Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
  • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
  • A61N5/1027—Interstitial radiation therapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
  • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
  • A61N2005/1019—Sources therefor
  • A61N2005/1024—Seeds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
  • A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
  • A61N5/1002—Intraluminal radiation therapy

Definitions

• the present invention relates to the field of radiation treatment and in particular relates to the use of radioactive sources for irradiation of cells of the human or animal body.
• Brachytherapy is generally the term that covers therapeutic treatments inducing the placement of a radioactive source that emits radiation inside the human body.
• the implantation of such a source can be either permanent type or non-permanent type.
• High dose rate (HDR) devices are usually used for nonpermanent implantations, while permanent implantations deliver a lower dose, usually called a low dose rate (LDR).
• LDR low dose rate
• the delivered dose is also fractionated.
• these implants are arranged in or near the tumor or in or near the volume of the diseased tissue. These implants are usually in the form of grains of rice
• seeds of a length of a few millimeters for a diameter of less than 1 millimeter are traditionally made from a biocompatible material, preferably sealed, serving as a capsule in which is enclosed a radioactive source.
• a radioactive source for some time, it has been proposed to use for such radiotherapy devices, windings (springs) of a wire made of an alloy comprising the radionuclide.
• windings (springs) of a wire made of an alloy comprising the radionuclide The nature of the coating material constituting the capsule or the metal wire for winding is such that it must be biocompatible, not be toxic to the cells in contact with the implant and possibly not be subject to opsonization phenomena.
• brachytherapy Two major treatment families are envisaged for the use of brachytherapy. This is, on the one hand, the sterilization of cancer cells or tissues in the case of localized tumors, for example in the case of breast cancer, brain cancer, liver cancer, ovarian cancer or even prostate cancer. Another family of therapy envisaged allows the use of brachytherapy for the elimination of possibly healthy cells, in the case of stenosis or necrosis of biological ducts, such as coronary arteries. [0009] Traditionally, the emitted radiation comes from a single type of radionuclide chosen according to the zone to be treated. Among the most commonly used are 125 I, 103 Pd, 90 Y, 32 P, 192 Ir, ... or the 213 Bi today used in experimental stage.
• Each radionuclide has a typical radiation: low energy photon ( 103 Pd), medium energy photon ( 125 I), high energy photon ( 192 Ir), particle of the same mass as an electron (beta radiation ( 90 Y or 32 P) or Auger electron), alpha particle ( 216 Bi).
• LET Linear Energy Transfer
• the alpha, beta and Auger electrons are very little penetrating, photon radiation penetrate more or less deeply depending on their energy.
• the use of low photon radiation energy or a particle facilitates the shielding of the source, the preservation of healthy tissue, and the protection of hospital personnel but has the disadvantage of limiting the effective volume of treatment that can only be overcome by longer exposure (HDR) or the use of a very large number of implants (LDR).
• HDR longer exposure
• LDR very large number of implants
• the use of radionuclides emitting highly penetrating radiation has the advantage of treating a large volume but also irradiates healthy tissue, hospital staff and can not be shielded easily.
• the decay time can be as short as a few seconds or as long as a few weeks or years.
• radionuclides are more suitable for aggressive tumors and those with longer half-lives adapted for mildly aggressive tumors or background treatments.
• these radionuclides are included in a source that may be in the form of an ink (dried liquid). They can be present in an ion exchange resin, in a mixture consisting of a gel or a powder, in zeolytes or else absorbed on the surface of activated particles or graphite balls or others.
• 103 Pd In the particular case of breast cancer or prostate, it is most often used permanent brachytherapy devices comprising either 103 Pd or 125 I.
• the 103 Pd emits low energy RX photons with a dose distribution drops rapidly, while 125 I has a slightly higher energy, with a smoother dose distribution.
