Introduction
Different techniques and methods are being used for improving the effectiveness of radiation therapy, to increase the target dose and reduce the delivered dose to surrounding healthy tissues. One of the methods is delivering a radio-sensitisation agent to the target to intensify cumulative dose by physical phenomenon like photoelectric or nuclear fusion. In proton therapy, some studies have been done to evaluate the proton dose enhancement by fusion-released energy. In this theory, when a proton collides with 11B nuclei, the 11B(p,α)2α + γ (719-keV prompt gamma) reaction occurs. The Q-value of this reaction is 8·6 MeV, which means that one ionising particle (proton) produces three ionising particles (alpha) with higher relative biological effectiveness.
The first study on radio-sensitivity by fusion was introduced in 2014. Reference Yoon, Jung and Suh1
Yoon et al. Reference Yoon, Jung and Suh1 simulated the irradiation of an 80-MeV proton beam on a water phantom by Monte Carlo (MC) N Particle Transport (MCNPX) computer programming, also known as coding (Los Alamos National Laboratory). Reference Hendricks, McKinney and Fensin2 They inserted a cubic of boron-11 (11B density = 2·08 g/cm3) in the water phantom at the Bragg peak depth to magnify the peak. A maximum of 79·5% increment in the peak height was reported. So, it was claimed that the proton–boron fusion therapy (PBFT) method can increase the proton therapy dose to the treatment target. Consequently, they proposed further studies on the effectiveness of their concept.
In 2016, Jung et al. published another article about PBFT for 60-, 70-, 80- and 90-MeV proton beams with boron concentrations of 14·4, 16·8, 19·2, 21·6 and 25·0 mg/g3. Although they used a pure 11B in the boron uptake region (BUR), they assumed that the mentioned concentration is obtained by changing the amount (size) of 11B in the water phantom. Latterly, a 96·62% amplification of proton dose was reported. Reference Jung, Yoon and Lee3 Therefore, it was concluded that this method decreases the normal tissues dose, and it can be used for an accelerated treatment.
In March 2017, the same researchers presented the results of treatment planning simulation for a simple phantom that had volumes for planning target volume (PTV) and organ at risk (OAR). Reference Kim, Yoon and Shin4 Again, they used a cubic BUR with pure 11B. They reported the dose increment to PTV and better sparing of the OAR in the cases with BUR placement. As a result of this research, they point to the requirement of additional investigations to benchmark the possible clinical applications.
In February 2017, Jung et al. compared PBFT with boron neutron capture therapy (BNCT) by MC simulation. Reference Jung, Yoon and Barraclough5 The energy range was 75–85 MeV with 1-MeV steps. The concentration of the boron was 1·04 mg/g. They used this high-level concentration to observe the amplification of proton peak. The results were similar to their previous works. In addition, they suggest that the produced prompt gamma ray in the PBFT fusion reaction may be used for imaging purposes (which was investigated in their following publication Reference Shin, Kim and Kim6 ). In addition, they concluded that the PBFT benefits from the advantages of both BNCT and proton therapy.
In all of the above papers that are published by a unique research group, the Bragg peak occurred inside the pure or very high concentration of boron cube. Furthermore, the results are based on MCNPX simulations.
In January 2018, a paper published by Cirrone et al. concentrated on the first experimental proof of PBFT. Reference Cirrone, Manti and Margarone7 Their in vitro study reported a significant cell lethality and chromosome aberration in a PBFT case. However, their findings were questioned by Mazzone et al., some months later. Reference Mazzone, Finocchiaro and Meo8 Mazzone et al. performed some MC calculations by GEANT4 Reference Collaboration and Agostinelli9 and, consequently, indicated that the results cannot demonstrate the dose enhancement for the in vitro setup because the yield of alpha particles is too low to affect the proton therapy dose. In addition, any boron carrier agents such as boronophenylalanine have a small uptake in the tumour. The mentioned in vitro investigation Reference Cirrone, Manti and Margarone7 will not be prepared in the current study, because it was prepared by the above-mentioned study, Reference Mazzone, Finocchiaro and Meo8 and it has a different structure than our work. However, the first group’s results Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3–Reference Jung, Yoon and Barraclough5 will only be dealt on to see whether the used 11B concentration is realistic? And also how much is the proton dose enhancement by the produced alpha particles? In fact, the current study contests the results of specific literatures Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3–Reference Jung, Yoon and Barraclough5 in terms of physical scientific basis and validity of the MCNPX simulation. Therefore, the cross section of the 11B(p,α)2α reaction, as well as simulation of interaction between proton beam and a BUR inside a water phantom, was investigated.
