Treatment method for central nervous system tumors

Abstract

A method of treating central nervous system tumors, such as gliomas, is provided that includes delivering a beta-emitting radionuclide-containing composition to the tumor via the cerebral vasculature.

Description

Technical Field

[0001] The present invention relates to the treatment of central nervous system (CNS) tumors using radionuclides that emit beta rays (radionuclides that emit beta rays), particularly when delivered via the cerebrovascular system. In particular, the present invention relates to the use of injectable compositions containing radionuclides in the treatment of CNS tumors, more particularly highly malignant axial brain tumors including hypervascular tumors such as gliomas.

Background Art

[0002] Cancer of the central nervous system (CNS) can be very difficult to treat, and high-grade gliomas are often difficult to surgically resect and are frequently resistant to radiotherapy and chemotherapy. Glioblastoma multiforme (GBM) is the most common and aggressive malignant cancer in the central nervous system.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Current standard treatment is external beam radiotherapy (EBRT) combined with chemotherapy, and the outcomes are relatively poor.

Means for Solving the Problems

[0004] The present invention relates to the treatment of central nervous system (CNS) tumors using radionuclides that emit beta rays (radionuclides that emit beta rays), particularly when delivered via the cerebrovascular system. In various aspects, the present disclosure provides a method of treating a patient in need of treatment for a CNS tumor, the method comprising the step of selectively administering a beta-emitting composition to the cerebrovascular system. In some embodiments, the CNS tumor can be a glioma. In some embodiments, the CNS tumor can be an intra-axial brain tumor. In some embodiments, the CNS tumor can be a meningioma. In some embodiments, the CNS tumor can be a brain metastasis.

[0005] In some embodiments that can be used in combination with any of the above aspects and embodiments, the β-emitting composition is further localized in the T2 hyperintense regions of the brain. In this regard, localization in the T2 hyperintense regions surrounding the tumor is added to targeting the tumor itself. This additional scope of application can be advantageous, for example, when the tumor extends into the T2 hyperintense region but does not appear in the imaging.

[0006] In some embodiments that can be used in combination with any of the above aspects and embodiments, the β-ray emitting composition 3 H, 14 C, 32 P, 59 Fe, 47 Ca, 89 Sr, 90 Y, 131 I, 153 Sm, 177 Lu7, 166 Ho, and 169 contains one or more radionuclides selected from Er.

[0007] In some embodiments that can be used in combination with any of the above aspects and embodiments, the β-ray emitting composition can include particles having an average diameter of 1 to 100 μm and containing a radionuclide that emits β-rays. In certain embodiments, the particles are oil, glass, or polymer particles having an average diameter of 1 to 100 μm and containing a radionuclide that emits β-rays. In some of these embodiments, the average diameter is 10 to 50 μm, more particularly 15 to 35 μm. In some of these embodiments, the diameter of the particles is 15 to 35 μm, more particularly 20 to 30 μm.

[0008] In some embodiments that can be used in combination with any of the above aspects and embodiments, the β-ray emitting particles 3 H, 14 C, 32 P, 59 Fe, 47 Ca, 89 Sr, 90 Y, 131 I, 153Sm, 177 Lu7, 166 Ho, and 169 contains one or more radionuclides selected from Er.

[0009] In some embodiments that can be used in combination with any of the above aspects and embodiments, the β-emitting particles are glass particles or polymer particles. In some embodiments that can be used in conjunction with any of the above aspects and embodiments, the β-emitting particles are alumina silicate glass particles containing yttrium. For example, the glass particles are glass obtained from a mixture of 35-45% Y2O3, 15-25% Al2O3, and 35-45% SiO2, such as glass particles formed from glass obtained from a mixture of about 40% Y2O3, about 20% Al2O3, and about 40% SiO2. In some cases, at least a portion of the yttrium in the glass is 90 converted to Y by exposure to radiation.

[0010] In some embodiments that can be used in combination with any of the above aspects and embodiments, the particles are pure β-emitting particles that substantially irradiate 100% β-rays. In some embodiments that can be used in combination with any of the above aspects and embodiments, the particles have a specific activity in the range of 0.05-0.005 GBq / mg when administered, more specifically, a specific activity in the range of 0.0231-0.03894 GBq / mg at the time of administration.

