proton beams directly emitted from the cyclotron. In mini-TEPC measurements, however, proton energies at the detector were slowed and broadened from the emitted energies due to the slowing-down and straggling of protons in the housing. Thus the lineal energy spectra measured by the mini-TEPC represent results for protons with lower and broader energies than simulated data. Applying the range-energy relation (Berger et al., 2011), it was estimated that proton energies at the detector (cavity) were 12.88 and 28.83 MeV for 15 and 30 MeV nominal energies. This makes the main peaks of measured data shift to higher lineal energies compared to simulated results. The spectra at y410 keV/μm correspond to scattered protons in the mini-TEPC, thus revealing a maximum attainable lineal energy 140 keV/μm, the so-called proton edge (ICRU, 1993), as indicated in Fig. 2(b) by a logarithmic plot. Indeed, the measured TEPC spectra were calibrated using the proton edge method, i.e. by analyzing the maximum energy that can be deposited by a recoil proton in the neutron field (Hsu et al., 2003). The proton edge is not seen in Fig. 2(a) because there is only a negligible amount of scattered protons with the maximum lineal energies in the cavity. Variations of the spectra at y4 20 keV/μm are due to the poor statistics because of the small number of ionization events in the cavity. The discrepancies between measurements and simulations are, possibly, due to the uncertainties in experimental setup, the pileup effect, and the limitations in FLIKA configurations and simulations (Böhlen et al., 2012). To inspect the trend of lineal energy spectra with increasing proton energy, MC simulated spectra of 70 MeV protons are also plotted in Fig. 2(a). It is seen that the spectra move to higher lineal energies as proton energy decreases, indicating an increased LET for lower-energy protons. It is also seen that proton lineal energy spectra are mainly distributed between 1 and 10 keV/μm, compared to the 60Co γ-ray spectrum between 0.1 and 10 keV/μm (Rollet et al., 2010). Applications of the lineal energy spectra to specify radiation quality can readily, but approximately, be achieved through the microdosimetry parameter: dose-mean lineal energy, y¯D . This parameter provides important information for the assessment of biological effectiveness of radiation. Previously, there have been measurements of the lineal energy spectra for protons with energies between 50 and 200 MeV using the spherical TEPC (Borak
Fig. 3. Dose-mean lineal energies obtained from the mini-TEPC measurements (open squares) and the MC simulations (open circles), as compared to measured data (solid squares) of the TEPC (Borak et al., 2004).
Fig. 4. Plots of RBE(LET ¼y) data (shaded area, left ordinate) and biological weighting functions (right ordinate), r(y), for the intestinal crypt regeneration (solid curve) and the DNA DSB (dashed curve). Also plotted is y¯D (triangles) 7 one standard deviation (horizontal lines with circles on the ends) for protons and 60Co γ-rays.
et al., 2004). Fig. 3 plots such measured data on y¯D (solid squares), compared to the present results of mini-TEPC measurements (open squares) and MC simulations (open circles). It reveals that y¯D increases with decreasing proton energy, by a steeper slope for proton energies below 40 MeV. Using available data of RBE(LET) and the simplified biological model, RBE values were determined from the parameter y¯D . Fig. 4 plots the region of scattered data on RBE(LET) (shaded area), i.e. bounded by the upper and lower limits. It shows that RBE equals 1.0 for y o1 keV/μm, and increases with y for y41 keV/μm. Also plotted in this figure is y¯D (triangles) 7 one standard deviation (horizontal lines with circles on the ends) for protons and 60Co γrays. Although the range of y-spectrum could not provide detailed information on the biological response, this range indicates the trend of y-spectrum with proton energy. As proton energy decreases, the fraction in the lineal energy spectra for y41 keV/μm increases, indicating higher RBE values for lower proton energies. To calculate the RBE values, the full y-spectra were substituted into Eq. (2). In Fig. 4, two biological weighting functions (right ordinate) are plotted, one for the intestinal crypt regeneration, rICR(y) (solid curve), and the other for the DNA DSB, rDSB(y) (dashed curve). Here rICR(y) is taken from the experimental data using therapeutic neutron beams with different radiation qualities (Pihet et al., 1990); rDSB(y) is derived using the MCDS code for proton beams with different energies (Semenenko and Stewart, 2006). It is seen that both weighting functions fall in the region between upper and lower limits of RBE(y) data. Below 25 keV/μm, rICR(y) orDSB(y); above 25 keV/μm, rICR(y) 4rDSB(y). Applying the simplified biological model, Fig. 5 shows that RBE ¼1.00–1.23 (15 MeV) and 1.00–1.22 (30 MeV) for MC simulations, and RBE ¼ 1.00–1.24 (12.88 MeV) and 1.00–1.15 (28.83 MeV) for mini-TEPC measurement. Based on the biological weighting function model, RBEICR ¼1.01 (15 MeV) and 1.00 (30 MeV) from MC simulations, and RBEDSB ¼1.19 (12.88 MeV) and 1.12 (28.83 MeV) from mini-TEPC measurements. In summary, RBE tends to increase with decreasing proton energy although the increase is fairly slow. All RBE values determined using the biological weighting functions fall within the range of those determined using the simplified model. RBE values for the crypt cell regeneration are close to the lower limit of this range. RBE values for the DNA DSB are approaching the upper limit of the range.
