logo

Study of neutron production and moderation for Sulfur Neutron Capture Therapy

NUCLEAR PHYSICS AND INTERDISCIPLINARY RESEARCH

Study of neutron production and moderation for Sulfur Neutron Capture Therapy

Meng Peng
Guo-Zhu He
Qi-Wei Zhang
Bin Shi
Hong-Qing Tang
Zu-Ying Zhou
Nuclear Science and TechniquesVol.30, No.1Article number 2Published in print 01 Jan 2019Available online 02 Jan 2019
48000

Neutron capture therapy with Sulfur-33, similar to boron neutron capture therapy with Boron-10, is effective in treating some types of tumors including ocular melanoma. The key point in sulfur neutron capture therapy is whether the neutron beam flux and the resonance capture cross-section of 33S(n,α)30Si reaction at 13.5 keV can achieve the requirements of radiotherapy. In this research, the authors investigated the production of 13.5 keV neutron production and moderation based on an accelerator neutron source. A lithium glass detector was used to measure the neutron flux produced via near threshold 7Li(p,n)7Be reaction using the time of flight method. Furthermore, the moderation effects of different kinds of materials were investigated using Monte Carlo simulation.

Sulfur Neutron Capture TherapyBoron Neutron Capture Therapy33S(n,α)30Si resonance reaction7Li(p,n)7Be neutron source

1 Introduction

Shortly after the discovery of neutrons by Chadwick in 1932 [1], the principles of Neutron Capture Therapy (NCT) were proposed by Locher in 1936 [2]. A patient suffering from malignant glioma was treated using the Brookhaven Graphite Research Reactor in 1954, as the first case of Boron Neutron Capture Therapy (BNCT) [3]. BNCT may initially appear to be a complex therapy, however, the approach is in fact relatively simple. Tumor cells with a high concentration of 10B can capture thermal neutrons, which results in 10B(n,α)7Li reaction. The products of this capture reaction have such a high linear energy transfer (LET) in a short range (4-10 μm) that their energy deposition is limited to a single cell. Therefore, these products can selectively irradiate and kill tumor cells that absorb a sufficient amount of 10B, while avoiding damage to normal, healthy cells from damage [4].

In addition to 10B, an interesting isotope for NCT of cancer is 33S [5], which has a large (n,α) cross-section in the keV range, which is much greater than that of (n,γ) [6]. The LET for 3.1 MeV α-particles emitted by 33S(n,α)30Si reaction is sufficiently large to effectively destroy cancer cells, so 33S can be utilized for NCT, which is called Sulfur Neutron Capture Therapy (SNCT). C. Wagemans et al. (1986) [7] measured the resonance cross-section of 33S(n,α)30Si reaction, and the experimental result exhibited some resonances in the keV range. These resonances are illustrated in Fig. 1, where the most important resonance peak (with a cross-section above 20 barns) occurs at a neutron energy close to 13.5 keV. Sulfur is an essential component of all living cells, and its concentration in cells is three orders of magnitude larger than boron. Therefore, 33S-carriers [5] are a promising option because it results in a high local concentration in tumors. Some studies [5, 8-15] have shown an enhancement in the neutron absorbed dose for a combination of 33S and 10B.

Fig. 1.
The resonance structure of 33S(n,α)30Si.
pic

The therapeutic effect of SNCT is evaluated by estimating the biological dose, which is a common dosimetric reference for a given treatment scheme. The biological dose partly depends on the resonance cross-section of 33S(n,α)30Si reaction and the neutron flux and energy within the area of a lesion. Our work is devoted to designing a neutron generator for SNCT.

2 Neutron source selection

A neutron source based on a low energy, high current, and light ion accelerator is being developed as a potential replacement of reactors to meet the requirements of a clinical NCT facility [16]. Accelerators have several potential advantages related to safety, cost and high neutron flux in the keV range, compared to reactor-based neutron sources for clinical radiotherapy. In this regard, they are optimal neutron sources for SNCT.

