WO2023281539A1

WO2023281539A1 - Multi purpose compact apparatus for the generation of high-flux of neutrons, particularly for intraoperative radiotherapy

Info

Publication number: WO2023281539A1
Application number: PCT/IT2021/000032
Authority: WO
Inventors: Maurizio MARTELLINI; Giuseppe GHERARDI; Ka-Ngo Leung; James Kin-Bon LEUNG; Massimo SAROTTO; Anotonietta RIZZO
Original assignee: Theranosticentre S.R.L.; ENEA - Agenzia nazionale per le nuove tecnologie, l'energia e lo sviluppo economico sostenibile
Priority date: 2021-07-05
Filing date: 2021-07-05
Publication date: 2023-01-12
Also published as: WO2023281539A8

Abstract

An apparatus (10, 100) for generating a high-flux of neutrons comprising a neutron generator (20, 120) which comprises an emission window (21, 121) and it is configured to emit, from said emission window (21, 121), a flow of neutrons (99), said neutron generator (20, 120) comprising a deuterium ion source chamber (40, 140) wherein positive deuterium ions (D+) or negative deuterium ions (D-) are generated, characterized in that said deuterium ions source chamber (40, 140) is provided with at least one exit electrode (50, 150) that is provided with at least one opening (51, 151) for the outward passage of at least some of said deuterium ions (D+, D-) from said deuterium ion source chamber (40, 140) in an axial direction (Y) towards said emission window (21, 121) through an acceleration tunnel (51,151); wherein said neutron generator (20, 120) comprises a titanium target (14, 114) that is arranged at one end of said acceleration tunnel (51, 151), before said emission window (21, 121), and that is connected to a voltage generator (AV+, AV-) so as to be biased, said titanium target (14, 114) being configured to be struck by the deuterium ions (D+, D-) emitted from said deuterium ion source chamber (40, 140) and consequently to emit neutrons (99) from said emission window (21, 121); and wherein said acceleration tunnel (51, 151) extends along said axial direction (Y) from said at least one exit electrode (50, 150) to said titanium target (14, 114) and is defined by a lateral wall (27, 127) made of an electrical insulating material.

Description

MULTI PURPOSE COMPACT APPARATUS FOR THE GENERATION OF A HIGH-FLUX OF NEUTRONS, PARTICULARLY FOR INTRAOPERATIVE RADIOTHERAPY

The present invention relates to an apparatus for the generation of a flux of neutrons and more particularly a compact high-flux neutron generator which can be useful for several different applications, such as radiotherapy, study of materials, imaging, nuclear research, geological applications, etc.

The neutron irradiation, in fact, has a very large application domain and it is usually adopted to study the structure of materials (ranging from crystals up to human tissues), their activation analyses, the production of radioisotopes, the fast neutron imaging, the geological prospecting, the fundamental nuclear research and the computation of nuclear data.

In particular, the apparatus to which the present invention relates is suitable for the intraoperative radiotherapy (IORT).

Intraoperative radiotherapy (IORT) is a treatment technique, in particular for treating tumors, which associates radiotherapy with surgery. This technique entails the administration of a dose of radiation directly on the tumor in order to irradiate the tissue that cannot be attacked surgically or, after having removed the neoplastic tissue, directly on the tumor bed.

The apparatuses nowadays commonly used to carry out this therapy comprise a source of radiation which emits, through an emission mouth, a beam of high-energy electrons and/or X-rays.

The radiation source is positioned so as to direct the beam of radiation directly on the tissue to be treated by way of an adjustable supporting structure which generally has an arm that can be rotated about the operating table.

In particular, there is a general clinical consensus that single dose targeted intraoperative electron radiotherapy (IOERT) is non-inferior to the External Beam Radiation Therapy (EBRT) for the treatment of early solid tumors which are eligible for the IOERT treatment. The IOERT allows for small Surgery Cavity (SC) volume treatment, complete skin sparing and maintaining high Local Control (LC) of the tumor, reducing the risks of radiation-induced secondary malignancies as it could be the case in the EBRT which requires multiple doses over several days, in general for 5/6 weeks of daily irradiation.

Such conventional apparatuses, although very useful and practical, have a number of drawbacks.

First of all, in practice, the radiation emitted by these conventional apparatuses is absorbed unevenly by the tissues, in that the charged particles (such as electrons) deposit most of the total dose in a limited cross-section of the tissue (the region where absorption is concentrated is known as the Bragg peak).

In particular, the Relative Biological Effectiveness (RBE) weight of the Ionizing Radiation (IR) provided by the IOERT with low-energy electrons is set to 1 (as for photons) because it supplies a low-dose Linear Energy Transfer (LET).

Furthermore, the depth that can be reached in the irradiated tissue by the electrons emitted by conventional apparatuses is limited to around 3 cm.

X-ray radiation, on the other hand, passes through the entire body, irradiating the healthy tissues as well.

Another problem that is found in using conventional apparatuses is the exposure time necessary to reach the optimal dose for the therapy: this time, in some cases, can reach or exceed an hour and therefore, since it is impossible to keep the tissues immobile for such a long time, the exposure ends up being incorrect and uneven.

EP3522177 discloses an apparatus for intraoperative radiotherapy (IORT) based on neutrons, also known as nIORT® (neutrons intraoperative radiotherapy), which comprises a neutron generator having a cylindrical geometry and a beam shaping element consisting in a separate device formed by two superimposed disks. More precisely, in the generator, deuterium ions are emitted from a deuterium ions source that is arranged at the center of the generator so as to strike a cylindrical target which surrounds the ions source. Consequently, the cylindrical target emits, radially, a flux of neutrons which exit from a lateral window.

Although of a great interest, this known apparatus for the intraoperative radiotherapy (IORT) based on neutrons is not easy to manufacture.

Another drawback of this known apparatus consists in that it requires high voltages and the stability of the system is not optimal.

Furthermore, the size of such apparatus tends to be too large for the use inside an operating room and the costs tends to be too high.