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Fig. 5. Results of RBE values obtained using the simplified biological model: RBE¼ 1.00–1.23 (15 MeV) and 1.00–1.22 (30 MeV) from MC simulations; 1.00–1.24 (12.88 MeV) and 1.00–1.15 (28.83 MeV) from mini-TEPC measurement. Corresponding results using the biological weighting function model: RBEICR ¼ 1.01 (15 MeV) and 1.00 (30 MeV) from MC simulations; RBEDSB ¼ 1.19 (12.88 MeV) and 1.12 (28.83 MeV) from mini-TEPC measurements.
4. Conclusions Data are available for lineal energy distributions measured using the TEPC for protons of energies ranging from 50 to 200 MeV (Borak et al., 2004). Data are also available for corresponding distributions simulated using the MC code for protons in the range 40–200 MeV (Palajova et al., 2006). Because of the limited penetration of proton beams below 40 MeV, there is a lack of data on these microdosimetry distributions. But low-energy protons exist as part of the slowing-down process from high-energy therapeutic proton beams and as secondary particles produced by therapeutic neutrons and heavy-ions. Besides, low-energy protons are directly generated from medical cyclotrons that can be used for biology experiments. Therefore, microdosimety investigations are required in order to assess the RBE values of low-energy protons. In the present work, a home-made mini-TEPC was constructed to test its capability of measuring the lineal energy spectra of low-energy protons from the TR 30/15 cyclotron. Also, the FLUKA code was used to test its ability of simulating the same distributions. It was demonstrated that both the mini-TEPC and the FLUKA were satisfactory in determining the lineal energy spectra of low-energy protons. Combining the lineal energy spectra and the biological models, RBE values were estimated for various biological endpoints. It showed that RBE values of 15 and 30 MeV protons were in the range 1.00–1.25, depending on the biological endpoints. It also showed that RBE values for the DNA DSB were higher than those for the crypt cell regeneration.
Acknowledgments This research was supported by the National Science Council of the Republic of China and the Chang Gung Medical Research Program (CMRPD1C0662 and CMRPD1C0642).
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Microdosimetry spectra and relative biological effectiveness of 15 and 30 MeV proton beams C.Y. Pan a, Y.W. Huang a, K.H. Cheng a, T.C. Chao a, C.J. Tung a,b,n a b
Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Kweishan 333, Taiwan Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital at Linkou, Kweishan 333, Taiwan
H I G H L I G H T S
There is lack of data on microdosimetry parameters of low-energy ( o40 MeV) protons. TEPC was built to measure lineal energy spectra of protons from TR 30/15 cyclotron. Monte Carlo FLUKA code was used to simulate lineal energy spectra of these protons. RBE was estimated for several biological endpoints using the lineal energy spectra.
art ic l e i nf o
a b s t r a c t
Article history: Received 14 July 2014 Received in revised form 16 November 2014 Accepted 18 December 2014 Available online 20 December 2014
The relative biological effectiveness (RBE) of high-energy protons has been well investigated, but estimates of RBE for lower-energy (o 40 MeV) protons are scarce. In the present work, measurements were made of the lineal energy spectra using a home-made miniature tissue-equivalent proportional counter for 15 and 30 MeV protons from the TR 30/15 cyclotron. Monte Carlo simulations were made for the same spectra using the FLUKA code. These spectra were coupled to several biological models to evaluate the RBE for various biological endpoints. & 2014 Elsevier Ltd. All rights reserved.