Table 1 lists the properties of several neutron-producing charged-particle reactions proposed for use in an accelerator-based neutron source [16-18]. The neutron energies via 9Be(p,n)9B, 9Be(d,n)10B and 13C(d,n)14N reactions are too high to increase the resonance neutron intensity after moderation. Although 45Sc(p,n)45Ti reaction can generate quasi-monoenergetic 13.5 keV neutrons, its cross-section is too small, and a small change of the proton energy leads to a great influence on the emitted neutrons. The threshold value (Eth) of 7Li(p,n)7Be reaction is 1880.57 keV, and the emitted neutron energy (about 29.68 keV) is close to the resonance energy [19]. The neutron yield of this reaction is high, and the relatively low energy neutrons require less moderation than those generated via other reactions to enhance the 13.5 keV neutron intensity.

TABLE 1.
Characteristics of charged-particle reactions considered for accelerator-based SNCT neutron source.
Reaction Bombarding energy (MeV) Cross section (mb) Neutron energy at 0° angle (MeV) Target melting point (℃) Thermal conductivity (W m-1 K-1)
7Li(p,n)7B 1.9 232 0.030 181 85
9Be(p,n)9B 4.0 120 1.060 1287 201
9Be(d,n)10B 1.5 2.010 1287 201
13C(d,n)14N 1.5 396 1.080 3550 230
45Sc(p,n)45Ti 2.91 3.73 0.014 1541 15.8
Show more

3 Neutron source simulation and experimental measurement

3.1 Neutron source simulation and moderation

There are many factors that affect the neutron flux via 7Li(p,n)7Be reaction such as target thickness, outgoing angle, and proton energy. In addition, with the increase of the incident proton energy, the proton has a large range, which can produce more accompanied γ-rays via 7Li(p,p)7Li and 7Li(p,γ)8Be reactions [24] that are the harmful biological dose. An optimal experimental scheme should be based on the balance of these three facts for neutron production and moderation.

The neutron energy and yield via near threshold 7Li(p,n)7Be reaction were investigated using TARGET [20, 21] code. In this work, two proton separation threshold energies (1.885 MeV and 1.930 MeV) and two target separation thicknesses (6.2 μm as the thin target and 152 μm as the thick target) were chosen to calculate neutron production.

In addition, different kinds of moderator materials were used to enhance the intensity of resonance neutrons. These materials should have a high scattering cross-section and a low capture cross-section in the keV range. They also do not exhibit decomposition in the radiation field, high long-term radioactivity or moisture during long time operation [22]. The following materials as water (H2O), graphite, heavy water (D2O), and polythene (CH2) have been suggested. The moderation effects of the aforementioned materials were calculated using the Geant4 (Version: 10.2) Monte Carlo code [28]. In this study, the geometric model was built according to the actual experimental conditions presented in Sec. 3.2, and the cylindrical moderator close to the neutron source was placed in the collimator aperture. The GGST_BERT_HP [29, 30] has been used as a standard physics model to describe neutron transportation, which employs a high precision neutron package used for neutrons with energies below 20 MeV, down to thermal energies.

3.2 Experimental neutron source

The time of flight (TOF) method was used to measure the neutron beam via near threshold 7Li(p, n)7Be reactions based on the HI-13 Tandem Accelerator at the China Institute of Atomic Energy [25]. The minimum energy of the proton beam generated by the accelerator was approximately 7 MeV, and the pulse length was less than 3 ns (full-duration at half-maximum). An aluminum slice with a thickness of 280 μm was used as the absorber to reduce the proton energy to a mean energy of 2.5 MeV.

Although 7Li(p,n)7Be reaction is favorable for enhancing neutron intensity in the keV range, some difficulties are still encountered when lithium is used as an ideal target. As shown in Table 2, the low melting point and poor thermal conductivity of pure lithium make it a poor candidate. A good water-cooling system is essential for the timely removal of heat from the target, otherwise, the integrity of the lithium target will be compromised. The chemical properties of lithium cause it to rapidly react with air to form compounds, which directly affects the neutron energy and yield. During the fabrication and installation of the lithium target, it is not allowed to come into contact with air [16].

TABLE 2.
The experimental parameters.
Experimental condition Value
Proton energy (MeV) 7
Averaged current (nA) 100
Repetition frequency (MHz) 3
Absorber thickness (μm) 280
Detector volt (V) - 2020
Detector type Lithium glass
Neutron flight distance (cm) 58.0
Show more

A schematic of the experimental setup is shown in Fig. 2. A lithium glass detector (ϕ 1.6 cm×0.95 cm) used to monitor the neutron beam was positioned at 0° with respect to the proton beam axis. The detector signals were used to trigger a Time-to-Digital Converter (TDC) to reduce dead-time, while the delayed signals of proton beams were recorded for data acquisition of neutron flight time. Two parameters were registered simultaneously for each event: the pulse height (PH) and the TOF. The detection efficiency of the lithium glass detector was previously calibrated by partners [23]. The experimental parameters are summarized in Table 2.