[0011] In another aspect, the present disclosure provides an injectable composition containing a suspension of a β-emitting substance in an aqueous liquid for use in the treatment of CNS tumors. In some embodiments, the substance is 3 H, 14 C, 32 P, 59 Fe, 47 Ca, 89 Sr, 90 Y, 131 I, 153 Sm, 177 Lu7,166 Ho, and 169 comprises one or more radionuclides selected from Er.

[0012] In some embodiments, the substance can include particles such as oil, glass, or polymer particles having, among other possible values, an average diameter, for example, of 1 to 100 μm. In some embodiments, the particles are 3 H, 14 C, 32 P, 59 Fe, 47 Ca, 89 Sr, 90 Y, 131 I, 153 Sm, 177 Lu7, 166 Ho, and 169 beta-emitting particles containing one or more radionuclides selected from Er.

[0013] In some embodiments, the particles include insoluble glass microspheres having yttrium 90 ( 90 Y) as an integral component of the glass, which can have, among other possible values, a diameter in the range of 20 to 30 μm. In certain embodiments, there can be 22,000 to 73,000 microspheres per milligram of the glass microspheres. In some embodiments that can be used in combination with any of the above aspects and embodiments, the beta-emitting particles are supplied in sterile pyrogen-free water.

[0014] Additional aspects and embodiments will be apparent to those skilled in the art upon review of the following detailed description.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0016] As described above, the present invention relates to the treatment of central nervous system (CNS) tumors using radionuclides that emit beta rays (radionuclides that emit beta rays), particularly when delivered via the cerebrovascular system. In particular, the present invention relates to the use of an injectable composition containing a radionuclide-containing substance in the treatment of CNS tumors, more particularly, high-grade axial brain tumors including hypervascular tumors such as gliomas.

[0017] In a preferred embodiment, the present disclosure also relates to the use of an injectable composition containing a radionuclide-containing substance in the treatment of CNS tumors, more particularly, (1) intra-axial brain tumors (including but not limited to primary axial brain tumors) including astrocytomas, primary CNS lymphomas, glioblastomas, and gliomas (such as gliomas or oligodendrogliomas), (2) extra-axial tumors such as meningiomas, and (3) secondary brain tumors (i.e., brain metastases) that occur in other locations in the body.

[0018] CNS cancers can be very difficult to treat. High-grade gliomas are difficult to surgically resect and are often resistant to radiotherapy and chemotherapy. Glioblastoma multiforme (GBM) is the most common and aggressive malignant cancer in the central nervous system. The current standard treatment is external beam radiation therapy (EBRT) combined with chemotherapy, and the outcomes are relatively poor. Researchers at the Johns Hopkins Comprehensive Brain Tumor Center developed the GliaSite (trademark) Radiation Therapy System (RTS), which irradiates radiation from within the cavity created by the surgical removal of malignant brain tumors. Internal radiation "brachytherapy," which uses manually inserted encapsulated gamma emitters, is an established treatment for cancers of tissues such as the prostate and has been tried for GBM.

[0019] GBM is a tumor with excessive blood vessels and always has an infiltrative tumor component. This prevents surgical cure in virtually all cases and makes the treatment of GBM very difficult. The poor surgical outcomes also distinguish GBM from solid abdominal organ tumors (HCC, RCC) in that the role of surgical resection is very limited. After considering the surgical treatment options for GBM, the standard treatment is fractionated external beam radiation therapy (EBRT).

[0020] Typically, EBRT consists of 35 daily fractions of 1.8 Gy, for a total of 63 Gy delivered including a 1- to 2-cm margin from the tumor and enhancing edge. Radiation therapy has been used to treat GBM since the 1940s, and a preliminary radiobiological threshold identified in the 1970s shows a modest 2.3-fold increase in survival at 60 Gy. Recent EBRT treatments using stereotactic techniques and dose escalation protocols have not had a reproducible effect on survival improvement (Gzell, C., Back, M., Wheeler, H., Bailey, D. & Foote, M. Radiotherapy in Glioblastoma: the Past, the Present and the Future. Clinical Oncology 29, 15-25 (2017)). However, the combination of EBRT and chemotherapy (e.g., temozolomide, an alkylating agent) has been the standard treatment since 2002 following the data of Stupp et al. showing a median survival of 16 months (see Stupp, R. et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J. Clin. Oncol. 20, 1375-1382 (2002)).