Keywords: Lineal energy Relative biological effectiveness Tissue equivalent proportional counter FLUKA code TR 30/15 cyclotron
1. Introduction The relative biological effectiveness (RBE) of high energy proton beams used in radiotherapy is reasonably well investigated (ICRU, 2007). The study of RBE for lower energy proton beams with higher linear energy transfer (LET) is scarce. This study, however, helps to increase the understanding of biophysical actions at the subcellular level, providing information that is required for radiobiological applications, and is relevant in the assessment of biological effectiveness of secondary particles produced by neutrons or ions. For example, an enhanced biological effectiveness has been found for 20 MeV protons in a submicrometer irradiation field (Schmid et al., 2012). The lineal energy distribution in a microscopic volume has been determined in n Corresponding author at: Department of Medical Imaging and Radiological Sciences, Chang Gung University, Kweishan Taoyuan 333, Taiwan. Fax: þ886 3 2118620. E-mail address: [email protected] (C.J. Tung).
http://dx.doi.org/10.1016/j.apradiso.2014.12.019 0969-8043/& 2014 Elsevier Ltd. All rights reserved.
order to analyze the in vitro biological data of low-energy protons (Folkard et al., 1989). Also, microdosimetric characteristics of 9.6 to 30 MeV proton beams have been examined with respect to secondary particles generated through nuclear reactions (Ghergherehchi et al., 2011). Measurements of microdosimetric lineal energy distributions have been previously performed using a spherical tissue-equivalent proportional counter (TEPC) for protons with energies ranging from 50–200 MeV (Borak et al., 2004). These protons were obtained by applying polycarbonate absorbers of different thicknesses to 194 MeV proton beams extracted from a synchrotron. The same experiments have not been made for proton energies below 50 MeV because of the large energy straggling as proton beams pass through thicker absorbers. In order to perform such experiments, it is necessary to use low-energy extracted proton beams. The TR 30/15 cyclotron at the Institute of Nuclear Energy Research (Shen et al., 2004), mainly used for the production of radioisotopes applied in nuclear medicine, is planned to be used for the biological experiments. Therefore, the RBE of TR 30/15
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proton beams should be assessed. Based on the microdosimety approach, RBE values can be determined from the lineal energy spectra using the biological models (Scholz, 2006). A simplified model makes use of the dose-mean lineal energies of the lineal energy spectra. A more comprehensive model applies the biological weighting functions for the various biological endpoints, e.g. the intestinal crypt cell regeneration (Pihet et al., 1990) and the induction of DNA double-strand break (DSB) (Semenenko and Stewart, 2006; Stewart et al., 2011). The biological weighting function for the intestinal crypt regeneration was derived using neutron measurements of the lineal energy spectra for a sensitive volume of 2 μm diameter. The biological weighting function for the induction of DSB was calculated using the Monte Carlo (MC) damage simulation code, MCDS. The lineal energy spectra of a micrometer sensitive volume are of considerable value in predicting the long-term biological effects (Hugtenburg, 2012). The individual DNA strands in a sub-micrometer sensitive volume are of particular interest in dictating the short-term biological effects such as radiation induced apoptosis of tumor cells (Carlson et al., 2008). In the present work, measurements of the lineal energy spectra were made using a home-made miniature TEPC (mini-TEPC) for 15 and 30 MeV protons extracted directly from a dual-energy compact cyclotron TR 30/15. To compare with measured data, MC simulations were also performed using the FLUKA code to compute the same spectra. It is found that the measured lineal energy spectra are generally reproduced by the MC simulated results. RBE values of 15 and 30 MeV protons are found in the range 1.00–1.25, depending on the biological endpoints.