Fig. 2.
(Color online) The experimental setup. Left figure shows the profile of the neutron source shield and collimator system, and right figure shows the structure of the lithium target.
pic

4 Results and discussion

4.1 Simulated neutron spectra and discussion

The calculated neutron energy spectra obtained via the near threshold 7Li(p,n)7Be reaction under different conditions are shown in Fig. 3, and the neutron yields under the different energy ranges are shown in Table 3. The neutron spectra at 0° angle have an obvious peak at 30 keV, while the resonance neutron yields are very small. Compared with the target thickness, the incident proton has a greater influence on the neutron spectra and yields. According to the TARGET results, the neutron energy spectrum corresponding to the 0° output angle in Fig. 3(d) was selected to study neutron moderation at a high flux.

TABLE 3.
The neutron flux in different energy ranges via 7Li(p,n)7Be reaction.
Proton energy (MeV) Target thickness (μm) Output angle (°) Total neutron yield (sr-1·μA-1) Neutron yield (≤ 30keV) (sr-1·μA-1)
1.885 6.2 0 2.64×106 5.22×105
10 2.19×106 3.58×105
20 1.44×106 3.27×105
152 0 5.24×106 1.03×106
10 4.29×106 8.39×105
20 2.50×106 6.65×105
1.930 6.2 0 2.03×107 1.97×106
10 1.79×107 7.77×105
20 1.61×107 8.70×105
152 0 2.39×107 2.39×106
10 2.15×107 1.35×106
20 1.84×107 1.45×106
Show more
Fig. 3.
(Color online) The neutron energy spectra via 7Li(p,n)7Be reaction under different conditions. (a) represents the conditions of 1.88 MeV proton beams and a thick target (6.2 μm), (b) represents the conditions of 1.88 MeV proton beams and a thick target (152 μm), (c) represents the conditions of 1.93 MeV proton beams and a thick target (6.2 μm), (d) represents the conditions of 1.93 MeV proton beams and a thick target (152 μm).
pic

The moderation effects of different kinds of materials was calculated using the Geant4 code; the results are shown in Fig. 4. The resonance neutron yields increased gradually with the thickness of the moderators until there was a dynamic balance between the neutron absorption and moderation. Graphite could sufficiently moderate fast neutrons (>30 keV) in order to enhance the intensity of the 13.5 keV neutrons, while the hydrogen-containing materials slowed down more neutrons to epithermal energies. The resonance neutron yields in the 12.6-15.8 keV range could reach 6.45×105 sr-1 μA-1, 6.93×105 sr-1 μA-1, 1.29×106 sr-1 μA-1 and 5.97×105 sr-1 μA-1 respectively. According to the calculated results, graphite is an optimal moderator to generate more resonance neutrons.

Fig. 4.
(Color online) The neutron energy spectra after (a) H2O, (b) D2O, (c) Graphite, and (d) CH2 moderation of different thicknesses with calculated neutron flux.
pic
4.2 Experimental neutron spectrum and discussion

A two-dimensional spectrum of "PH-TOF" based on the measured raw data is provided to allow for the discrimination of the n-γ signals, as shown in Fig. 5. The region labeled peak-1 corresponds to 240 keV neutrons because of the high detection efficiency of the lithium glass detector. The region labeled peak-2 corresponds to the 560 keV neutrons produced by the 2.5 MeV protons at the surface of the lithium target. The neutron flight distance was so short that these neutrons (< 20 keV) could not be discriminated using the TOF method. They were therefore treated as fast neutrons (> 700 keV) produced in the next pulse because their flight times were longer than that of the proton pulse period. According to the calculated results, the neutron peak at 30 keV should be clearly visible. In fact, the recorded neutron flux was moderated by the water used to cool the lithium target.