The aim of the present invention is to provide an apparatus for generating a high-flux of neutrons which solves the above technical problems, eliminates the drawbacks and overcomes the limitations of the known art.

Within this aim, an object of the present invention is to provide an apparatus for generating a high-flux of neutrons which is more versatile and suitable for different applications.

Another object of the invention consists in providing an apparatus for generating a high-flux of neutrons suitable for intraoperative radiotherapy (IORT) that is stable and compatible with the use inside an operating room.

A further object of the invention consists in providing an apparatus for generating a high-flux of neutrons that makes it possible to have available a neutron flux which can be, at least in some respects, more efficacious with respect to the known.

Another object of the invention consists in providing an apparatus for generating a high-flux of neutrons that has a more compact and lighter structure with dimensions which can be smaller than the prior art.

Another object of the invention consists in providing an apparatus for generating a high-flux of neutrons that is more flexible and versatile in their design with respect to the prior art.

Another object of the invention consists in an apparatus for generating a high-flux of neutrons that is easy to manufacture and at competitive costs.

This aim and these and other objects which will become better apparent hereinafter are achieved by an apparatus for generating a high-flux of neutrons according to claim 1. This aim and these and other objects are also achieved by a method according to claim 20.

Further characteristics and advantages of the invention will become better apparent from the description of two preferred, but not exclusive, embodiments of an apparatus for generating a high-flux of neutrons which are illustrated by way of non-limiting example with the aid of the accompanying drawings wherein:

Figure 1 is a schematic representation of a longitudinal section of a generic embodiment of the apparatus for generating a high-flux of neutrons, according to the invention; Figure 2 is an enlarged detail of the apparatus of figure 1;

Figures 3 to 10 are cross-section, along different planes, of the apparatus of figure 1 ;

Figure 11 is a longitudinal sectional view of a first possible embodiment of the apparatus for generating a high-flux of neutrons, according to the invention, based on the generation of positive deuterium ions, during the functioning;

Figure 12 is a longitudinal sectional view of a second possible embodiment of the apparatus for generating a high-flux of neutrons, according to the invention, based on the generation of negative deuterium ions, during the functioning;

Figure 13 is a chart related to the neutron weighting factor of the neutrons with energy which represents the ratio between the biological and physical doses as a function of their energy;

Figure 14 depicts an example of the use of the apparatus for generating a high-flux of neutrons, according to the invention. The apparatus for generating a high-flux of neutrons is generally designated by the reference numerals 10 or 100 depending on the embodiment; figure 1 shows features which are shared by all the preferred embodiments, including the embodiments of figure 11 and 12.

With reference to the figures, the apparatus 10, 100, for generating a high-flux of neutrons comprises a neutron generator 20, 120 which in turn comprises an emission window 21, 121.

Such neutron generator 20, 120 is configured to emit, from the emission window 21, 121 a flow of neutrons 99 (which, in practice, normally contains also gamma photons and therefore can be considered a mixed flow of neutrons and gamma photons).

In particular, the neutron generator 20, 120 comprises a deuterium ion source chamber 40, 140 wherein positive deuterium ions D+ or negative deuterium ions D- are generated.

In some embodiments (such as the one depicted in figure 11), the deuterium ion source chamber 40 is configured to generate positive deuterium ions D+; in other and more advantageous embodiments (such as the one depicted in figure 12) the deuterium ion source chamber 140 is configured to generate negative deuterium ions D-.

In the preferred and illustrated embodiments, the deuterium ion source chamber 40, 140 is enclosed in an isolated chamber 60, 160 provided inside the body of the neutron generator 20, 120, which isolated chamber 60, 160 is closed (i.e. at least partially surrounded) by an isolation wall 61, 161 made of an electrical insulating material such as high density polyethylene.

Preferably, the apparatus 10 comprises also a beam shaping assembly 30 for the shaping (and/or collimation and/or moderation) of the flow of neutrons 99 emitted from the emission window 21, 121, which is arranged at the emission window 21, 121.

According to the invention, the deuterium ions source chamber 40, 140 is provided with at least one exit electrode 50, 150 that is provided with at least one opening 51, 151 for the outward passage of at least some of the deuterium ions D+, D- from the deuterium ion source chamber 40, 140 in an axial direction Y towards the emission window 21, 121 through an acceleration tunnel 51,151.

According to the invention, the neutron generator 20, 120 comprises a titanium target 14, 114 that is arranged at one end of the acceleration tunnel 51, 151, before the emission window 21, and that is connected to a voltage generator AV+, AV- so as to be biased.

Such titanium target 14, 114 is configured to be struck by the deuterium ions D+, D- emitted from the deuterium ion source chamber 40, 140 and consequently to emit neutrons 99 from the emission window 21, 121 (toward the beam shaping assembly 30 in the illustrated embodiments).

In practice, in the titanium target 14, 114 the incoming deuterium ions D+, D- react with the deuterium atoms contained (i.e. trapped) in the titanium target 14, 114 and so a D-D fusion reaction occurs generating neutrons. Titanium is used as the target material because each titanium atom can hold onto two deuterium atoms and, for prolong operation, titanium is only weakly activated.

Preferably, the titanium target 14, 114 comprises a hemispherical shaped target surface 15, 115 in order to reduce the power density of the incoming deuterium ions D+, D-. In practice, the hemispherical-shaped target surface 15, 115 reduces the power density of the incoming deuterium ion beam by a factor of two comparing to a planar target surface.

In other words, the titanium target 14, 114 comprises a concave portion forming the target surface 15, 115.

Preferably, in correspondence of the hemispherical-shaped target surface 15, 115 (i.e. in the concave portion), the titanium target 14, 114 has a thickness comprised between 1,8 and 2,2 mm, more preferably 2 mm.

In the preferred embodiments, the titanium target 14, 114 is struck by the incoming deuterium ions D+, D- only on the target surface 15, 115 (i.e. on the concave portion), and thus the neutrons 99 are emitted only by the concave portion.

As an alternative, the target surface 15, 115 may have a concave shape different than hemispherical, but still preferably curve, such as hemi- elliptical or the like.