[0021] Separate from EBRT, manual low-dose-rate brachytherapy has been investigated for the treatment of GBM. 125I and more recently 131Cs brachytherapy have been used in combination with standard external beam radiotherapy for salvage after recurrence. For newly diagnosed GBM, overall survival up to 28.5 months has been reported in several series (see Neurosurgical review (2016). doi:10.1007 / s10143-016-0727-6 and Schwartz, C. et al. Outcome and toxicity profile of salvage low-dose-rate iodine-125 stereotactic brachytherapy in recurrent high-grade gliomas. Acta neurochirurgica 157, 1757-64 discussion 1764 (2015)).

[0022] However, both EBRT and manual brachytherapy using low-energy gamma emitters are associated with high radiation doses to healthy brain parenchyma and result in a high frequency of neurotoxicity. To counter neurotoxicity, advanced techniques such as protons or X-ray microchannels that use microbeam fields to irradiate tumors have shown the potential to spare non-cancerous parenchyma (see Girst, S. et al. Improved normal tissue protection by proton and X-ray microchannels compared to homogeneous field irradiation. Phys Med 31, 615-620 (2015)).

[0023] High-grade gliomas, by definition, are characterized by increased vascular enhancement on MR that differentiates them from low-grade (WHO I, II) gliomas. In relation to the various classifications of high-grade gliomas, numerous angiogenic factors have been discovered (see Hanif, F., Muzaffar, K., Perveen, K., Malhi, S. M. & Simjee, S. U. Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pacific journal of cancer prevention: APJCP 18, 3-9 (2017)).

[0024] GBM typically presents as hypercellularity and enhances the tumor. In fact, the contrast enhancement on CT can be more than 20 times higher in the tumor compared to normal peritumor parenchyma (Figure 1). The challenging aspect of GBM therapy is the relatively hypocellular infiltrative disease that is always present. The infiltrative component poses a therapeutic challenge, but recurrence after EBRT usually occurs centrally within 1 - 2 cm from the original margin of tumor enhancement.

[0025] The dose - response relationship of GBM to radiotherapy is well - described. Brachytherapy, which places a sealed radiation source within the tumor, has shown efficacy in some reports, but the heterogeneous overall survival reflects a rate of neurotoxicity approaching 50%. The high neurotoxicity in manual brachytherapy may be due to the broad dose margins resulting from the use of low - energy gamma emitters. This toxicity can be partially reduced with stereotactic EBRT by avoiding critical neurological structures. See Corwin, D. et al. Toward Patient - Specific, Biologically Optimized Radiation Therapy Plans for the Treatment of Glioblastoma. PLoS ONE 8, e79115 (2013).

[0026] The present inventors hypothesized that transarterial radioembolization (TARE), an established treatment for treating liver tumors, may be a potentially viable and improved treatment for central nervous system cancers of the brain. GBM has a well-described dose-response relationship with radiotherapy, and the brain does not have a dual blood supply like the liver, but GBM is by definition hypervascular (contrast enhancement of 10:1 is possible in GMB). This limits the concentration of intra-arterial substances in normal brain parenchyma, and modern EBRT has targeted particularly high-dose hypervascular regions to improve response and achieved some success, so a similar effect can be expected from TARE.

[0027] Manual brachytherapy using low-energy gamma emitters (125I, 131Cs) is known for GBM, but high doses are associated with high neurotoxicity to nearby nerve structures. To mitigate such effects, the present inventors hypothesized that radiation emitted from radionuclides placed in the cancer vasculature with a limited decision range would limit the dose and damage to normal tissues. In particular, they determined that radionuclides emitting beta rays may have the right profile for limiting the dose to nearby normal tissues, especially when in a form particularly suitable for TARE.

[0028] Superselective angiography of GBM was described nearly 20 years ago and has been reported many times since. See Tomura, N. et al. Superselective angio-CT of brain tumors. AJNR Am J Neuroradiol 17, 1073-1080 (1996). Superselective intra-arterial cerebral infusion (SIACI) has been used with some success by delivering drugs in combination (see Riina HA, Knopman J, Greenfield JP, et al. Balloon-assisted superselective intra-arterial cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note. Interventional Neuroradiology. 2010;16:71-76).