Fig. 5.
(Color online) The two-dimensional spectrum of "PH-TOF" measured with lithium glass.
pic

We can obtain the neutron energy spectrum by combining the two-dimensional spectrum (Fig. 5) and the detection efficiency of the lithium glass after ticking out the γ-ray background, as shown in Fig. 6. The right peak corresponds to the region labeled peak-2 in Fig. 5, while the left peak corresponds to the approximately 180 keV neutrons produced by the 1.9-2.0 MeV proton beams. There are three issues that affect these low energy proton beams: (1) the energy of protons after the absorber was broadened and the spectrum followed a Gaussian distribution (Full Width at Half Maximum > 0.5 MeV); (2) the energy loss of protons in the Li target leads to low energy neutrons (approximately 180 keV) production; (3) these neutrons could be produced via 7Li(p, n)7Be reaction (Eth = 2.373 MeV).

Fig. 6.
The final neutron energy spectrum.
pic

According to the experimental results, the neutron flux reached 1.41103 sr-1 μA-1 at a distance of 58 cm from the lithium target. Moreover, the neutron source strength reached 4.74106 sr-1 μA-1, which is lower than the calculated results by an order of magnitude. The difference is mainly attributed to the moderation and absorption of the cooling water, scattering, and absorption of the collimator.

With the experimental neutron flux, the same moderators were chosen to study the moderation effects. The Geant4 simulation results are shown in Fig. 7. The resonance neutron yield values in the 12.6-15.8 keV range, and could reach 4.76×104 sr-1 μA-1, 1.23×105 sr-1 μA-1, 5.23×104 sr-1 μA-1 and 4.76×104 sr-1 μA-1 respectively. It is possible to obtain more 13.5 keV neutrons with deuteron-containing materials compared to those that contain carbon and hydrogen. However, none of these materials were capable of fully moderating the maximum number of fast neutrons (hundreds of keV) down to the desired resonance energy range, while increasing the resonance neutron yield. A high incident proton energy is adverse to neutron production and moderation in terms of increasing the resonance neutron yield near the threshold of 7Li(p, n)7Be reaction. This is an essential requirement for further SNCT neutron source studies.

Fig. 7.
(Color online) The neutron energy spectra after (a) H2O, (b) D2O, (c) graphite, and (d) CH2 moderation of different thicknesses with experimental neutron flux.
pic

5 Conclusion

33S can be used for NCT because it has a large (n,α) cross-section, and the emitted α-particles produce a large energy deposition near the interacting site to kill tumor cells. The key aspect of SNCT depends partially on the resonance cross-section of 33S(n,α)30Si reaction and the resonance neutron flux. In this study, we built a 7Li(p,n)7Be reaction accelerator-based neutron source for SNCT. The energy and intensity of the neutrons were measured using a lithium glass detector based on the TOF method. We also studied the optimal moderation scheme to enhance the intensity of the resonance neutrons. Using a simple moderator material can increase the 13.5 keV neutron flux, but it still has a large share of the high energy neutrons in the neutron beam. Composite materials may be the best candidator to slow down more high-energy neutrons to enhance the resonance neutrons.

The combination of a near threshold 7Li(p,n)7Be reaction neutron source and the use of graphite for the production of neutron beams is potentially promising for SNCT. To achieve the best therapeutic effect, this approach needs to be studied further to obtain quasi-monoenergetic 13.5 keV neutron beams (for SNCT), or neutron beams with a maximum energy of 13.5 keV (combined SNCT with BNCT). There are some discrepancies in the experimental data for 33S(n,α)30Si reaction [7, 32, 33] in the keV range. This neutron source can potentially be used to clarify the existing discrepancies.

References
[1] J. Chadwick,

The Existence of a Neutron

. Proc. Roy. Soc. 136, 692-708 (1932). doi: 10.1098/rspa.1932.0112
Baidu ScholarGoogle Scholar
[2] G.L. Locher,

Biological effects and the therapeutic possibilities of neutrons

. Am. J. Roentgenol. 36, 1-13 (1936)
Baidu ScholarGoogle Scholar
[3] L.E. Farr, W.H. Sweet, H.B Locksley et al.,

Neutron capture therapy of gliomas using boron

. Trans Am Neurol Assoc 13, 110-113 (1954)
Baidu ScholarGoogle Scholar
[4] R.L. Moss,

Critical review, with an optimistic outlook, on Boron Neutron Capture Therapy (BNCT)