• the number of implants or brachytherapy elements used for example to treat breast cancer will be greater in the case of a use of the radionuclide 103 Pd, that for the 125 I. It is also observed that the half-life duration of the 103 Pd is 16,991 days, while that of the 125 I is 59,40 days. As a result, 103 Pd is more likely to be used for an aggressive tumor and 125 I for a less aggressive tumor. Moreover, it can be observed in the case of the use of 103 Pd, the presence of "cold spots" which are points on which the minimum dose distributed to eliminate cancer cells is not delivered; this will occur in particular in the case of displacement of the rods within the target volume.
• the present invention aims to provide an improved solution compared to solutions of the state of the art that reduces the disadvantages.
• the present invention aims in particular to combine the advantages offered by several types of radionuclides.
• the present invention aims to allow the combination of different nuclides for the same therapeutic application, and in particular in the case of the treatment of breast and prostate cancer.
• the present invention is more particularly to propose to play on different types of energies, different life time or different radiations for the same therapeutic treatment.
• the present invention is incidentally to provide a solution that allows to visualize and thus locate the brachytherapy sticks.
• the object of the invention is to assemble, within the same radioactive device constituted by an implant, at least two different types of radionuclides, with a view to producing a composite source and this regardless of the geometry or the presentation of said radioactive device.
• This device may also correspond to a product comprising a suitable solid pharmaceutical vehicle transparent to radioactive radiation and encompassing both types of radionuclides.
• This product can be used as a medicine.
• the subject of the invention also relates to the use of this product for the preparation of a medicament for the treatment or prevention of tumors, in particular prostate, breast, liver and / or brain tumors. .
• the subject of the invention also relates to the use of said product for the preparation of a medicament intended to eliminate cells and / or tissues, in particular cells or tissues suffering from stenoses and / or necroses, in particular at the level of the coronary arteries.
• This device or this product may be in the form of a rod, an element of a chain of rods, an extensible stick, a catheter metal or plastic, a wire, a clip, a spiral, a plate ...
• radioactive nuclides of the same chemical nature (same number of protons Z) and the same atomic mass (A) and derivatives derived from the decay (ex: 103 Pd * ⁇ 103 Rh + Gamma + RX, 103 Pd * and 103 Rh represent the same type of radionuclide).
• a radionuclide is defined as being a radioactive atom characterized by its number of Z protons and its number of AZ neutrons.
• the two types of radionuclides are not radioisotopes, that is to say that they have different chemical natures (Z different for the two types).
• a radioisotope being defined by a radioactive isotope of a particular element, e.g. iodium has two isotopes, 125 I and 131, that is to say as radioisotopes have an atomic mass (A) for different a number of protons (Z) identical.
• This device may be implanted in the human body, either permanently or non-permanently.
• radionuclides present in the same medical device, mention may be made of the non-exhaustive list of the following radionuclides:
• radioactive element By radiation is meant either a particle type radiation (such as a radiation, ⁇ , Auger electron or neutron), or a wave type radiation (radiation ⁇ or Rx).
• a particle type radiation such as a radiation, ⁇ , Auger electron or neutron
• a wave type radiation radiation ⁇ or Rx
• different configurations of combinations of radioactive elements are envisaged within the same device: - Use of different types of radionuclides to obtain different types of radiation.
• radionuclides emitting radiation of different types are then collected and encapsulated.
• concentration within the device there is a setting to promote radiation (eg beta), compared to another (eg Auger).
• this configuration allows to combine a type of radiation used for diagnostic purposes (e.g., 99m Tc) and a radiation used for curative purposes (e.g., 211 At). In doing so, it is possible to follow the regression of the tumors in real time.
• a type of radiation used for diagnostic purposes e.g., 99m Tc
• a radiation used for curative purposes e.g., 211 At
• Radionuclides emitting radiation of the same type (RX, Beta or Auger), but of different energy are then collected and encapsulated.
• RX, Beta or Auger Radionuclides emitting radiation of the same type
• Radionuclides emitting radiation of the same type RX, Beta or Auger
• concentration within the device there is a setting to promote for example a low energy radiation, compared to a highly energetic radiation.