It should be noted that the acceleration tunnel 51, 151 extends along said axial direction Y from the at least one exit electrode 50, 150 to the titanium target 14, 114 and is defined by a lateral wall 27, 127 made of an electrical insulating material. In the illustrated examples, the lateral wall 27, 127 is tubular (i.e. cylindrical) so as to define a cylindrical acceleration tunnel 51, 151.

Preferably, the electrical insulating material is high density polyethylene which shields neutrons and it also functions as a vacuum chamber. In fact, the acceleration tunnel 51, 151 is in practice a vacuum chamber

(wherein there is 0,001 Torr pressure, or less).

Preferably, also the ion source chamber 40, 140 is a vacuum chamber.

The high density polyethylene to which reference is made is the material also known as “High-density polyethylene” (HDPE). Normally, the density of HDPE can range from 930 to 970 kg/m3.

In the preferred embodiments, the neutron generator 20, 120 comprises a sealing flange 22, 122, made of the above-mentioned electrical insulating material, which seals the acceleration tunnel 51, 151 on the titanium target side and defines the emission window 21, 121. Preferably, the apparatus 10, 100 further comprises a radial shield 28,

128, preferably made of borated polyethylene, which surrounds the lateral wall 27, 127.

In all the preferred embodiments, the apparatus 10 further comprises an external shell 29, 129 - preferably made of lead in order to optimally shield gamma radiation - which is provided with an open passage 36, 136 (which may be cylindrical or frustum-shaped) in correspondence of said emission window 21, 121. The external shell 29, 129 has a frontal portion wherein the open passage 36, 156 is proved. Such frontal portion of the external shell 29, 129 may be made of bismuth or graphite in place of lead.

In the illustrated embodiments, the open passage 36, 136 is frustum- shaped having a larger inlet opening which is adjacent to the emission window 21, 121 and a smaller exit opening which is coaxial and opposite with respect to the larger opening.

In order to have an optimal output flux, the apparatus 10, 100 comprises a flange wall 31, 131 that is at least partially transparent for the neutrons emitted by the generator 20, 120. More precisely the flange wall 31, 131 is arranged between the open passage 36, 136 and the emission window 21, 121, so as to close the latter.

Preferably the flange wall 31, 131 is made of high density polyethylene.

The optimal thickness of the flange wall 31, 131 is comprises between 0,08 and 0,22 cm, preferably 0,2 cm.

According to an optional and advantageous feature, between the flange wall 31, 131 and the titanium target 14, 114 it is defined a cooling chamber 78 which is connected with inlet and outlet ducts 77, 177 for the passage of air, so that the flow of neutrons 99 emitted from the target 14, 114 passes through a layer of air contained in the cooling chamber 78.

Preferably, the cooling chamber 78 (and thus the layer of air contained therein) has a width comprise between 0,19 and 0,22 cm (preferably 0,2 cm).

According to another optional and advantageous feature, the apparatus 10, 100 further comprises an external layer 39, 139 which partially shields neutrons (to as to at least partially moderate the mixed flow of neutrons and gamma photons 99).

The external layer 39, 139 is provided with an irradiation window 38, 138 placed in correspondence of the exit window 21, 121 and of the open passage 36, 136. In practice, in the preferred embodiments, the external layer 39, 139 and the open passage 36, 136 form, or are part of, the beam shaping assembly 30, 130. In other words, the beam shaping assembly 30, 130 to which reference is made advantageously consists of a part of the external shell 29, 129 (i.e. the front side wherein the open passage 36, 136 is provided) and the external layer 39, 139.

In these embodiments, the external shell 29, 129 (or at least its front side wherein the open passage 36, 136 is provided) has a thickness comprised between 0,9 and 1,1 cm, preferably 1 cm.

In the preferred embodiments, the external layer 39, 139 is made of high density polyethylene and preferably has a thickness comprised between 0.5 and 2 cm, more preferably between 0.5 cm and 1.5 cm (optimally 1 cm which has been used in the simulations to estimate the irradiation performances of the apparatus).

The external layer 39, 139 is an interface surface in the sense that, in the use, as shown in figure 2, a target to be irradiated O, S, M can be placed in contact with the external layer 39, 139. In the illustrated example the target to be irradiated is a tissue of the patient (e.g. the skin S and/or an exposed organ O such a breast).

Therefore, according to an optimal combination of features, the flow of neutrons 99 emitted from the target 14, 114 (and more precisely from the portion consisting in the hemispherical-shaped target surface 15, 115), before reaching the target to be irradiated O, passes through: the layer of air contained in the cooling chamber 78 (i.e. 0,2 cm of air), the flange wall 31, 131 (i.e. 0,2 cm of high density polyethylene), the open passage 36, 136 and the irradiation window 38 in the external layer 39, 139; part of the flow of neutrons 99 is shielded by the external shell 29, 129 (i.e. 1 cm of lead), more precisely all the flow 99 is shielded by the external shell 29, 129 except a central portion centered around a central axis corresponding to the axial direction Y. It should be noted that the flow of neutrons 99 emitted from the irradiation window 38, 138 also comprises gamma photons which are generated by the physical interactions occurring along the path of the neutrons. In the radiotherapeutic application of this invention, these gamma photons contribute to reduce the number of external beam radiation therapy (EBRT) needed after the conventional IORT.

Furthermore, these gamma photons generate Reactive Oxygen Species (ROS) that together with the DNA’s Double Strand Breaks of the quiescent cancer cells infiltrating the tumor bed and its margins resulting by the IORT treatment impair the tumor genetic development and further potential metastasis.

The optimal diameter of the irradiation windows 38, 138 is comprises between 1 and 6 cm. In this manner, the output of neutrons and gamma photons 99 can be focused only on the tissue to be treated O (e.g. an exposed organ) limiting the irradiation of the other tissues (e.g. skin S and muscles M). Therefore, the described solution makes it possible to deliver high doses to the tumor tissues O and limited doses to the surrounding healthy ones S, M. In the preferred embodiments, the neutron generator 20, 120 is powered by a lOOkV DC, 10mA, power supply.