[0029] The inventors of the present invention 125 I, 131 Compared with those from gamma-ray emitters such as Cs, the dose deposition margin of beta rays is much narrower, so it is hypothesized that it may not harm soft tissues not involved in cancer. 90 Y has the highest energy among pure beta emitters commonly used in radionuclide therapy. 131 I and 177 substitutes for Y such as 90 Lu have low-energy beta emission and may not harm the tissues surrounding the ring-enhanced GBM, but with a low margin, they may often not be able to effectively treat the existing cellular and / or acellular infiltrative tumor components. Therefore, the inventors believe that the use of any beta-emitting radionuclide is within the scope of the present disclosure, particularly substances containing high-energy radionuclides, particularly 90 Y and 166 substances such as Ho used in TARE are envisioned.

[0030] In recent years, an adjusted EBRT algorithm has been shown to be promising. This technique is premised on delivering a higher dose to the enhancing tumor component, assuming that the area with the highest vascular distribution represents the area with high cellularity. Assuming this reflects infiltrative tumors or low-cellular edema, a low dose is administered to the area of the T2 / FLAIR hyperintense region. The adjusted EBRT protocol treats the enhancing region at a high dose (100 - 130 Gy) to improve the response without significantly increasing the absorbed dose to the normal parenchyma associated with high-dose treatment of the entire tumor. The inventors hypothesized that 90 higher energy β-ray emitters, such as from Y radionuclides, might be comparable to or improve upon this. 90 Y has been shown to irradiate a large absorbed dose (~1000 Gy) to the tumor periphery with many blood vessels in biopsy specimens after liver cancer treatment, and in this regard, it might improve EBRT.

[0031] Other EBRT techniques, such as X-rays and proton microchannels, which do not harm the brain parenchyma not involved in cancer, are of glass 90 Y microspheres have been shown to reduce neurotoxicity in a comparison similar to that done for the difference in toxicity (which can be 3 - 5 times) in liver treatment when compared with EBRT. In particular, the sparse distribution of glass 90 Y microspheres in normal brain parenchyma might preserve this tissue and might function mechanically similar to X-rays and proton microchannels, which are currently the subject of important research in EBRT.

[0032] Particularly suitable compositions for use in the methods of the present disclosure include radionuclide-containing substances with a minimally occlusive morphology, such as oil, polymer, or glass microspheres, and the minimally occlusive β-ray emitting radionuclides containing particles are 3 H, 14 C, 32 P, 59 Fe, 47 Ca, 89 Sr, 90 Y, 131 I, 153 Sm,177 Lu7, 166 Ho, 169 It may contain a radionuclide selected from Er. More preferably, 89 Sr, 166 Ho, 153 Sm, 177 Lu, 169 Er and 90 It is a relatively pure β-emitter selected from Y. Optimally, in the form of glass or polymer microspheres 90 Y radionuclide. In some cases, iodinated 131 I oil such as lipiodol can also be used.

[0033] In one embodiment, a non-radionuclide can be administered to the microspheres and delivered to the tumor, and then the non-radionuclide can be activated in situ to convert the nuclide into a radionuclide. In a preferred embodiment, the activation is performed using an electron beam. In a more preferred embodiment, the activation is performed by directing an electron beam at the perfused target volume or treatment site.

[0034] In one embodiment, the radionuclide can be irradiated from the outside (i.e., irradiated in situ) instead of being irradiated before transport. In a preferred embodiment, the in situ irradiation can be performed using an electron beam. In a more preferred embodiment, the irradiation is performed by directing an electron beam at the perfused target volume or treatment site.

[0035] Delivery of β-ray emitters by a super-selective method such as oil or microspheres that provide minimal embolization should be technically feasible in CNS tumors of the brain such as GBM because there is little variation in the supply and perfusion of the cerebral vasculature, especially compared to the anatomy of the hepatic vasculature treated by conventional methods. Super-selective delivery also has the advantage of further limiting the absorbed dose to normal brain parenchyma. See Tomura, N. et al. Superselective angio-CT of brain tumors. AJNR Am J Neuroradiol 17, 1073-1080 (1996).

[0036] TheraSphere (registered trademark, also known as SIR-Spheres or Theraspheres), available from Biocompatibles UK Limited, is composed of insoluble glass microspheres in which yttrium-90 ( 90 Y) is an essential component of the glass. The glass is an aluminosilicate glass containing yttrium, obtained from a mixture of 35 - 45% Y2O3, 15 - 25% Al2O3, and 35 - 45% SiO2, and more specifically, obtained from approximately 40% Y2O3, approximately 20% Al2O3, and approximately 40% SiO2. At least a portion of the yttrium in the glass is converted to 90 Y upon exposure to radiation.