• this configuration makes it possible to treat dispersed tumors efficiently and homogeneously. For example, the association of 90 Y (beta radiation with an average energy of 934 keV) and of 199 Au (beta radiation with average energy of 115 keV).
• radionuclides with different half-life times. Used in nuclear medicine, a radionuclide with a short half-life gives a "boost" to the treatment and can be mixed with a radionuclide with a longer half-life used as a background treatment. This modulation must obviously be studied according to the radiosensitivity of the cells.
• the 103 Pd the 103 Pd
• contrast agents may be magnetic materials, such as Fe, Gd and Ga oxides, which allow use in magnetic resonance imaging (MRI) to allow the localization of brachytherapy elements.
• MRI magnetic resonance imaging
• Radionuclides mixed with non-radioactive elements, such as 102 Pd, 103 Rh or elements that will be chosen in order to generate additional RX photons by fluorescence.
• radionuclides and / or associated elements are included in one and the same source, preferably solid, presented in the form of, for example, an ink, in a resin exchange resin.
• ions in a mixture consisting of a gel or in a powdery mixture in a polymeric coating, in zeolytes or absorbed on the surface of activated particles or graphite beads, or other. According to another embodiment, one could consider a liquid or gaseous source.
• the capsule constituting the outer envelope of the brachytherapy element (radioactive device) is made of a biocompatible material, possibly biodegradable.
• this material is a polymeric material, such as phenyletheretherketone (PEEK), nylon or polyurethane.
• PEEK phenyletheretherketone
• metallic materials such as a titanium envelope, a carbon envelope, etc.
• the fractions of internal activity for two radionuclides of different type are in a ratio within a range of 0.01 / 99.99% to 99.99 / 0.01%.
• fraction of internal activity of a radionuclide contained in a source with several radionuclides is meant the ratio of the internal activity of the radionuclide considered and the sum of the internal activities of the radionuclides present in the source.
• internal activity specifies that this is the activity in terms of the number of decays per second of the radioactive source.
• the fractions of internal activity for the 103 Pd / 125 I pair are included in a ratio which is itself in a range from 60/40% to 90/10% and preferably is close to one. ratio of 75/25%.
• Figures 1, 2, 3 and 4 show different embodiments of capsules or other supports implementing the principle according to the present invention.
• FIG. 5 represents the distribution of a radial dose with respect to the irradiation distance, for the two types of radionuclides most commonly used in the case of prostate cancer, namely 103 Pd and l ' 125 I.
• the present invention relates to the combination of at least two types of radionuclides within the same source which is therefore a composite source included in a element of brachytherapy.
• This combination makes it possible not only to take up the advantages of each of the two radionuclides, but to obtain a synergistic effect in the treatment of cancers or apoptosis (proliferation of healthy and / or cancerous cells).
• it is envisaged to combine two types of radionuclides which have the advantage of emitting both the same type of radiation, namely radiation by RX, but which have lifetimes relatively different.
• This combination is particularly interesting in the case of target volumes populated with cancer cells of variable aggressiveness.
• the combination of 103 Pd (16,991 days) with 125 I (59,40 days) can be cited.
• Another embodiment aims to combine several types of radionuclides having the same type of radiation, but with relatively different energies, in order to increase the effectiveness of a treatment of heterogeneous tumors whose volume is important. .
• PET Positron Emission Tomography
• SPECT Single Photon Emission Tomography
• 18 F PET
• 89 Zr PET
• 99m Tc Spect
• 111 In Spect
• the combination of two types of radionuclides within a composite radioactive source can be carried out in two different ways: it is possible to envisage the combination of the two radionuclides in radioactive form before their mixing, or else the combination of two compounds, which after irradiation, will generate two radionuclides to create the radioactive source.
• the radionuclides are obtained individually, either directly by production in a nuclear reactor, for example, by neutron activation, or from a production process using a particle accelerator.