. Appl. Radiat. Isot. 88, 2-11 (2014). doi: 10.1016/j.apradiso.2013.11.109
Baidu ScholarGoogle Scholar
[5] I. Porras,

Sulfur-33 nanoparticles: A Monte Carlo study of their potential as neutron capturers for enhancing boron neutron capture therapy of cancer

. Appl. Radiat. Isot. 69, 1838-1841 (2011). doi: 10.1016/j.apradiso.2011.04.002
Baidu ScholarGoogle Scholar
[6] M. Sabaté-Gilarte, J. Praena, I. Porras et al.,

Measurement of the 33S(n,alpha) cross-section at n_TOF(CERN): Applications to BNCT

. Rep Pract Oncol Radiother. 21, 113-116 (2016). doi: 10.1016/j.rpor.2014.08.007
Baidu ScholarGoogle Scholar
[7] C. Wagemans, H. Weigmann, R. Barthelemy,

Measurement and resonance analysis of the 33S(n,alpha) cross section

. Nucl. Phys. A 469, 497-506 (1987). doi: 10.1016/0375-9474(87)90035-2
Baidu ScholarGoogle Scholar
[8] I. Porras,

Enhancement of neutron radiation dose by the addition of sulphur-33 atoms

. Phys. Med. Biol. 53, L1 (2008). doi: 10.1088/0031-9155/53/7/L01
Baidu ScholarGoogle Scholar
[9] I. Porras, J. Praena, M. Sabatégilarte et al,

33S(n,α) cross section measurement at n_TOF: Implications in neutron capture therapy

. http://digital.csic.es/handle/10261/123302
Baidu ScholarGoogle Scholar
[10] J. Praena, M. Sabaté-Gilarte, I. Porras et al.,

33S as a cooperative capturer for BNCT

. Appl. Radiat. Isot. 88, 203-205 (2014). doi: 10.1016/j.apradiso.2013.12.039
Baidu ScholarGoogle Scholar
[11] I. Porras, P.L. Esquinas, M.G. Feldmann et al.,

A potential selective radiotherapy for ocular melanoma by sulfur neutron capture

, 16th International Congress on Neutron Capture Therapy (ICNCT-16), Helsinki, Finland, Jun. 14-19, 2014
Baidu ScholarGoogle Scholar
[12] J. Praena,

Experimental study of the 13.5 keV resonance of the 33S(n,α)30Si reaction at CERN n_TOF fa-cility for BNCT

, 16th International Congress on Neutron Capture Therapy (ICNCT-16), Helsinki, Finland, Jun. 14-19, 2014
Baidu ScholarGoogle Scholar
[13] I. Porras, M. Sabaté-Gilarte, J. Praena et al.,

33S for Neutron Capture Therapy: Nuclear Data for Monte Carlo Calculations

. Nucl. Data Sheets 120, 246-249 (2014) doi: 10.1016/j.nds.2014.07.058
Baidu ScholarGoogle Scholar
[14] M. Sabaté-Gilarte,

The 33S(n,α)30Si cross section measured at n_TOF Experimental Area 2(CERN):from thermal to the resolved resonance region

, International Nuclear Data Conference for Science and Technology (ND2016), Bruges, Belgium, Sep. 11-16, 2016
Baidu ScholarGoogle Scholar
[15] M. Sabaté-Gilarte, J. Praena, I. Porras et al.,

Measurement of the 33S(n,α) cross-section at n_TOF(CERN): Applications to BNCT

. Reports Prac. Onco. Radio 21, 113-116 (2016). doi: 10.1016/j.rpor.2014.08.007
Baidu ScholarGoogle Scholar
[16] T.E. Blue, J.c. Yanch,

Accelerator-based epithermal neutron sources for boron neutron capture therapy of brain tumors

. J. Neuro-Oncol. 62, 19-31 (2003)
Baidu ScholarGoogle Scholar
[17] D.M. Minsky, A.J. Kreiner,

Near threshold 7Li(p,n)7Be reaction as neutron source for BNCT

. Applied Radiation and Isotopes 106, 68-71 (2015). doi: 10.1016/j.apradiso.2015.07.038
Baidu ScholarGoogle Scholar
[18] K.V.K. Iyengar, S.K. Gupta, K.K. Sekharan et al.,

