Single Photon Emission Tomography Approach for Online Patient Dose Assessment in Boron Neutron Capture Therapy

Single Photon Emission Tomography Approach for Online Patient Dose Assessment in Boron Neutron Capture Therapy Daniel M Minsky a,b,c*, Alejandro Valda a,b, Andrés J Kreiner a,b,c and Alejandro A Burlon a,b a Comisión Nacional de Energía Atómica, Departamento de Física, Av. Gral. Paz 1499, 1650, San Martín, Argentina b Universidad Nacional de San Martín, Escuela de Ciencia y Tecnología, M. de Irigoyen 3100, 1650, San Martín, Argentina c CONICET, Av. Rivadavia 1917, 1033, Buenos Aires, Argentina Abstract. A tomographic imaging system for the measurement of the spatial distribution of the absorbed dose during a Boron Neutron Capture Therapy (BNCT) session is presented. The 10 B(n,α) 7 Li boron neutron capture reaction produces a 478 kev gamma ray in 94% of the cases. Therefore its detection can serve as a basis for a non-invasive online absorbed dose determination since the dose absorbed by the tumor and healthy tissue strongly depends on the boron uptake and the neutron flux. For this purpose, a dedicated tomographic imaging system based on Single Photon Emission Computed Tomography is proposed. Monte Carlo numerical simulations are used for the system design aimed to have a spatial resolution of 1 cm. Prototypes based on CdZnTe semiconductor detectors and LaBr 3 (Ce) scintillators with optimized shielding were designed with Monte Carlo simulations. They were built and tested in reactor and accelerator based BNCT facilities. A projection of a phantom with two tumors with 400 ppm of 10 B was successfully measured at the accelerator facility of the University of Birmingham. KEYWORDS: BNCT; SPECT; dosimetry; prompt-gamma detection. 1. Introduction Boron neutron capture therapy (BNCT) [1] is a radiation therapy modality under development for the treatment of some types of cancers like melanoma and glioblastoma multiforme. It is performed in two steps: first, a stable isotope of boron ( 10 B) is administered to the patient via a carrier drug and then the patient is irradiated with an epithermal neutron beam. The neutrons are moderated as they penetrate into the patient s tissue and reach the tumor with thermal energy. 10 B has a high thermal neutron capture cross section (3840 b) leading to the 10 B(n,α) 7 Li reaction. The emitted charged particles have a high linear energy transfer (LET) and they deliver all their energy (1.47 MeV for the α particle and 0.84 MeV for the 7 Li) in a short range (9 µm for the α particle and 5 µm for the 7 Li). Hence only the cells in close proximity to the reaction point may suffer a lethal effect. In BNCT the dose delivered to a patient depends both on the neutron beam quality and on the selectivity and concentration of the drug used as the boron vector. As a consequence of the several neutron interactions with the different nuclei present in tissue, the dose delivered has several components with high and low LET. However in tumors having a typical boron concentration of 40 ppm, the neutron capture reactions in boron contribute to about 80 % of the total dose. The boron concentrations in tumour and in healthy tissue needed for the dose assessment are currently inferred from (a) the pharmacokinetics of the boron compound obtained from biodistribution studies not necessarily performed on the specific patient to be treated and (b) the measurement of 10 B concentration in patient s blood samples before and after irradiation. This method has large uncertainties due to patient-to-patient variability and provides only global concentration values in tumour and in healthy tissue. Finally the patient dose is evaluated from these 10 B concentrations together with a simulated neutron flux. * Presenting author, E-mail: minsky@tandar.cnea.gov.ar 1

