Patent Application
20230276563
The present invention relates generally to a device for the production, moderation and configuration of beams, and more specifically neutron beams for neutron capture therapies.
Boron neutron capture therapy (commonly abbreviated as BNCT) is a type of experimental cancer radiotherapy which is unique in that it is selective at the cellular level, such that the dose applied to healthy tissue and tumor tissue can be controlled in a differentiated manner. In this way, tumor cells can be killed without damaging the surrounding healthy tissue. BNCT techniques are mainly based on irradiating the patient, who has previously been administered a boron compound (since 10B has a high probability of being captured by neutrons), with neutrons. Generally, said neutron beam is generated by means of a nuclear reactor or more recently using a particle accelerator. Boron preferably binds to cancer cells such that, when a neutron interacts with it, a nuclear reaction which kills or severely damages the cancer cell occurs, leaving the cells of adjacent tissue with hardly any damage.
To be able to put boron neutron capture therapies into practice, there is a need to have a neutron beam with specific qualities. Said neutron beam must be of the epithermal type (that is, with energies comprised between 0.5 eV and 10 keV) and have an intensity adapted to the type of tumor to be treated. Furthermore, the beam must exhibit a low contamination of thermal neutrons (energies below 0.5 eV) and rapid neutrons (energies above 10 keV), as well as of gamma-radiation. Likewise, the treatment must take into account epithermal neutron thermalization effect (i.e., the process through which the energy of said neutrons decreases as they penetrate the tissue, reaching a thermal peak between 3 and 6 cm of depth). Furthermore, the neutron beam is required to have a low divergence as this allows maximizing the radiation dose to the tumor, while the rest of the patient’s body receives the lowest possible dose. These conditions have been standardized in technical document 1223 of the International Atomic Energy Agency (IAEA) (see D. Rorer et al., “Current Status of Neutron Capture Therapy, IAEA TECDOC 1223.”, International Atomic Energy Agency, Vienna, 2011).
In the state of the art (for example, [I. Porras et al., “Perspectives on Neutron Capture Therapy of Cancer”, CERN Proc., 1, 295-304, 2019] and in [Torres-Sánchez et al., “On the upper limit for the energy of epithermal neutrons for Boron Neutron Capture Therapy”, Radiation Physics and Chemistry, 156, 240-244, 2019]) it has been disclosed that the optimal neutron energy for BNCT treatment is in the range of a few keV (1-10 keV), depending on the tissue on which it is applied. Furthermore, to ensure the applicability of neutron beam in BNCT treatment, it is recommended to measure, among others, the following quality factors relating to radiation tissue penetration capacity:
The IAEA also defines another series of recommendations with respect to parameters relating to the energy of the generated neutrons:
Simulations with tissue reference models such as, for example, the ICRU4 standard tissue phantom (recommended by the “International Commission on Radiation Units and Measurements”) and the Snyder brain model (see W.S. Snyder et al., “Estimates of absorbed fractions for monoenergetic photon sources uniformly distributed in various organs of a heterogeneous phantom”, Oak Ridge National Lab, Tenn., J. Nucl. Med. 10: Suppl. No. 3, 7-5,1969) are often used to compare the different BNCT treatment devices.
In the past, BNCT was performed using neutron sources from nuclear reactors. As a reference, the FiR-1 facilities (a nuclear reactor located in Helsinki, currently dismantled) and the KURRI facility in Kyoto should be mentioned. However, today and as a result of the development of low-energy and high-intensity accelerator technology, BNCT treatments can be carried out in a hospital setting (see Brugger, R. M., et al. “Rapporteurs’ report. Neutron beam design, development, and performance for neutron capture therapy”. Springer, Boston, MA, 1990. 3-12). For example, the “Cyclotron Based Epithermal Neutron Source” (abbreviated as C-BENS and located in Kyoto) is a cyclotron accelerator-based BNCT facility for producing an epithermal neutron source and is currently in operation.