2. Materials and methods
TEPC
Rexolite
hole
A 150 A-150
A-150 Rexolite
1
0 3 mm Al housing 0.3 0.01 mm anode wire
2.1. Mini-TEPC measurements TEPC is a primary instrument used to measure the single-event energy deposition of ionizing radiation in a biologically sensitive volume resembling the subcellular target. The deduced quantity of measurements is the microdosimetric lineal energy, y (ICRU, 1983). Biological damages induced by an ionizing radiation in the sensitive volume depend on its featured distribution of lineal energy for all primary and secondary particles. The difference in lineal energy distributions of various radiations can be used to explain the difference in their biological effects under equal absorbed doses (ICRU, 2007). Since both the gas and the wall of TEPC are made of tissue equivalent materials, the biological site in the tissue is then simulated according to the Fano theorem (Fano, 1954), i.e. the flux of secondary radiation is independent of the density of a medium with given composition. The TEPC should be operated under a low pressure and the voltage must be applied in the proportional counter region. Measuring and analyzing the pulse heights of all individual ionizing events, the TEPC is capable to determine the absorbed dose as a function of lineal energy, i.e. D(y). TEPC is particularly useful for applications in mixed field and particle beam dosimetry (Hsu et al., 2003, Kase et al., 2011), where each component of radiations (primary or secondary) makes its separate contribution to the absorbed dose. A typical TEPC has a spherical cavity of 25.4 mm in diameter. In the measurements of high intensity particle beams, TEPC easily undergoes the pile-up effect because of its large cavity volume. In such a case, a miniature TEPC is needed to facilitate the measurements. (De Nardo et al., 2004) In the present work, a home-made mini-TEPC with a cylindrical cavity of 1 mm in both diameter and height was constructed to measure the lineal energy spectra of low-energy proton beams emitted from the TR 30/15 cyclotron. All measurements were
Fig. 1. Photographs of the home-made mini-TEPC. Panel (a) shows the complete mini-TEPC, with the detector (at the left end) enclosed in an aluminum housing. Panel (b) shows the mini-TEPC detector, made of two Rexolite cylinders and a A-150 cylinder. The hole through the wall is to allow alpha particles (during calibrations) and protons (during measurements) to pass through it and reach the cavity. Panel (c) is the perspective view of the mini-TEPC with components and dimensions.
performed using the propane-based tissue-equivalent gas mixture, i.e. 55% C3H8, 39.6% CO2 and 5.4% N2 by partial pressures. The gas pressure of 422 Torr was used for the measurements of lineal energies in a 1 μm diameter site. Fig. 1 shows the photographs of this mini-TEPC. Panel (a) is the complete mini-TEPC, with the detector (at the left end) enclosed in an aluminum housing of 0.3 mm thickness that provides the electrostatic shielding and serves as a vacuum tight container. Removing the housing, Panel (b) shows the mini-TEPC detector consisting of two insulating Rexolite R cylinders and a conducting A-150 cylinder. The central hole through the wall is to allow alpha particles from an internal source to pass into the sensitive volume during TEPC calibrations. This hole is aligned along the central axis of the proton beam to allow 15 and 30 MeV protons reaching the cavity during measurements. Panel (c) shows the perspective view of the mini-TEPC with all components and dimensions. The 1 1 mm (height diameter) cylindrical cavity in the 13 13 mm A-150 plastic is the sensitive volume that actually detects the ionization signal. This volume is defined by the cylindrical extrusions of the Rexolite cylinders that enter the cavity. The anode is a 10 μm goldplated tungsten wire stretched by a spring. Before measurements, the mini-TEPC was filled with tissue equivalent gas by a predetermined pressure in order to simulate the microscopic site. The filling procedure included repeated runs of pumping out the gas down to 1 10 3 Torr and then filling up