Referring now in particular to the neutron generator 20, 120, in some embodiments such generator 20 is based on positive deuterium ions D+, in other embodiments the generator 120 is based on negative deuterium ions D-. Both the alternatives will be described in detail hereinafter.

Figure 11 shows one of the possible embodiments of the apparatus 10 wherein the neutron generator 20 is based on the generation of positive deuterium ions D+.

In these embodiments, the deuterium ion source chamber 40 is configured to generate positive deuterium ions D+ and the titanium target 14 is biased negatively with respect to ground potential, so that an electric field is generated in the acceleration tunnel 51 which accelerates the positive deuterium ions D+ towards the titanium target 14.

Further, the apparatus 10 comprises a feeding channel 44 for the introduction of deuterium gas into the ion source chamber 40.

The deuterium ion source chamber 40 is at least partially enclosed by a quartz cup 41 which is connected with a RF (Radio-Frequency) antenna 42 configured to emit radio frequency radiation into the deuterium gas contained in the deuterium ion source chamber 40 for the creation of a plasma of deuterium ions D+ from the deuterium gas; in a particular preferred embodiment, the plasma is generated by a 13.5 MHz RF discharge.

It has been observed that more of the 90% the deuterium ions contained in the plasma so generated are positive atomic deuterium ions D+.

In the illustrated embodiment, the quartz cup 41 is fixed to a copper flange 43, to which the exit electrode 50 is fixed and which contributes to delimit the ion source chamber 40.

Still in these embodiments, the exit electrode 50 is provided with a plurality of openings 51 for the outward passage of at least some of the positive deuterium ions D+ generated inside the ions source chamber 40.

Such exit electrode 50 is at ground potential

In the preferred of such embodiments, the openings 51 have a diameter of 1 mm (+/- 0,1 mm).

Preferably, the openings 50 are designed so that at the exit of these openings (inside the acceleration tunnel 51) the deuterium ions D+ merge to form a 10 mm diameter beam.

In the preferred embodiment, the titanium target 14 is biased at -100 kV and the accelerated positive deuterium ions D+ react with the deuterium in the titanium target 14 (i.e. the deuterium trapped in the titanium) to form 2.45 MeV neutrons.

In other embodiments the titanium target 14 can be biased at a different potential (e.g. between -90 kV and -110 kV). In order to ensure electrical stability, in the generator 20 based on the generation of positive deuterium ions D+, the titanium target 14 is biased maximum at -100 kV. When the titanium target 14 is biased negatively with respect to ground potential, the secondary emission electrons produced on the target will accelerate back to the ion source. These 100 keV electrons can generate unwanted high energy X-rays. They can also cause high voltage sparking along the HDPE column. Therefore, in the preferred embodiments, at least one, and preferably both, of the following optional two solutions are employed: permanent magnets 18, 19 in the titanium target and a suppression electrode 52.

In greater details, at least two (preferably a pair of) permanent magnets 18, 19 are installed on the titanium target 14 as shown in figure 11.

The suppression electrode 52 is placed on the inside side of the titanium target 14 (i.e. on the acceleration tunnel 51 side) and is biased negatively with respect to the titanium target 14 by means of a battery 53 which is connected to both the titanium target 14 and the suppression electrode 52.

In this manner, the secondary emission electrons will be kept inside the target by the electric field. This magneto-electrostatic containment scheme will ensure that the secondary electrons do not stream back to the ion source.

Figure 12 shows one of the possible embodiments of the apparatus 100 wherein the neutron generator 120 is based on the generation of negative deuterium ions D-.

In these embodiments, the deuterium ion source chamber 140 is configured to generate negative deuterium ions D- and the titanium target 114 is biased positively with respect to the ground potential, so that an electric field is generated in the acceleration tunnel 151 which accelerates the negative deuterium ions D- towards the titanium target 114.

In the preferred of these embodiments, the titanium target is biased at +100 kV and so the negative deuterium ions D- are accelerated, in the acceleration tunnel 151 , to 100 ke V. The accelerated negative deuterium ions D- react with the deuterium in the titanium target 114 to form 2.45 MeV neutrons.

In other embodiments the titanium target 114 can be biased at a different potential (e.g. between +90 kV and +110 kV).

In yet other embodiments, the titanium target 114 can be biased at higher potential (such as +400 kV or more), since in the neutron generator 120 based on the generation of negative deuterium ions D- the electrical stability is ensured also for very high voltages.

It should be noted that the deuterium ions source chamber 140 is delimited by a chamber wall 149 that is preferably cylindrical More preferably, such chamber wall 149 is made of copper, titanium or aluminum.

According to an optimal solution, the (preferably cylindrical) chamber wall 149 is closed at the two opposite ends by two closing flanges coupled at the two ends of the cylindrical ions source chamber 140. More precisely, in the preferred of these embodiments, there is a copper flange (not visible in the cross-section of figure 12) coupled to the chamber wall 149 at a first end of the ions source chamber 140, and the other flange (that is coupled to chamber wall 149 at second end of the ions source chamber 140) comprises a quartz window 181.

Conveniently, the chamber wall 149 is provided with a passage opening wherein the exit electrode 150 is arranged.

In these embodiments, a radio-frequency induction device is configured to produce radio-frequency discharge within the deuterium gas contained in the deuterium ion source chamber 140 for the creation of a deuterium plasma. Preferably, the plasma in the ion source chamber 140 is produced by a radio- frequency induction discharge, more preferably by 13.5 MHz RF induction discharge, provided for example by an antenna; in the preferred embodiment, for this purpose, an RF antenna coil is attached to the quartz window 181 of the ion source chamber 140 for creating the plasma.

The deuterium gas can be fed inside the ion source chamber 140 via a feeding inlet which can be made according to different design choices; in the preferred embodiment, such feeding inlet is provided in the copper flange at the first end of the ions source chamber 140.