In recent years, efforts have been made to search for an optimal neutron beam, with different reactions for the production of neutrons, such as 7Li(p,n), 9Be(p,n) or 9Be(d,n), as disclosed in A. J. Kreiner et al. “Present status of accelerator-based BNCT.” Reports of Practical Oncology & Radiotherapy 21.2 (2016): 95-101, being tested. However, the neutrons produced with these reactions have energies exceeding those required in BNCT treatment (of the order of hundreds of keV to MeV). There is therefore a need for a device for the production, moderation and configuration (DPMC) of a neutron beam for neutron capture therapy which adapts the neutrons produced to treatment needs and is capable of adequately meeting all IAEA recommendations considering exclusively the epithermal range of neutrons, i.e., 0.5 eV-10 keV, which is the most suitable for BNCT treatments.
As mentioned in the preceding section, there is a need, in the field corresponding to devices for the production, moderation and configuration (DPMC) of neutron beams, to develop devices capable of meeting all the International Atomic Energy Agency (IAEA) recommendations considering exclusively neutrons in the epithermal range (0.5 eV- 10 keV). The present invention provides a solution to said need by means of a device capable of providing ranges of energy that are more suitable and safer for use in boron neutron capture treatments.
More specifically, the main object of the present invention relates to a DPMC of neutron beams based on the production of neutrons from proton beams, which allows obtaining a neutron flux above 109 n/(s cm2) between 1 eV and 20 keV, keeping (i) the thermal neutron flux below 5% of the total flux, (ii) the dose produced by the rapid neutrons below 2 10-13 n/(s cm2) per neutron between 1 eV and 20 keV, and (iii) the dose produced by the secondary photons below 2 10-13 n/(s cm2) per neutron between 1 eV and 20 keV.
This DPMC of neutron beams based on the production of neutrons from proton beams comprises:
Said DPMC is characterized in that the filtration stage acts on the neutron beam before it exits the device through the outlet opening. The neutron beam obtained can be applied, for example, on patient’s tissues.
In a preferred embodiment of the invention, the proton beam striking the inlet opening is obtained by means of a particle accelerator, said proton beam being accelerated against a target, manufactured from a metal material, in order to generate neutrons.
In another preferred embodiment, the target comprises 7Li and the nuclear reaction with the incident proton beam is 7Li(p,n)7Be.
In particular embodiments, the moderator comprises at least one of the following materials: graphite, D2O, AlF3, CaF2, Li2CO3, MgF2, Al2O3, Fe. In particular, if the energy source (proton beam) is a low-energy source, the use of MgF2 is preferred. If the source is a high-energy source, then it is preferable to gradually replace MgF2 with AlF3, and replace both in turn with CaF2 and Fe.
In other particular embodiments, the moderator comprises at least one section with one of the following geometries: cylindrical, conical, prismatic, truncated pyramid.
In some preferred embodiments of the invention, the reflective cover comprises at least one of the following materials: Ni, Pb, BeO, Bi.
In some advantageous embodiments of the invention, the rapid neutron filtration layer of the filtration stage comprises at least one of the following materials: Al, Fe, Ni.
In other particular embodiments of the invention, the thermal neutron filtration layer of the filtration stage comprises at least one of the following materials: 10B, 6Li, Gd, Cd, LiF. Excess thermal radiation that healthy surface tissue would receive during the application of the neutron beam is thereby reduced. Thermal neutrons are not useful for application in tissues because they hardly penetrate deeply into these tissues, such that they are only applicable if used on surface or shallow injuries. Gd and Cd are among the materials having the largest thermal capture cross-sections, so the use thereof to remove thermal neutrons would be optimal if it is not required to minimize the gamma-radiation production in the same way. In both cases, gamma-radiation production is significant, which would imply a greater thickness of Pb or Bi as a gamma-radiation filter. Alternatively, this filtration layer can be placed in a part prior to moderation, such that gamma-radiation would be partially attenuated by the passage of the rest of the materials, but in such a case, the effect thereof as a thermal neutron attenuator would be reduced.