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the tissue equivalent gas up to 500 Torr. After several runs, the final gas filling was set to the predetermined pressure. During measurements, the pulse height analysis system was used to examine the signals. This system included the high voltage supply (ORTEC 556), low-noise preamplifier (ORTEC 142PC), linear amplifier (ORTEC 572A), and multi-channel analyzer (Canberra ASA100 Board 5031820C). To avoid radiation damage and signal pileup, a reduced current (in the range 0.03–0.5 nA) was applied to the TR 30/15 cyclotron. 2.2. Monte Carlo simulations MC transport codes have extensively been employed to simulate the response of a detector for photon and neutron sources (Rollet et al., 2004). Recent studies demonstrated that MC FLUKA code (Battistoni et al., 2007; Ferrari et al., 2005) was able to predict the TEPC response under irradiation of proton beams (Rollet et al., 2010) and heavy-ion beams (Böhlen et al., 2012). To compare with the measured lineal energy spectra, FLUKA was used here to simulate the same spectra for proton beams ejected from the TR 30/ 15 cyclotron. Simulations were performed using a circular proton beam of 1.5 mm diameter by uniform irradiation. A Gaussian distribution for the energy spread was implemented with a standard deviation of 3.3%. The distance from the cyclotron beam exit to the detector (chamber) center was 50 mm. All experimental conditions, including detector geometry and materials, were simulated as closely as possible in FLUKA. In each simulation, 5 106 particles were executed. The energy losses, energy loss straggling, scattering, and nuclear interactions of all primary and secondary particles were included. The code was configured in a way that ensured the production and transport of all essential radiation particles. Descriptions of the experimental setup in FLUKA included dimensions and materials of the detector, the proton beam, and the irradiation geometry. To treat delta-electrons entering and leaving the mini-TEPC cavity, a threshold energy of electromagnetic particles was set to 1 keV, the minimum possible value in FLUKA. All simulations were made using FLUKA 2011 version.
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(Loncol et al., 1994). This function was obtained from experimental measurements using neutron therapy beams with different radiation qualities by the iterative procedure for the early effect of intestinal crypt regeneration (Pihet et al., 1990). Applying the biological weighing function, the RBE can be calculated from
RBE =
∫ d(y)⋅r(y)⋅dy.
(2)
Eq. (2) indicates the weighting of the single-event dose spectrum, d(y), by the y-dependent biological effectiveness function, r (y). Its validity was discussed previously by applying the unfolding calculations for different sets of RBE-d(y) data to high energy photons, protons and neutrons (Loncol et al., 1994). The model has been previously applied to boron neutron capture therapy (Hsu et al., 2003) and proton therapy (Coutrakon et al., 1997). More recently, the same method has been applied to heavy ion beams (Gerlach et al., 2002). In the present work, a similar biological weighting function for the DNA DSB derived using the MCDS code (Stewart et al., 2011) was also applied.
3. Results and discussion Fig. 2(a) shows a comparison of the dose-weighted lineal energy spectra, yd(y), measured using the mini-TEPC (solid curves) and simulated using the FLUKA code (dashed curves) for, nominally, 15 and 30 MeV protons emitted from the TR 30/15 cyclotron.
2.3. Biological models The lineal energy distribution can be coupled to a biological model to estimate the RBE of ionizing radiation. For example, a simple model involves the use of the dose-mean lineal energy defined by
y¯D =
∫ yd(y)dy,
(1)
where d(y) is the normalized dose probability density as a function of lineal energy. Based on this model, one can determine the RBE from the large database containing in-vitro and in-vivo data for a variety of biological effects (Loeffler and Durante, 2013, ICRU, 2007). Assuming y¼LET and adopting y¯D as the LET descriptor, one determines the RBE from measured RBE(LET) data. Note that LETΔ, a non-stochastic quantity, is the mean collisional (ionization and excitation) energy loss per unit path length by imposing an energy cutoff Δ (ICRU, 1970). On the other hand, y, a stochastic quantity, is the energy deposition per unit mean chord length subject to a geometric cutoff (e.g. a sphere) (ICRU, 1983). In general, these two quantities are different, however, it is common to assume y ELET for practical applications (Sabol and Weng, 1995). Due to the variation of measured RBE(LET) data, it was established previously the upper and lower bounds of measured data (Chu et al., 1993). Therefore, corresponding upper and lower limits of the RBE values can be determined. A more detailed model is based on the lineal energy spectrum, d(y), combining with the biological weighting function, r(y)
Fig. 2. Panel (a) shows a comparison of dose-weighted lineal energy spectra, yd(y), obtained from the mini-TEPC measurements (solid curves) and the MC simulations (dashed curves) for, nominally, 15 and 30 MeV proton beams from the TR 30/15 cyclotron. Also shown are the MC simulated results of 70 MeV protons and 60Co γrays (Rollet et al., 2010). Panel (b) is a similar comparison by plotting the same spectra with a logarithmic scale. Here the maximum attainable lineal energy 140 keV/μm, the so-called proton edge (ICRU, 1993), is indicated.