Materials and Methods
For unifying the conditions between this and the mentioned studies, Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3–Reference Jung, Yoon and Barraclough5 it was tried to apply same situations, methods and tools as much as possible. Accordingly, the MCNPX code version 2.6 Reference Pelowitz10 was also used in this study. The calculation MODE was set to electron, proton and alpha (e, h and a) particles. In MCNP, the MODE is used to define the type of source particles to be tracked. The particles’ importance (IMP) was set as unit. The IMP keyword tells MCNP what weight to assign to particles inside a cell (inside BUR, water phantom, air, etc.). Furthermore, to include the alpha and proton capture, the energy cut-off (CUT) was set to zero. If the energy of a particle becomes lower than CUT value, its tracking is stopped. MCNP has some calculation functions named Tally that are used for scoring different radiation parameters such as flux, current, kerma, dose and energy deposition. For calculating the absorbed dose and the energy deposition, F6 tally and mesh-tally types 1 and 3 were employed. The F6 tally without the plus character (+F6) only calculates the indicated specific particle’s dose. However, the +F6 tally scores the energy deposition from all particles. The mesh-tally type 1 with the predefined PEDEP keyword acts like the F6 tally. Consequently, the mesh-tally type 3 is an equivalent to +F6 tally. However, the mesh-tallies score the energy deposition per unit of volume, not unit of mass. Therefore, the mesh-tallies are not suitable for a heterogeneous medium.
The circular proton surface source diameter was 4 cm and its energy considered as 80 MeV that irradiated on a water phantom with a 2-cm diameter BUR with a thickness of 0·5 cm at the depth of 5·1 cm (Figure 1).
The circular proton source (a), the water phantom (b), the dose scoring cells (c) and the BUR (d).
The MCNP uses Data Libraries or Model Physics depending on the energy range, the isotope and the particle type. For proton particles, the data libraries (LA150 Reference Chadwick11 and ENDF/B-VII Reference Chadwick, Herman and Obložinský12 ) are available only for limited isotopes that do not include the boron. Therefore, the MCNP applies model physics instead.
To obtain the proton and alpha percentage depth doses, the depth of 4·4 to 5·8 cm of the water phantom (including the BUR) was divided into 200-micron-thick cells. These cells score the absorbed dose at every 200-micron-step depths by tally F6. Consequently, a same strategy was employed through the mesh-tally types 1 and 3.
Results
Mesh-tally results (energy deposition)
As described above, the mesh-tallies do not score the dose; they calculate energy deposition per unit of volume. As shown in Figure 2, the total energy deposition for all particles (protons and alphas) shows 92% increment in the peak height with the BUR, in comparison to without the BUR case. By inserting the BUR, the continuous-slowing-down approximation (CSDA) range was decreased from 5·4 to 5·2 cm.
The total energy deposition per unit of volume for all particles in water phantom with and without the BUR.
Figure 3 shows the alpha particles’ energy deposition per unit of volume. By inserting the BUR, an energy deposition peak is appeared. This peak is the result of three alpha particles’ production per each proton–boron interaction. Here, the CSDA ranges with and without the BUR are 5·15 and 5·1 cm, respectively.
The alpha particles’ energy deposition per unit of volume in water phantom with and without the BUR.
The comparison of total particles’ and alpha particles’ energy deposition in the phantom, with and without the BUR, can be seen in Figure 4. The peak height of the total energy deposition is 500 times of alpha particles with BUR insertion.
Comparison between total particles’ and alpha particles’ energy deposition with and without the BUR.
F6 and +F6 tallies results (dose)
By considering the density of BUR (2·08 g/cm3) through +F6 tally, the total dose of all particles is shown in Figure 5. The Bragg peak shows a 20% decrease in the height by taking into account the BUR. Consequently, the alpha particles’ dose, calculated by F6 tally, has been shown in Figure 6. The total particles’ and alpha particles’ Bragg peaks with the BUR show a significant reduction in comparison with their energy deposition curves (Figures 2–4). In addition, the total particles’ dose is 500 times of alpha particles (Figure 7).
Total dose of all particles with and without the BUR.
The alpha particles’ dose with and without the BUR.