A better technique is hence necessary to improve the dosimetry in BNCT. In this regard it is important to point out that in 94 % of the neutron captures in 10 B, the 7 Li ion is emitted in an excited state which promptly decays through a characteristic 478 kev gamma-ray. As the linear attenuation coefficient in tissue at this energy is about 0.1 cm -1, the gamma-rays escape out of the patient s body to a large extent. Therefore the extracorporeal measurement of the 478 kev prompt-gamma radiation can be performed and directly related to the boron dose component. Moreover, the use of a radiation detection system with imaging (in particular, tomographic) capabilities could provide a non-invasive way to determine the boron dose distribution (dose mapping) delivered to the patient as well as an online dose monitoring. Several groups have studied different approaches for this online dosimetry [2, 6]. In this work we present the design of a SPECT (Single-Photon Emission Computed Tomography) imaging system especially dedicated to operate under the particular conditions (gamma-ray and neutron radiation background) present in a BNCT treatment room. The system is designed in order to provide the boron dose distribution with a spatial resolution of about 1 cm. Results of Monte Carlo numerical simulations for the final system are presented as well as numerical and experimental results obtained with a prototype systems using CdZnTe semiconductor detectors and LaBr 3 (Ce) scintillation detectors. 2. Design considerations for a complete system The system was designed for imaging the boron captures in a patient head. In a complete BNCT treatment there are about 2 10 9 emissions of 478 kev photons per cubic centimeter in tumor. This emission number is determined by the dose needed to obtain a significant tumor control without exceeding the maximum healthy tissue dose. Considering an intrinsic detector efficiency of the order of 10 % and a collimator geometrical efficiency of the order of 10 3 %, there is a small number of events expected to be detected during the treatment that finally will limit the image quality. As a compromise between detector efficiency and spatial resolution we designed our collimators to obtain 1 cm resolution at a distance of 20 cm with a geometrical efficiency 3.4 10 3 %. In order to largely cover a transaxial field of view of 20 cm, a collimator of 23.7 cm in lateral length was chosen; having 37 parallel holes with 4.4 mm in diameter. This collimator configuration can house an array of 37 independent detectors [6]. For the tomographic acquisition a total of 20 angular positions (evenly spaced at 9 degrees, from 0 to 171 degrees) are considered giving a total of 740 projection data. The image consists of 21 21 pixels of 1 cm 1 cm size each. The algorithm chosen for the tomographic reconstruction was Expectation Maximization - Maximum Likelihood (EM-ML) [7]. The system matrix A needed for the reconstruction was calculated by Monte Carlo numerical simulations using the MCNP v5.140 code [8]; attenuation, scatter in collimator and photoelectric absorption in the scintillator were considered. Figure 1: (a) Phantom used in the numerical simulations. (b) Reconstructed image with acquired Poisson statistical noise negligible. (c) Reconstructed image having a 10 % signal to noise ratio in the most significant projection. 2

The MCNP code was also used for simulating the acquisition of the phantom shown in Fig. 1. This phantom consists of a water-filled cylinder of 8 cm radius containing four cylindrical tumors of different radii: 0.25, 0.5, 0.75 and 1 cm. The activity concentration was 4 (arbitrary units) for tumors and 1 for the rest of the phantom in agreement with the concentration ratio between tumor and healthy tissue found for p-boronphenylalanine (BPA), the usual boron carrier drug in BNCT [1]. The energy of the simulated gamma emission was 478 kev. The simulations take into account the attenuation and scattering processes in the phantom and the collimator but no other sources of background such as gamma rays produced by neutron capture in hydrogen. Fig. 1 also shows the reconstructed images for two cases: where the statistical fluctuations (Poisson noise) in the acquired projections are negligible and where the signal to statistical fluctuation ratio in the projections is 10 %. 3. Prototype design 3.1 Collimator and detectors The collimator was designed in order to maximize the detection efficiency with a spatial resolution of 1 cm at the center of the field of view (FOV). The detector to FOV center was chosen to be 60 cm due to practical considerations. Therefore the other dimensions resulted in 0.5cm for the hole diameter and 30 cm for the collimator length with a geometric efficiency of 4.34 10-6. Two kind of detectors were tested in the prototype: CdZnTe room-temperature semiconductors and LaBr 3 (Ce) scintillation detectors. The CdZnTe have a size of 5 5 5 mm 3 and LaBr 3 (Ce) are 2.54 cm 2.54 cm (diameter height) cylindrical scintillators. The CdZnTe prototype was tested in the BNCT facility located in the RA6 reactor of the Centro Atómico Bariloche (Argentina) and the scintillatorbased prototype in the accelerator based BNCT facility (AB-BNCT) of the University of Birmingham (United Kingdom). 3.2 Shielding The shielding was designed for blocking not only gammas but also neutrons, since they can generate gamma contamination inside the detectors. The proposed shielding, in the case of the prototype for the AB-BNCT facility, consists of several layers as shown in Fig. 2: an external layer of a moderator material with high concentration of hydrogen (paraffin) mixed with lithium (14% in mass of Nat Li 2 CO 3 ) to thermalize and capture neutrons, a second layer of lead to shield from gammas and a layer of 95% 6 Li enriched lithium carbonate to capture residual thermal neutrons before reaching the detector. Figure 2: Detector shielding. A material with high hydrogen content thermalizes the neutrons, a lead layer blocks gammas and a 6 Li layer captures thermal neutrons before reaching the detectors. Collimator Paraffin with Nat Li 2CO 3 Pb 6 Li 2CO 3 Detector The proposed shielding has been simulated with MCNP 5 for different paraffin and lead thicknesses in order to estimate the expected background under the 478keV peak. Two different contributions to the background have been taken into account: the gamma background coming from outside the detectors and the gamma background generated inside them by neutron captures. The background decreases 3