In other preferred embodiments of the invention, the gamma-radiation filtration layer of the filtration stage comprises at least one of the following materials: Pb, Bi. In this way, contamination of the neutron beam obtained with the invention by gamma-radiation is reduced.
As a result of the three aforementioned layers which the filtration stage of the invention at least comprises, radiation sources which are not epithermal neutrons are reduced. This gives the spectrum of the generated neutron beam a high energy selectivity, having maximums in the range of 2-3 keV, and being highly suitable for neutron capture treatment, and more specifically BNCT.
In some particular embodiments of the invention, the outlet opening for the neutron beam comprises at least one section with one of the following geometries: cylindrical, conical, prismatic, truncated pyramid. In this way, the divergence of the neutron beam obtained is reduced.
In certain advantageous embodiments of the invention, the outlet opening (6) for the neutron beam comprises a movable closure to stop irradiation.
In other embodiments of the invention, the shield arranged around the outlet opening for the neutron beam comprises at least one of the following materials: LiF, 6LiF, B4C, polyethylene, Pb, Bi. In other preferred embodiments, the shield only comprises Pb and lithiated polyethylene. In some even more advantageous embodiments, two additional layers of natural LiF and 6Li-enriched LiF are added to the Pb layer and to the lithiated polyethylene layer. As a result of the shield, most neutrons diverting from the main axis and the gamma-radiation associated therewith can thus be suppressed, in order to reduce the radiation dose received by normal tissue or regions close to the irradiated tissue, in which the residual radiation received should the lowest possible. B4C is the commonly used material as it has 10B and is solid.
The preferred use of the DPMC of the neutron beam of the invention consists of boron neutron capture therapy. As a result of the filtration stage, prior to the exit of the neutron beam of the invention, said neutron beam has a spectrum suitable for use thereof in this type of therapy.
Throughout the text, the word “comprises” (and its derivatives) should not be understood in an exclusive manner, but rather in the sense of allowing the possibility that what is defined may include additional elements or steps.
A set of figures which are integral part of the description and illustrate a preferred embodiment of the invention is provided to complete the description of the invention. Said figures should be interpreted in a non-limiting illustrative manner and are described in detail below.
A series of reference numbers, corresponding to the following elements, accompany the mentioned figures:
Surrounding the lithium target (2) and extending in the front direction and to the sides, there is placed the core of the moderator (3) with a thickness (W2) in said front direction, from the target (2) to the filter (5), of 21.80 cm ±10%, preferably 21.8 cm. Preferably, the moderator will be manufactured with MgF2. Other materials which can be used as the moderator (3) are combinations of Al, Mg or Ca metals with F, as well as carbon in the form of graphite, or water (H2O or heavy water, D2O). These materials are chosen based on their neutron interaction properties. Therefore, isotopes having a large elastic cross-section and a small absorption cross-section are required. Neutrons can lose energy gradually by means of elastic collisions. This energy loss by collision is greater for lightweight isotopes, such as hydrogen or deuterium, or carbon. The suitability of the elements Al, Mg, Ca or F is mainly due to their energy resonances of the range of tens to hundreds of keV, which allows reducing the amount of high-energy neutrons which transition to the epithermal range through moderation. MgF2 is chosen over other materials due to its larger elastic cross-section, while the production of gamma-radiation per capture is lower than in other materials such as water. Furthermore, the nuclei are not as lightweight as to lose a large proportion of energy in each collision, which allows the neutrons to lose their energy much more gradually and controllably. Other metals such as Al or Ca have higher energy resonances, so the use thereof as low-energy sources is not as suitable as Mg. In other preferred implementations of the invention, the moderator can be manufactured with at least one of the following materials: D2O, Al2O3, Li2CO3, or others having equivalent or similar properties known by one skilled in the art. In
Preferably, there is arranged around the moderator (3) a reflective cover (4), made with a material with a large elastic collision cross-section and at the same time a high mass number, such that the neutrons do not lose more energy in these collisions, and furthermore the probability of backward collision is higher, which allows neutrons to be recovered towards the core of the moderator. The reflector therefore redirects the diverted neutrons to the main axis of the neutron beam, which increases the epithermal neutron flux. In its rear part, from the moderator to the inlet opening, the cover (4) has a thickness (L6) of 25.00 cm ±40% in the direction of the beam.