• the two types of radionuclides are mixed and are eventually joined to a support to form the composite source.
• each of the radionuclides is provided in the form of a preparation of a dried ink and are then mixed at the end of their preparation, in order to obtain the composite radioactive source.
• Another way to prepare the source is to deposit successive layers of each of the types of radionuclides prepared individually, or a layer of a mixture of the two radionuclides on a suitable support (solid pharmaceutical vehicle adequate product of the invention) using physical or chemical deposition methods.
• physical deposition process means processes such as “ion plating”, “magnetron sputtering”, “evaporation”, CVD ("chemical vapor deposition”).
• Another alternative for realizing the radioactive source is to mix, before irradiation, two non-radioactive compounds that will generate the two types of radionuclides after irradiation.
• the mixing is carried out before irradiation, by any conventional means, such as the mixture of two powders, the creation of alloys, or by the deposition of successive layers on a suitable support, in order to make the composite material that will be irradiated.
• This composite material will be activated by irradiation of a particle beam from an accelerator or in a nuclear reactor.
• the final product will be the composite radioactive source. Examples of brachytherapy are shown in FIGS. 1 to 4.
• a first embodiment consists in including the composite radioactive source within a biocompatible capsule or envelope (forming the appropriate solid pharmaceutical vehicle of the product of the invention), as shown in FIG. 1.
• capsules which are made of metallic (for example Ti) or polymeric (for example PEEK) materials are described in detail in US Pat. No. 1,753,287, US Pat. No. 3,351,049 or US Pat. 702 228.
• the brachytherapy elements may also be in the form of a coil or spring made from a wire made of an alloy which must also be biocompatible (for example). forming the suitable solid pharmaceutical carrier of the product of the invention).
• Preferred example mixture of 103 Pd and 125 I in the same radioactive composite source for the treatment of prostate cancer or breast cancer by brachytherapy.
• the second method has an advantage over the first.
• the target enriched with 102 Pd also contains impurities that can be activated.
• the chemical or physical purification will therefore only relate to these impurities and not to the separation of 103 Pd from the other (radio) isotopes of palladium.
• no other (radio) isotope of palladium is present in the target and high purity at 103 Pd can be obtained by chemical or physical separation of 103 Rh and 103 Pd.
• the specific activity in 103 Pd will therefore be greater with the second method.
• the half-life time of 103 Pd is 16,991 days and is therefore considered adequate for the treatment of aggressive tumors.
• it is necessary to implant a large number of implants within the tumor the number can reach up to a hundred.
• An implant is particularly described in a patent application in the name of International Brachytherapy, Inc. (IBt in Belgium).
• This implant is made from two concentric titanium tubes.
• it is envisaged to produce a 103 Pd- 125 I mixture in the form of a uniformly distributed ink in three strips printed on the inner tube and for which the 103 Pd is involved at 75% of its weight. total activity and 125 I at 25%.
• a distribution dose will be obtained as shown in Figure 5. It is observed that the x-axis represents the variation as a function of the distance of the dose deposited by the source during its lifetime multiplied by the square of the distance. so as to ignore the decay due to the solid angle and normalized by its maximum value. As shown in FIG.
• the difference in half-life duration will induce a dose distribution that will evolve as a function of time. Indeed, at the beginning of tissue irradiation, the deposited dose will mainly be deposited at a short distance due to the presence of 103 Pd '. the half-life of 103 Pd, it will be observed that the dose deposited corresponds essentially to the presence of 125 I.

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• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Pathology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Radiology & Medical Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Radiation-Therapy Devices (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2005
  • 2005-12-19 EP EP05846348A patent/EP1846103A1/de not_active Withdrawn
  • 2005-12-19 US US11/721,947 patent/US20090247807A1/en not_active Abandoned
  • 2005-12-19 WO PCT/BE2005/000187 patent/WO2006063419A1/fr not_active Ceased

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