Fluctuations in the integrated cross section of the reaction 45Sc(p,n)45Ti

. Nuclear Physics A 96, 521-528 (1967). doi: 10.1016/0375-9474(67)90602-1
Baidu ScholarGoogle Scholar
[19] M.S. Herrera, G.A. Moreno, A.J. Kreiner et al.,

New method to evaluate the 7Li(p,n)7Be reaction near threshold

. Nucl. Instrum. Meth. B 349, 64-71 (2015). doi: 10.1016/j.nimb.2015.01.080
Baidu ScholarGoogle Scholar
[20] D. Schlegel, TARGET USER's MANUAL. Abteilung Ionisierende Strahlung Laborbericht, 2005
[21] D. Schlegel, S. Guldbakke, Why Do We Need TARGET?. Springer Berlin Heidelberg, 2001, 881
[22] IAEA-TECDOC-1223, Current Status of Neutron Capture Therapy. Austria: International Atomic Energy Agency, 2001
[23] Q.W. Zhang, G.Z. He, X.C. Ruan et al.,

Calibration of Neutron Detection Efficiency of Li-glass Detector

. Nuclear Physics Review 34, 2460-2469 (2013). doi: 10.11804/NuclPhysRev.30.02.156. (in Chinese)
Baidu ScholarGoogle Scholar
[24] R. Mateus, A.P. Jesus, B. Braizinha, et al.,

Proton-induced γ-ray analysis of lithium in thick samples

. Nucl. Instrum. Meth. B 190, 117-121 (2002). doi: 10.1016/S0168-583X(01)01222-8
Baidu ScholarGoogle Scholar
[25] B. Yang, X. Guan, X. Cao et al.,

Progresses in the project of upgrading HI-13 tandem accelerator at CIAE

. Nuclear Techniques 31, 41-46 (2008). (in Chinese)
Baidu ScholarGoogle Scholar
[26] J. A. Coderre, S. Packer, R. G. Fairchild et al.,

Iodothiouracil as a melanoma localizing agent

. J. Nucl. Med. 27, 1157-1164 (1986)
Baidu ScholarGoogle Scholar
[27] COLLABORATIVE OCULAR MELANOMA STUDY GROUP,

"The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma III: local complications and observations following enucleation COMS report no. 11

. Am J Ophthalmol. 126, 362-372 (1998)
Baidu ScholarGoogle Scholar
[28] Geant4 Collaboration,

User's Guide: For Application Developers

. http://geant4.web.cern.ch/geant4/UserDocumentation/UsersGuides/ForApplicationDeveloper/BackupVersions/V10.2/fo/BookForAppliDev.pdf, (2015)
Baidu ScholarGoogle Scholar
[29] Geant4 Collaboration,

Physics Reference Manual

. http://geant4.web.cern.ch/geant4/UserDocumentation/UsersGuides/PhysicsReferenceManual/fo/PhysicsReferenceManual.pdf, (2015)
Baidu ScholarGoogle Scholar
[30] C.L. Lan, M. Peng, Y.Z. et al.,

Geant4 simulation of 238U(n,f) reaction induced by D-T neutron source

. Nucl. Sci. Tech. 28, 8 (2016). doi: 10.1007/s41365-016-0158-7
Baidu ScholarGoogle Scholar
[31] K. Zhou, J.R. Zhou, Y.S. Song et al.,

Compact lithium-glass neutron beam monitor for SANS at CSNS

. Nucl. Sci. Tech. 29, 127 (2018). doi: 10.1007/s41365-018-0468-z
Baidu ScholarGoogle Scholar
[32] Auchampaugh, G. F. and Halperin, J. and Macklin et al.,

Kilovolt 33S(n, α0) and 33S(n, γ) cross sections: Importance in the nucleosynthesis of the rare nucleus 36S

. Phys. Rev. C 12, 1126-1133 (1975). doi: 10.1103/PhysRevC.12.1126
Baidu ScholarGoogle Scholar
[33] P.E Koehler, J.A Harvey, N.W Hill,

Two detectors for (n,p) and (n,α) measurements at white neutron sources

. Nucl. Instrum. Meth. A 361, 270-276 (1995). doi: 10.1016/0168-9002(95)00123-9
Baidu ScholarGoogle Scholar