Comparison between total particles’ and alpha particles’ dose with and without the BUR.
Discussions
The B11(p,2α)He4 interaction with a Q-value of 8·6 MeV has a maximum cross section of 800-mb (millibarn) peak (Figure 8). Reference Soppera, Dupont and Bossant13,Reference Rochman and Koning14 This cross-section value is quite low for having significant interactions and, correspondingly, desirable alpha particles’ dose to boost the primary proton dose. Compared with similar nuclear fusion reactions that are being used in clinic, such as BNCT in which 10B has a cross section of 3,837 b for thermal neutrons, the 800 mb is quite low. In addition, the indicated cross-section peak (800 mb) occurs at the end of protons range, after the Bragg peak, Reference Alrumayan, Okarvi and Nagatsu15,Reference Price, Esposito and Poludniowski16 where the energy of incident protons falls to below 1 MeV. Therefore, in the Bragg peak region, the cross section is less than 800 mb.
The cross section of B11(p,2α)He4 interaction according to TENDL-2011Reference Rochman and Koning14 and JANIS (D0017·002).Reference Soppera, Dupont and Bossant13
The proton beam energy in our study was 80 MeV that is similar to Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3–Reference Jung, Yoon and Barraclough5 the 80-MeV Reference Yoon, Jung and Suh1 ; 60-, 70-, 80-, 90-MeV Reference Jung, Yoon and Lee3 ; 60- to 120-MeV Reference Kim, Yoon and Shin4 ; 75- to 85-MeV Reference Jung, Yoon and Barraclough5 protons that were used in the mentioned papers. Furthermore, they used pure 11B cubics Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3,Reference Kim, Yoon and Shin4 as proton dose booster, which was done in the current work as well. However, no enhancement was seen in the proton ‘dose’ that has a full agreement with the physical basis of the low cross-section fusion of 11B.
As mentioned above, the MCNPX uses model physics for interaction between protons and boron, so there are no experimental data libraries. The model physics in MCNP applied in a specific range of energy that the code uses in purely theoretical-based calculations (model) for particle transport, instead of experimentally obtained libraries. This range of energy varies for different isotopes and particles. However, the literatures Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3,Reference Jung, Yoon and Barraclough5,Reference Shin, Kim and Kim6 talk about using the ‘default library’ in their MCNPX calculations, while there is no ‘default’ library available.
The maximum non-toxic concentration of boron in tumour is under 100 μg/g, Reference Yanagië, Ogata and Sugiyama17–Reference Ozawa, Santos and Lamborn19 but the literature concentrations were hundreds of clinical values, varied from 1 g/g (100%) Reference Yoon, Jung and Suh1,Reference Kim, Yoon and Shin4 to 1·04 mg/g Reference Jung, Yoon and Barraclough5 and 25 mg/g. Reference Jung, Yoon and Lee3
As shown in Figures 6 and 7, the alpha particles’ Bragg peak had a neglectable amplitude in comparison with the protons dose. However, the mentioned studies reported 79·5 Reference Yoon, Jung and Suh1 to 96·62% Reference Jung, Yoon and Lee3 increase in the Bragg peak intensity. These reported increments are similar to Figure 2 in the current study, which is the energy deposition per unit of volume. In addition, even in terms of energy deposition, the amplification is due to the higher mass density of boron in comparison with the water, not alpha particles’ energy deposition.
Despite the analytical and theoretical methods used in this work, it is recommended that an experimental research is done to investigate the real word. Because of the analytical part of the current work and the results of the past works, Reference Yoon, Jung and Suh1,Reference Jung, Yoon and Lee3–Reference Jung, Yoon and Barraclough5 the results are based on the MCNPX simulation, which uses model physics, not experimental data. For instance, a similar setup can be established with a dosimetric film sandwiched in solid water and BUR. The film sheet is parallel with the irradiating proton beam. As an alternative, the gel dosimetry can be applied.
Conclusion
The published literature presents the energy deposition enhancement, not the dose. The energy deposition enhancement is due to the higher density of the boron in comparison with water, not the alpha production. In addition, at the presented levels of concentrations in the literature, they are higher than the tolerable level for human body.
Our findings demonstrated that the PBFT is an ineffective and unrealistic method in proton therapy.
Acknowledgement
We would like to thank the Talented Young Scientist Program, China Science and Technology Exchange Center for their support (No. P160U4908), and National Natural Science Foundation of China (No. 11375047, 11005019).