with the lead thickness due to attenuation of the external gamma rays, and it also reduces with the moderator thickness since it prevents captures in the crystal and the subsequent gamma production. Due to weight and space limitations, the shielding lead and paraffin layers have been chosen to be 10 cm thick each. Under this condition the expected background count rate is 120 cps for the measurements at the AB-BNCT facility. 4. Experimental results Fig. 3 shows the built scintillator-based prototype placed in the BNCT accelerator facility of the University of Birmingham. Figure 3: Experimental setup with the shielding partially removed. Beam shapping assembly Beam Port SPECT prototype The collimator resolution has been tested with the CdZnTe detectors; Fig. 4 shows the measured and simulated responses. A simple phantom containing a 241 Am point source has been used to test the reconstruction algorithm. The source was placed in a 9.22 cm radius cylindrical phantom at 4 cm from its axis. The acquisition and reconstruction scheme was as in the designed final setup: 20 projections of 41 bins each reconstructed on a 21 21 image matrix using the EM-ML algorithm. The reconstructed image is shown in Fig. 4. Figure 4: Comparison of experimental spatial resolution of the collimators with simulations. Figure 5: Reconstructed image of a phantom with a point 241Am source. 1.2 1.0 Experimental Simulation Reconstructed Intensity [Bq] 25000 Normalized intensity 0.8 0.6 0.4 0.2 R=0.97cm 20000 15000 10000 0.0-1.0-0.5 0.0 0.5 1.0 Off-axis position [cm] 5000-10 -8-6 -4-2 0 X [cm] 2 4 6-2 0 2 4 6 810 8-8 -6-4 10-10 Y [cm] 4