The moderator also covers the target and part of the tube of the accelerator to the rear part (beam inlet). In a preferred embodiment, the total thickness of the moderator (L4+L5) is comprised between 24.64 and 36.96 cm.
Furthermore, the material of the reflective cover (4) must absorb the gamma-radiation generated in the moderation process. For this reason, materials with a high atomic number are ideal for this task. In this way, the optimal materials for this function are lead and bismuth. Pb has an elastic collision cross-section that is larger than Bi, such that it has been used as a reflector in general, except in the front direction, where the divergence of the beam is a factor to be considered. In the radial as well as rearward directions, increasing the thickness (L6) of the Pb layer allows recovering more neutrons which have escaped the core of the moderator (3). This relationship is maintained until a maximum thickness, at which the increase in epithermal neutrons becomes saturated, is reached.
A filtration stage (5), also surrounded by the reflective cover (4), is arranged after the core of the moderator (3). Said filtration stage (5) functions to provide an additional filtration of the spectrum of neutrons which do not contribute to BNCT treatment (rapid and thermal neutrons), as well as to reduce the gamma-radiation minimally affecting the epithermal neutron flux. Preferably, the mentioned filtration stage (5) comprises at least these layers:
The thickness of this layer (L2) is 0.20 cm ±20%. In particular, in the implementation of
Preferably, the gamma-radiation filtration layer is arranged last according to the direction of travel of the neutron beam produced. Even more preferably, the thermal neutron filtration layer and the gamma-radiation filtration layer are arranged in that order according to the direction of travel of the neutron beam produced.
It can be seen in
As a result of the filtration stage (5), the spectrum of the neutrons obtained is suitable for BNCT treatment (the rapid and thermal neutrons have been filtered, allowing the thermal neutron flux to be kept below 5% of the total flux, and also residual gamma-radiation has been removed).
Next there is arranged an outlet opening (6) which determines the shape and focalization of the beam. In particular, it has a cylindrical-conical section, as shown in
Finally there are arranged various layers of shield (7) which act as protection of the patient against gamma-radiation, as well as absorb the neutrons which would otherwise exit somewhere other than via the outlet opening (6). After the outlet opening (6) there are placed various materials which make it possible to absorb the neutrons which would otherwise exit the invention in an uncontrolled manner. As shown in
The shield (7) may contain only the above two layers, the Pb layer and the lithiated polyethylene layer, in case a mixture with a sufficiently high proportion of 6Li is achieved. Alternatively, the following two layers can be used additionally to increase the concentration of the 6Li isotope: a natural LiF layer and a 6Li-enriched LiF layer, which together with the natural LiF layer prevent contamination of the neutron beam obtained with contributions off the main axis.
In different preferred implementations of the invention, there can be a plurality of one or more layers of the shield (7) of the aforementioned materials: lithiated polyethylene, lead, LiF, 6Li-enriched LiF. In other implementations, the lithiated polyethylene can be replaced with borated polyethylene.