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It is seen that the general shapes of the measured spectra are reproduced by the MC simulations. It was noticed that for the purpose of simulating irradiated cells in the biological experiments, the aluminum housing of the mini-TEPC was removed in MC simulations. Thus the simulated lineal energy spectra represent results for proton beams directly emitted from the cyclotron. In mini-TEPC measurements, however, proton energies at the detector were slowed and broadened from the emitted energies due to the slowing-down and straggling of protons in the housing. Thus the lineal energy spectra measured by the mini-TEPC represent results for protons with lower and broader energies than simulated data. Applying the range-energy relation (Berger et al., 2011), it was estimated that proton energies at the detector (cavity) were 12.88 and 28.83 MeV for 15 and 30 MeV nominal energies. This makes the main peaks of measured data shift to higher lineal energies compared to simulated results. The spectra at y410 keV/μm correspond to scattered protons in the mini-TEPC, thus revealing a maximum attainable lineal energy 140 keV/μm, the so-called proton edge (ICRU, 1993), as indicated in Fig. 2(b) by a logarithmic plot. Indeed, the measured TEPC spectra were calibrated using the proton edge method, i.e. by analyzing the maximum energy that can be deposited by a recoil proton in the neutron field (Hsu et al., 2003). The proton edge is not seen in Fig. 2(a) because there is only a negligible amount of scattered protons with the maximum lineal energies in the cavity. Variations of the spectra at y4 20 keV/μm are due to the poor statistics because of the small number of ionization events in the cavity. The discrepancies between measurements and simulations are, possibly, due to the uncertainties in experimental setup, the pileup effect, and the limitations in FLIKA configurations and simulations (Böhlen et al., 2012). To inspect the trend of lineal energy spectra with increasing proton energy, MC simulated spectra of 70 MeV protons are also plotted in Fig. 2(a). It is seen that the spectra move to higher lineal energies as proton energy decreases, indicating an increased LET for lower-energy protons. It is also seen that proton lineal energy spectra are mainly distributed between 1 and 10 keV/μm, compared to the 60Co γ-ray spectrum between 0.1 and 10 keV/μm (Rollet et al., 2010). Applications of the lineal energy spectra to specify radiation quality can readily, but approximately, be achieved through the microdosimetry parameter: dose-mean lineal energy, y¯D . This parameter provides important information for the assessment of biological effectiveness of radiation. Previously, there have been measurements of the lineal energy spectra for protons with energies between 50 and 200 MeV using the spherical TEPC (Borak
Fig. 3. Dose-mean lineal energies obtained from the mini-TEPC measurements (open squares) and the MC simulations (open circles), as compared to measured data (solid squares) of the TEPC (Borak et al., 2004).
Fig. 4. Plots of RBE(LET ¼y) data (shaded area, left ordinate) and biological weighting functions (right ordinate), r(y), for the intestinal crypt regeneration (solid curve) and the DNA DSB (dashed curve). Also plotted is y¯D (triangles) 7 one standard deviation (horizontal lines with circles on the ends) for protons and 60Co γ-rays.