A cylindrical water-filled phantom (radius 9.22 cm) containing a cylindrical tumor model (radius 3 cm) having 1000 ppm in 10 B concentration was used to perform measurements with the CdZnTe prototype in the RA6 reactor BNCT facility. Fig. 6 shows a detailed view, around the 478 kev region, of spectra obtained when the tumor is placed respectively inside and outside the detector FOV. In both of them appears the 511 kev annihilation peak. The boron capture peak is visible when the tumor is in front of the detector although it is difficult to quantify due to the low statistics caused by the low detector efficiency. Figure 6: Measured spectra (detailed view) obtained with the CdZnTe system when the tumor is (is not) in the detector FOV. 0.25 Counting Rate [s -1 ] 0.20 0.15 Tumor zone Blank zone 0.10 350 400 450 500 550 600 650 Energy [kev] The γ background was measured with the LaBr 3 (Ce) system mounted at the BNCT accelerator facility of the Birmingham University and a spurious 478 kev peak was found. Those photons came from captures in the photomultiplier tube which is made of borosilicate. A 2 mm Cd layer between the paraffin and the lead reduced this unwanted peak and also the background (Fig. 7). Figure 7: A Cd layer between paraffin and lead reduced the spurious signal coming from neutron captures in the photomultiplier tube. A projection of the water-filled phantom with two tumors (400ppm 10 B and 3cm in diameter each) has been measured (Fig. 8). Fig. 9 shows the difference between the tumor and a pure water region. The small 478 kev peak in the water measurement is due to the remaining captures in the photomultiplier tubes. The projection spectra were adjusted with a simple model: an exponential background, a Gaussian 478 kev peak and a Gaussian 511 kev annihilation peak. After correction for remnant 478 kev, the measured profile across the phantom and tumors is shown in Fig. 10. Comparison with MCNP simulations shows a very good agreement. 5

Figure 8: Cross section of the water-filled cylindrical phantom with 2 tumors with 400ppm of 10B used in the experiments. Figure 9: Spectra measured at Birmingham s BNCT facility from a tumor and at a water region. Figure 10: Measured and simulated profiles of a phantom with two tumors. The shaded areas indicate tumor positions. 4. Conclusions A tomographic device for online dosimetry in BNCT has been proposed. Monte Carlo numerical simulations were used to evaluate its imaging performance. First results indicate that it would be possible to recover boron concentrations with an uncertainty of 10 % in tumors with 2 cm in diameter. Prototypes have been designed, built and tested in a reactor-based BNCT facility and in an accelerator- 6

based one. The LaBr 3 (Ce) system performed better than CdZnTe system mainly for its better detection efficiency. A profile of a phantom has been measured showing very good agreement with the simulations. Although the background must be further reduced, this work shows the feasibility of such a system. Acknowledgements The authors wish to thank Drs. S. Green, C. Wojnecki and. Z. Ghani for their help in performing the experiments in the BNCT accelerator facility of the University of Birmingham and Drs. O. Calzetta, H.R. Blaumann and J. Longhino for their help in performing the experiments in the RA6 reactor BNCT facility at the Centro Atómico Bariloche. The authors also acknowledge the financial support provided by ANPCyT, CNEA, CONICET and UNSAM. REFERENCES [1] JA Coderre and GM Morris, The radiation biology of boron neutron capture therapy, Radiation Research, 151, 1 (1999) and references therein. [2] WFAR Verbakel and F Stecher-Rasmussen, Gamma-ray telescope for on-line measurements of low boron concentrations in a head phantom for BNCT, Nucl. Instrum. Methods A 394(1-2), 163 (1997) [3] WFAR Verbakel et al., Boron concentrations in brain during boron neutron capture therapy: in vivo measurements from the phase I trial EORTC 11961 using a gamma-ray telescope, Int. J. Radiation Oncology Biol. Phys., 55(3), 743 (2003) [4] T Kobayashi, T., Y Sakurai, M Ishikawa, A noninvasive dose estimation system for clinical BNCT based on PG-SPECT - Conceptual study and fundamental experiments using HPGe and CdTe semiconductor detectors, Med. Phys. 27(9), 2124 (2000) [5] P Munck af Rosenschöld, et al., Prompt gamma tomography during BNCT - A feasibility study, Journal of Instrumentation 1, P05003 (2006) [6] A Valda, DM Minsky, AJ Kreiner, AA Burlon and H Somacal, Development of a Tomographic System for Online Dose Measurements in BNCT (Boron Neutron Capture Therapy), Br. Jour. Phys. 35(3B), 785 (2005) [7] LA. Shepp and Y Vardi, Maximum likelihood reconstruction for emission tomography, IEEE Trans. Med. Imaging MI-1(2), 113 (1982) [8] FB Brown, RF Barrett et al., MCNP VERSION 5, Technical report LA-UR-02-3935, Los Alamos National Laboratory, 2002 7