The layers of the shield (7) have been described in the sense in which they would be traversed by the neutron beam. However, they can be arranged in any technically possible order. The outlet opening (6) is thus covered by lead and LiF layers in both its conical and cylindrical cross-section. However, it should be noted that the arrangement of layers of the shield (7) shown
In summary, the DPMC must be capable of producing an epithermal neutron beam with high flux, while at the same time thermal and rapid neutron fluxes must be reduced to a minimum. The optimal energy of the neutrons which are applied in BNCT is a few keV, since it allows the treatment of deep tumors, so the maximum of the spectrum must be in this energy range. Likewise, the contamination of the beam by gamma-radiation must be avoided as much as possible. Finally, the neutron beam must have good collimation and a not very high divergence. In other words, the generated neutrons must exit towards the front and the beam must not open up excessively after exiting thorough the outlet opening (6). It should be noted that in the invention there are two different gamma-radiation filters, but their function is different: a layer included in the filtration stage (5), which filters said radiation for the beam that is to exit through the outlet opening (6) and that is to be used in the treatment; while the gamma-radiation filters included in the shield (7) only affect the diverted neutrons with respect to the main axis.
In the preferred embodiment of the invention laid out in
The validation of the preferred embodiment shown in
The results of the simulations on the phantoms are summarized in Table 1.
The following equation has been used to estimate the total radiation equivalent dose (DT), in units of equivalent grays (Gy-Eq.):
where Dth is the thermal neutron dose, r = 0.422 and χ denotes the concentration of boron applied with the treatment (its value is about 35 in tumor tissue and 10 in healthy tissue); while wth,wfast and wB are a series of weighting parameters depending on the relative biological effectiveness (RBE) of the contributions of thermal neutrons, rapid neutrons, and boron, respectively. In particular, wth as wfast are equal to 3.2 both for tumor tissue and for healthy tissue. In contrast, the weighting of boron is higher in tumor tissue (where wB = 3.8) in comparison with healthy tissue (wB = 1.3).
Secondly, in Table 2 various quality parameters of the neutron beam obtained in the DPMC are compared based on the IAEA recommendations. In particular, the results for a proton beam at 2.0 and 2.1 MeV, respectively, are shown. The epithermal limit of energy (LE) is set at 10 and 20 keV. It should be noted that about half of the dose produced by rapid neutrons corresponds to neutrons with an energy in the range of 10-20 keV. Furthermore, all the IAEA recommendations are met with the proposed invention when the incident proton beam has an energy of 2.1 MeV, while in the case of 2.0 MeV, it only falls below in terms of epithermal flux. Another aspect to be noted is that as a result of the proposed preferred embodiment, the IAEA requirements can be met considering exclusively epithermal neutrons in the range of 0.5 eV-10 keV, which are the most suitable for BNCT treatment. This is achieved as a result of the filtration stage (5) and the shield (7), as well as the materials forming same.
Thirdly, the neutron spectrum in the DPMC has been analyzed. In particular,
In addition, it has been compared with the spectrum provided by other DPMC facilities, in particular Fir-1 and C-BENS. The results are shown in
In some preferred embodiments of the invention, the reflective cover (4) comprises at least one of the following materials: Ni, Pb, BeO, Bi. In the case of beryllium oxide, the usable isotope is 9Be. This has a high elastic cross-section, which constitutes almost the entirety of its cross-section up to the MeV range, so that neutron absorption losses would be minimal in this case. However, it has two drawbacks, both due to the low mass of 9Be. On the one hand, neutron collisions do not occur predominantly at large angles (backward bouncing), so many neutrons will follow their path to the outside of the DPMC, slightly diverted and not reflected, thus requiring a larger thickness of material. On the other hand, the kinematics of the elastic collision cause the neutrons to lose much more energy compared to a heavier nucleus, so the neutrons would be excessively moderated. Thus, BeO might be more appropriate in the case of using higher initial energies for the neutrons, beyond the 2-2.1 MeV used in this embodiment of the invention. In such a case it would contribute to moderation together with MgF2, as a result of its intermediate behavior between a reflector and a moderator.
| Number | Date | Country | Kind |
|---|---|---|---|
| P202030854 | Aug 2020 | ES | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/ES2021/070607 | 8/9/2021 | WO |