Preferably, in the ion source chamber 140 the negative deuterium ions D- are generated by means of a surface-production system (i.e. the ion source is based on surface conversion of the positive deuterium ions), that means that the negative ions D- are produced on the surface of a low work-function converter surface 146 which is placed inside the deuterium ion source chamber 140.

Conveniently, the work-function converter surface 146 is made of a metal the work function of which becomes low when it is coated with an alkali metal such as cesium.

Materials are known for making a low work-function converter surface 146 having this behavior, such as copper and molybdenum. Preferably, the low work-function converter surface 146 is made of molybdenum.

Such low work-function converter surface 146 is biased negatively so as to emit deuterium negative ions D-, preferably between -240 V and -260 V, even more preferably at -250 V.

In greater details, by biasing the converter surface 146 negatively with respect to the plasma, positive ions from the plasma are accelerated and strike the converter surface 146. When the positive ions impact the low work- function converter surface 146 negative deuterium ions D- are formed which are then accelerated towards the exit electrode 150.

Preferably, the converter surface 146 is concave and more precisely curved to geometrically direct the deuterium negative ions D-, through the ions source chamber 140, to the opening 151 in the exit electrode 150.

Preferably, the converter surface 146 is cooled by means of a fluid (e.g. air) provided by a cooling duct 147.

Since the work-function of the converter surface 146 becomes low when it is coated with cesium, preferably, the apparatus 100 comprises a cesium dispenser 145 device, and more preferably a cesium dispenser 145 that is configured to emit cesium in consequence of heating. Such cesium dispenser 145 is arranged at least partially inside the deuterium ion source chamber 140 in order to cover the work-function converter surface 146 with the cesium.

As an alternative to cesium, other alkali metals such as Rb, K, Na, or Li can be used; therefore, in some alternative embodiments, the apparatus 100 comprises a different alkali metal dispenser 145 device, such as a Rb, K, Na, or Li dispenser that is configured to emit the chosen alkali metal in consequence of heating. However, the negative ions D- yield will not be as high as when Cs is used.

The cesium dispenser 145 can be, for example, a known SAES® getter dispenser.

In the preferred embodiment, in the copper flange, at the first end of the ions source chamber 140, there are two feed-through passages for mounting the cesium (or other chosen alkali metal) dispenser 145.

As can be understood by looking at figure 12, in this embodiment, a plurality of magnets 148 are arranged around the deuterium ions source chamber 140 so as to produce a confinement magnetic field B surrounding the converter surface 146.

The described surface-production of deuterium negative ions D- has several advantages over the volume-production type D- sources: it can be operated at a lower source filling pressure; electrons from the source plasma cannot leave the source chamber due to the presence of the cross magnetic field near the exit aperture; there is no weak component and the lifetime can be very long. The lifetime of the D- source in the 100 kV D-D neutron generator is expected to be several weeks or longer in continuous operation.

Optionally, the exit electrode 150 is biased positively (preferably at +10 V) with respect to the chamber wall 149 that delimits the deuterium ions source chamber 140, in order to reduce the amount of electrons in the deuterium negative ions D- beam.

In the preferred and illustrated embodiments of the apparatus 10, 100, which are particularly advantageous for radiotherapy, the titanium target 14, 114 is biased at +/-100 kV and consequently the accelerated deuterium ions D+ / D- react (nuclear D-D fusion) with the deuterium in the target 14, 114 to produce 2.45 MeV neutrons.

That, together with the described beam shaping assembly 30, 130, provides an output flow of neutrons which is optimal for example for intraoperative radiotherapy, that was studied also as an envelope case for all other neutron irradiation application fields requiring lower flux levels.

With reference to the possible use for radiotherapy, figure 13 shows the behaviour of radiation weighting factor (w_n) of the neutrons with energy. It measures their radiation efficiency and coincides with the ratio between the biological and physical doses (expressed in Sv and Gy, respectively) at different energies. It appears evident that the highest efficiency occurs around 1 MeV, where the weighting factor value is very high (º20). This is because neutrons with energy around 1 MeV produce a mixed radiation of secondary particles in the tissue, such as photons and recoiling light nuclei. Photons (usually considered as the reference radiation) are decisively less "harmful" particles with an associated radiation weighting factor equal to one for all energies (as for electrons).

The neutrons energy in the flow emitted by the preferred embodiments of the apparatus 10, 100 (2.45 MeV, and below after the scattering with beam shaping assembly 30, 130 and the external layer 39, 139) results to be very close to the maximum neutron weighting factor efficiency. As a main consequence, very high values of the induced biological dose rates - in the following indicated by D’_B,n and expressed in Sv per minutes (Sv/min) - can be obtained with the neutron flux level ~10⁸ cm ² s ¹ at the irradiation window of the apparatus 10, 100.

A number of simulations with the Monte Carlo Neutron Particle ver. 6.1 code (MCNP) developed by the LANL (USA) has been performed to evaluate the flux level at the irradiation window and the flux and dose values in the human tissue in front of it. The MCNP calculations start from the source neutron yield in the Ti Target (3.3 x 10⁹ s ¹) by considering the angular distribution of neutrons emission, 58% peaked in the forward direction. The neutron (n) and photon (g) flux levels in the tissues were calculated, as well as the physical dose rates due to them (D’f,_y and D’f,n) and the biological dose rates due to neutrons (D’_B^ = w_n D’f,n). While for photons the physical and biological dose values numerically coincide (w_y = 1), the behaviour with energy of w_n shown in Fig. 13 was accurately reproduced in the MCNP integrals for biological dose rate evaluations by obtaining an average value of about 16 for w_n. Roughly speaking, this means that when neutrons and photons deliver the same physical dose to a target tissue, the damage induced by neutrons to the tissue cellules is about 16 times higher than the damage obtained in standard radiotherapy techniques with photons (or electrons).

As reported in the following equation, the total dose rate (D’_B,tot) can be retrieved with:

D’s.tot = D’f + W_n D’f,n (1)

The following table 1 summarizes the main features and irradiation performances of the preferred embodiment of the apparatus, as depicted in figure 1, obtained with the diameter of the irradiation windows 38, 138 ranging between 1 and 6 cm. As a Monte Carlo code, MCNP is affected by the statistical noise of the results due to its stochastic nature. For briefness and easiness, the uncertainty of the results was not indicated in Table I, but the relative standard deviation is lower than 1% for all the physical quantities reported.