et al., 2004). Fig. 3 plots such measured data on y¯D (solid squares), compared to the present results of mini-TEPC measurements (open squares) and MC simulations (open circles). It reveals that y¯D increases with decreasing proton energy, by a steeper slope for proton energies below 40 MeV. Using available data of RBE(LET) and the simplified biological model, RBE values were determined from the parameter y¯D . Fig. 4 plots the region of scattered data on RBE(LET) (shaded area), i.e. bounded by the upper and lower limits. It shows that RBE equals 1.0 for y o1 keV/μm, and increases with y for y41 keV/μm. Also plotted in this figure is y¯D (triangles) 7 one standard deviation (horizontal lines with circles on the ends) for protons and 60Co γrays. Although the range of y-spectrum could not provide detailed information on the biological response, this range indicates the trend of y-spectrum with proton energy. As proton energy decreases, the fraction in the lineal energy spectra for y41 keV/μm increases, indicating higher RBE values for lower proton energies. To calculate the RBE values, the full y-spectra were substituted into Eq. (2). In Fig. 4, two biological weighting functions (right ordinate) are plotted, one for the intestinal crypt regeneration, rICR(y) (solid curve), and the other for the DNA DSB, rDSB(y) (dashed curve). Here rICR(y) is taken from the experimental data using therapeutic neutron beams with different radiation qualities (Pihet et al., 1990); rDSB(y) is derived using the MCDS code for proton beams with different energies (Semenenko and Stewart, 2006). It is seen that both weighting functions fall in the region between upper and lower limits of RBE(y) data. Below 25 keV/μm, rICR(y) orDSB(y); above 25 keV/μm, rICR(y) 4rDSB(y). Applying the simplified biological model, Fig. 5 shows that RBE ¼1.00–1.23 (15 MeV) and 1.00–1.22 (30 MeV) for MC simulations, and RBE ¼ 1.00–1.24 (12.88 MeV) and 1.00–1.15 (28.83 MeV) for mini-TEPC measurement. Based on the biological weighting function model, RBEICR ¼1.01 (15 MeV) and 1.00 (30 MeV) from MC simulations, and RBEDSB ¼1.19 (12.88 MeV) and 1.12 (28.83 MeV) from mini-TEPC measurements. In summary, RBE tends to increase with decreasing proton energy although the increase is fairly slow. All RBE values determined using the biological weighting functions fall within the range of those determined using the simplified model. RBE values for the crypt cell regeneration are close to the lower limit of this range. RBE values for the DNA DSB are approaching the upper limit of the range.
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Fig. 5. Results of RBE values obtained using the simplified biological model: RBE¼ 1.00–1.23 (15 MeV) and 1.00–1.22 (30 MeV) from MC simulations; 1.00–1.24 (12.88 MeV) and 1.00–1.15 (28.83 MeV) from mini-TEPC measurement. Corresponding results using the biological weighting function model: RBEICR ¼ 1.01 (15 MeV) and 1.00 (30 MeV) from MC simulations; RBEDSB ¼ 1.19 (12.88 MeV) and 1.12 (28.83 MeV) from mini-TEPC measurements.
4. Conclusions Data are available for lineal energy distributions measured using the TEPC for protons of energies ranging from 50 to 200 MeV (Borak et al., 2004). Data are also available for corresponding distributions simulated using the MC code for protons in the range 40–200 MeV (Palajova et al., 2006). Because of the limited penetration of proton beams below 40 MeV, there is a lack of data on these microdosimetry distributions. But low-energy protons exist as part of the slowing-down process from high-energy therapeutic proton beams and as secondary particles produced by therapeutic neutrons and heavy-ions. Besides, low-energy protons are directly generated from medical cyclotrons that can be used for biology experiments. Therefore, microdosimety investigations are required in order to assess the RBE values of low-energy protons. In the present work, a home-made mini-TEPC was constructed to test its capability of measuring the lineal energy spectra of low-energy protons from the TR 30/15 cyclotron. Also, the FLUKA code was used to test its ability of simulating the same distributions. It was demonstrated that both the mini-TEPC and the FLUKA were satisfactory in determining the lineal energy spectra of low-energy protons. Combining the lineal energy spectra and the biological models, RBE values were estimated for various biological endpoints. It showed that RBE values of 15 and 30 MeV protons were in the range 1.00–1.25, depending on the biological endpoints. It also showed that RBE values for the DNA DSB were higher than those for the crypt cell regeneration.
Acknowledgments This research was supported by the National Science Council of the Republic of China and the Chang Gung Medical Research Program (CMRPD1C0662 and CMRPD1C0642).
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