Among the physical parameters of Table I, the neutron flux levels at the irradiation window (that reaches ~10⁸ cm ² s ¹), the high neutron flux level in the tumor tissue and the very low neutron and photon flux levels in external air outside the lead shield 29, 139 can be noticed. The most significant parameter is represented by the total dose rate in tumour (D’_B,tot in (1); see last row of Table I) that results to be slightly greater than 2 Sv /min for every window diameter chosen (1 ÷ 6 cm). Table I Main features and irradiation performances of the apparatus

(1 ÷ 6 cm irradiation window diameter)

Parameter Units Value

Neutron yield at the Ti target (15) [s ¹] 3.3 10⁹

External diameter x length of the apparatus (10) [cm] 30 x 40

Irradiation window (38, 138) diameter [cm] 1 ÷ 6

Neutron Flux at irradiation window [cm ² s ¹] 1.01 ÷ 0.51 10⁸

Photon Flux at irradiation window [cm ² s ¹] 5.21 ÷ 4.48 10⁶

Max neutron flux in air (outside external layer 39, 139 of [cm ² s ¹] 4.35 ÷ 4.25 10⁶ HDPE)

Max photon flux in air (outside external layer 39, 139 of [cm ² s ¹] 7.66 ÷ 7.27 10⁵ HDPE)

Max neutron flux in tumour tissue O (breast cell, 0.5 cm thick) [cm ² s ¹] 9.1 ÷ 7.3 10⁷ Max photon flux in tumour tissue O (breast cell, 0.5 cm thick) [cm ² s ¹] 4.9 ÷ 4.8 10⁶ Max biological dose rate in tumour tissue O (breast) [Sv min ¹] 2.36 ÷ 2.10

It should be noted that the neutron flux distribution is peaked in the centre and decreases towards the boundary of the irradiation window 38, 138. As a main consequence, in comparison with the central peak value the dose level:

- is reduced by about 20% at the border of an irradiation window of 2 cm diameter; - is reduced by about 50% at the border of an irradiation window of 4 cm diameter;

- is reduced by about 80% outside the border of the 6 cm window diameter.

By adopting as reference the standard clinical end-points used in the intraoperative radiotherapy treatments, the potential performances of the apparatus results to be very promising for the very limited Treatment Time (TT), since it is able to reach the aimed dose levels in few minutes. By referring to the IORT technique with electrons (IOERT), two clinical end points are usually adopted in dependence of the tumour bed (and patient) conditions. The so-called Boost IORT and Radical IORT applications foresee clinical end-points of about 10 Sv and 20 Sv, respectively, representing the aimed dose to be delivered in the tumour tissue. Another reference value used in the neutron capture therapy research field is the 12.6 Sv threshold, that is commonly adopted as the maximum biological dose that can be delivered to the healthy tissues.

By assuming the clinical end-points of 12.6 Sv (for Boost IORT) and 20 Sv (for Radical IORT), that represent the biological dose targets (D_B,T) to be delivered in tumour tissue by a single irradiation, the Treatment Time (TT) can be easily retrieved from the total dose rate (1) by the following relation:

TT = D_B,T (12.6 or 20 Sv) / D’_B,tot (2)

The following table II reports the TT and dose levels obtained with three possible examples of clinical end-points. In particular, the three cases foresee 12.6 Sv as maximum and average doses (Boost) and 20 Sv as maximum dose (Radical) in tumour as target limits in a single irradiation. For each case, the maximum or average dose delivered in the tumour tissue inside the irradiation window is reported, together with the maximum dose in healthy skin outside the irradiation window. The most important result is that TT, that depends on the dose target limits assumed and the window diameter (1 ÷ 6 cm) chosen, is limited in the range between 5.5 and 10 minutes for all cases.

The clinical irradiation performances in the nIORT treatment reported in Table II refers to the 1 ÷ 6 cm range of the irradiation window diameter. The TT needed to reach a maximum dose level of 12.6 Sv is about 6 minutes almost independently from the diameter of the irradiation window (see first three rows of Table II). Otherwise, the TT needed to reach an average dose level of 12.6 Sv varies in the range 5.4 ÷ 10.2 minutes in dependence of the irradiation window diameter chosen. Finally, the TT needed to reach a maximum dose level of 20 Sv is about 9 minutes almost independently from the irradiation window diameter chosen (see last three rows of Table II).

Table II Three clinical irradiation performances in the nIORT treatment corresponding to three different clinical end-points (1 ÷ 6 cm irradiation window 38, 138 diameter)

Dose target (tumour) Parameter Units Value 12.6 Sv as Max Dose Treatment time [min] 5.4 ÷ 6.1

Average biological dose in [Sv] 12.6 ÷ 7.5 tumour tissue O (breast)

Max biological dose in [Sv] 8.7 ÷ 3.2 healthy tissue S (skin)

12.6 Sv as Average Dose Treatment time [min] 5.4 ÷ 10.2

Max biological dose in [Sv] 12.6 ÷ 21.3 tumour tissue B (breast)

Max biological dose in [Sv] 8.7 ÷ 5.5 healthy tissue S (skin)

20 Sv as Max Dose Treatment time (based on [min] 8.5 ÷ 9.6 Average biological dose)

Average biological dose in [Sv] 20 ÷ 11.8 tumour tissue O (breast) Max biological dose in [Sv] 13.8 ÷ 5.2 healthy tissue S (skin)

To be remarked that the maximum and average dose values coincide in the configurations having an irradiation window 38, 138 diameter of 1 cm, while for larger diameters the average values are lower than the peak ones in the window centre since, as expected, the average decreases by increasing the irradiation window 38, 138 diameter. In particular, from the results in Table II it can be deduced that by assuming:

- 12.6 Sv as maximum dose, the average dose is still 12.6 Sv with a 1 cm window diameter and decreases down to 7.5 Sv with the largest diameter (6 cm; otherwise it results 11.9 and 9.6 Sv with 2 and 4 cm window diameters, respectively);

- 12.6 Sv as average dose, the maximum dose is still 12.6 Sv with 1 cm window diameter and creases up to about 21 Sv (in the window centre) with the largest 6 cm window;

- 20.0 Sv as maximum dose, the average dose is still 20 Sv with 1 cm window diameter and decreases down to 11.8 Sv with the 6 cm window diameter.

From the results in Table II it can be also noticed that:

- in all cases (i.e., 3 clinical end-points with 1 ÷ 6 cm window diameters), the dose levels in healthy skin resulted to be below the 12.6 Sv threshold, by the exception of the Radical application with an irradiation window of 1 cm diameter (where it reaches 13.8 Sv, see last row of Table II);

- even higher dose levels, by assuming e.g., 20.0 Sv as average dose in tumour, could be obtained in a single irradiation by a small (and manageable) increase of the TT.

Therefore, potentially, with the apparatus 10 both the Boost IORT (i.e., 12.6 Sv in about 6 min) and Radical IORT (i.e., 20 Sv in about 9 min) applications can be implemented. Advantageously, the IORT performed by means of the apparatus 10 is applicable especially when the tumour bed presents heterogenic cancer cells with a high density (even after the chimrgic resection during the IORT treatment). In fact, the apparatus 10 results to be very suitable for the Radical IORT applications (foreseeing 20 Sv as maximum dose in tumour), but the dose levels could be further increased by satisfying clinical end-points beyond the Radical IORT requirements by a tuneable (and manageable) increase of the TT. As an example, by assuming 20 Sv as the average dose level to be delivered in tumour, the TT results to be limited to about 9 ÷ 16 minutes in dependence of the irradiation window diameter chosen. The TT of 16 minutes corresponds to the largest diameter of the irradiation window (6 cm): in this case, while the average dose in tumour is 20 Sv, the dose peak in the window centre reaches up to 44 Sv. To be finally remarked that the dose levels indicated in Table II refer to the surface tissues. Going in depth in the cancer breast tissue, the dose levels reduce by a factor = 2 in the first centimetre and by a factor º 4 at 6 cm depth, that should preserve the nearest organs from harmful radiations.

Advantageously, in the preferred and illustrated embodiments, the apparatus 10 has cylindrical shape with limited weight (< 100 kg) and dimensions: 30 cm diameter and 40 cm length, including the beam shaping assembly 30, 130, the radial shield 28, 128, external shell 29, 129 and the eternal layer 39, 139. Therefore, the apparatus 10, 100 can be made compact, lightly and mobile, with limited costs and suitable for a robotic arm or gantry system.

Figure 14 shows a possible embodiment of the apparatus 100 included in a radiotherapy system, wherein the apparatus 100 is supported by a robotic assembly 400 provided with a movable charter. The robotic assembly 400 comprises a plurality of arms 401a, 401b, 401c for positioning the apparatus 10 with respect to a patient P lying on an operating bed b.

Advantageously, in the apparatus according to the invention there is a very low risk of nuclear proliferation and low-level nuclear wastes, since the neutron generator is sealed before the reconditioning.

In practice it has been found that the apparatus for generating a high- flux of neutrons, according to the present invention, achieves the intended aim and objectives in that it is more versatile and suitable for different applications.

A relevant advantage of the apparatus for generating a high-flux of neutrons, according to the invention, consists in that the emitted flux of neutrons is not isotropic, but instead is forward peaked, differently from the flux emitted by a coaxial RF-driven neutron generator.

Another advantage of the apparatus for generating a high-flux of neutrons, according to the invention, consists in that it is suitable for intraoperative radiotherapy (IORT), being stable and compatible with the use inside an operating room.

Another advantage of the apparatus for generating a high-flux of neutrons, according to the invention, consists in that the irradiation window can be placed very close to the target tissues to be irradiated.

Another advantage of the apparatus for generating a high-flux of neutrons, according to the invention, consists in that it makes it possible to have available a neutron flux which can be, at least in some respects, more intense and stable with respect to the known positive D+ ion-based neutron generators.

Another advantage of the apparatus for generating a high-flux of neutrons, according to the invention, consists in that it has a more compact and lightly structure with dimensions which can be smaller than the prior art.

Another advantage of the apparatus for generating a high-flux of neu trons, according to the invention, consists in that it is more flexible and versa tile in their design with respect to the prior art.

Another advantage of the apparatus for generating a high-flux of neutrons, according to the invention, consists in that it is easy to manufacture and at competitive costs.

The apparatus for generating a high-flux of neutrons thus conceived is susceptible of numerous modifications and variations all of which are within the scope of the appended claims.

Moreover, all the details may be substituted by other, technically equivalent elements.

In practice the materials employed, provided they are compatible with the specific use, and the contingent dimensions and shapes, may be any according to requirements.

Where technical features mentioned in any claim are followed by reference signs, those reference signs have been included for the sole purpose of increasing the intelligibility of the claims and accordingly, such reference signs do not have any limiting effect on the interpretation of each element identified by way of example by such reference signs.

Claims

1. An apparatus (10, 100) for generating a high-flux of neutrons comprising a neutron generator (20, 120) which comprises an emission window (21, 121) and it is configured to emit, from said emission window (21, 121), a flow of neutrons (99), said neutron generator (20, 120) comprising a deuterium ion source chamber (40, 140) wherein positive deuterium ions (D+) or negative deuterium ions (D-) are generated, characterized in that said deuterium ions source chamber (40, 140) is provided with at least one exit electrode (50, 150) that is provided with at least one opening (51, 151) for the outward passage of at least some of said deuterium ions (D+, D-) from said deuterium ion source chamber (40, 140) in an axial direction (Y) towards said emission window (21, 121) through an acceleration tunnel (51,151); wherein said neutron generator (20, 120) comprises a titanium target (14, 114) that is arranged at one end of said acceleration tunnel (51, 151), before said emission window (21, 121), and that is connected to a voltage generator (AV+, AV-) so as to be biased, said titanium target (14, 114) being configured to be struck by the deuterium ions (D+, D-) emitted from said deuterium ion source chamber (40, 140) and consequently to emit neutrons (99) from said emission window (21, 121); and wherein said acceleration tunnel (51, 151) extends along said axial direction (Y) from said at least one exit electrode (50, 150) to said titanium target (14, 114) and is defined by a lateral wall (27, 127) made of an electrical insulating material.

2. The apparatus (10, 100) according to claim 1, further comprising a beam shaping assembly (30, 130) for the shaping of the flow of neutrons (99) emitted from said emission window (21, 121), which is arranged at said emission window (21, 121).

3. The apparatus (10, 100) according to claim 1 or 2, wherein said titanium target (14, 114) comprises a hemispherical-shaped target surface (15, 115) in order to reduce the power density of the incoming deuterium ions (D+, D-).

4. The apparatus (10, 100) according to one or more of the preceding claims, wherein said neutron generator (20, 120) comprises a sealing flange (22, 122), made of said electrical insulating material, which seals said acceleration tunnel (51, 151) on the titanium target side and defines said emission window (21, 121).

5. The apparatus (10, 100) according to any of the preceding claims, wherein said electrical insulating material is high density polyethylene. 6. The apparatus (10, 100) according to any of the preceding claims, further comprising a radial shield (28, 128) made of borated polyethylene.

7. The apparatus (10, 100) according to any of the preceding claims, further comprising an external shell (29, 129) made of lead or bismuth or graphite, which is provided with an open passage (36, 136) in correspondence of said emission window (21, 121).

8. The apparatus (10, 100) according to the preceding claim, wherein said open passage (36, 136) is cylindrical or frustum-shaped.

9. The apparatus (10, 100) according to claim 2 and one of claims 7 and 8, further comprising an external layer (39, 139) which partially shields neutrons; said external layer (39, 139) comprising an irradiation window (38, 138) in correspondence of said open passage (36, 136); said external layer (39, 139) and said open passage (36, 136) forming, or being part of, said beam shaping assembly (30, 130).

10. The apparatus (10, 100) according to claim 9, wherein said external layer (39, 139) is made of high density polyethylene and has a thickness comprised between 0.5 cm and 2 cm.

11. The apparatus (10, 100) according or to one or more of claims 7 to 10, characterized in that it comprises a flange wall (31, 131) that is at least partially transparent for the neutrons emitted by said generator (20), said flange wall (31) being arranged between said open passage (36, 136) and said emission window (21, 121).

12. The apparatus (10, 100) according to the preceding claim, wherein between said flange wall (31, 131) and said titanium target (14, 114) it is defined a cooling chamber (78, 178) which is connected with inlet/outlet ducts (77, 177) for the passage of air.

13. The apparatus (10) according to one or more of the preceding claims, characterized in that said deuterium ion source chamber (40) is configured to generate positive deuterium ions (D+), and in that it comprises a feeding channel (44) for the introduction of deuterium gas into said ion source chamber (40); wherein said deuterium ion source chamber (40) is at least partially enclosed by a quartz cup (41) which is connected with a RF antenna (42) configured to emit radio frequency radiation into the deuterium gas contained in said deuterium ion source chamber (40) for the creation of a plasma of deuterium ions (D+) from said deuterium gas, and wherein said titanium target (14) is biased negatively with respect to ground potential; said exit electrode (50) being provided with a plurality of openings (51) for the outward passage of at least some of said positive deuterium ions (D+) generated inside said ions source chamber (40).

14. The apparatus (10) according to claim 13, wherein: at least two permanent magnets (18, 19) are installed on the titanium target (14), and/or a suppression electrode (52) is placed on the inside side of the titanium target (14), said suppression electrode (52) being biased negatively with respect to the titanium target (14) by means of a battery (53) which is connected to both the titanium target (14) and the suppression electrode (52).

15. The apparatus (100) according to one or more of the claims 1 to 12, wherein said deuterium ion source chamber (140) is configured to generate negative deuterium ions (D-), and wherein said titanium target (114) is biased positively with respect to ground potential.

16. The apparatus (100) according to the preceding claim, comprising:

- a radio-frequency induction device configured to produce radio- frequency discharge into a deuterium gas contained in said deuterium ion source chamber (140) for the creation of a deuterium plasma; and

- a low work-function converter surface (146), placed inside said deuterium ion source chamber (140), which is biased negatively so as to emit deuterium negative ions (D-).

17. The apparatus (100) according to the preceding claim, comprising:

- a cesium dispenser (145), configured to emit cesium in consequence of heating, arranged at least partially inside said deuterium ion source chamber (140) in order to cover said work-function converter surface (146) with said cesium.

18. The apparatus (100) according to claim 16 or 17, wherein a plurality of magnets (148) are arranged around said deuterium ions source chamber (140) so as to produce a confinement magnetic field (B) surrounding said converter surface (146).

19. The apparatus (100) according to one or more of the claims 15 to 18, wherein said exit electrode (150) is biased positively with respect to a chamber wall (149) that delimits said deuterium ions source chamber (140).

20. Method for generating a flux of neutrons (99) comprising the steps of: a) generating positive deuterium ions (D+) or negative deuterium ions (D-) in a deuterium ion source chamber (40, 140); b) accelerating least some of said deuterium ions (D+, D-) from said deuterium ion source chamber (40, 140) in an axial direction (Y) towards a titanium target (14, 114), by biasing said titanium target (14, 114), so that the titanium target (14, 114) is struck by the deuterium ions (D+, D-) and consequently emits neutrons (99); c) emitting, from an emission window (21, 121), a flow of said neutrons

(99) emitted by the titanium target (14, 114).

21. The method according to claim 20, wherein the titanium target (14, 114) is biased at +/-100 kV so that the accelerated deuterium ions (D+, D-) react with the deuterium trapped in the titanium target (14) to form 2.45 MeV neutrons.