[0037] The average diameter of the spheres ranges from 20 to 30 μm. There are 22,000 - 73,000 microspheres per milligram. TheraSphere (registered trademark) is supplied as 0.6 mL of pyrogen-free sterile water contained in a 1.0 mL V-bottom vial fixed within a transparent acrylic vial shield. TheraSphere (registered trademark) is available in six dose sizes: 3 GBq (81 mCi), 5 GBq (135 mCi), 7 GBq (189 mCi), 10 GBq (270 mCi), 15 GBq (405 mCi), and 20 GBq (540 mCi). Custom dose sizes are also available.

[0038] In one embodiment, smaller dose sizes are used, or a portion of the above dose sizes is used. In a preferred embodiment, administration may use 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of any of the above dose sizes. In a more preferred embodiment, administration uses 5%, 10%, 15%, 20%, 25%, 30% of any of the above dose sizes. In an optimal embodiment, administration uses 5% or 10% of any of the above dose sizes.

[0039] The shelf life of TheraSphere® is 12 days. In one embodiment, the specific activity of the composition at the time of calibration is referenced. In one embodiment, the day of calibration is called day 0, the 1st to 7th days following the calibration day are called the 1st week, and the 8th to 12th days are called the 2nd week. In one embodiment, calibration refers to day 0 at time zero. In one embodiment, time zero on day 0 is noon of the US Eastern Standard Time.

[0040] In a preferred embodiment, the preferred treatment window is from Wednesday of the 1st week (also called the 1st Wednesday) to Tuesday of the 2nd week (sometimes called Tuesday of the 2nd week). In a more preferred embodiment, the preferred treatment window is from the 1st Thursday to the 1st Friday.

[0041] A pre-assembled disposable TheraSphere® administration set is provided for each dose. The TheraSphere® administration accessory kit is provided to a new user site. The kit includes reusable accessories such as an acrylic box base, a top shield, a removable side shield, a bag hook, a RADOS RAD-60R dosimeter (or equivalent).

[0042] Yttrium 90, a pure emitter, decays to stable zirconium 90 with a physical half-life of 64.1 hours (2.67 days). The average energy of the β radiation from yttrium 90 is 0.9367 MeV. Following the embolization of yttrium 90 glass microspheres in tumor tissue, the emitted β rays provide a therapeutic effect. Similar to other radionuclide-containing materials for use in the methods of the present disclosure, once TheraSphere® is administered, it loses its radioactivity over time and cannot be reused.

[0043] Microspheres are sent to the target via a catheter placed in the artery supplying blood to the tumor. Microspheres that cannot pass through the vasculature due to arteriolar capillary blockade are trapped in the tumor, exerting a local radiotherapy effect and simultaneously causing some damage to the surrounding normal tissue. See Campbell, A. M., Bailey, I. H. & Burton, M. A. Tumour dosimetry in human liver following hepatic yttrium-90 microsphere therapy. Phys Med Biol 46, 487-498 (2001).

[0044] TheraSphere® is indicated for the radiotherapy of patients with unresectable hepatocellular carcinoma (HCC) in whom a properly placed hepatic artery catheter can be placed, or as neoadjuvant therapy before surgery or transplantation.

[0045] Another beta emitter includes SIR-spheres®, 90 ion exchange resin beads containing the Y radionuclide. These beads have a diameter of 20-60 μm and are available from Sirtex Medical. For use in the present disclosure, SIR-spheres can be envisioned. In one embodiment, the SIR-spheres will be modified to increase their specific activity in order to enhance the therapeutic effect exerted during their use. In a preferred embodiment, this increase in specific radioactivity can be achieved by increasing the loading of 90 Y into the resin.

[0046] A further beta emitter is 131 Iodized oil, the use of which is described by a monograph of the European Association of Nuclear Medicine, and iodized oil is available from the Guerbet group.

[0047] In its broadest aspect, the method of the present disclosure involves administering a beta-emitting substance selectively to the vasculature supplying a CNS tumor. In particular, the method involves administering an injectable pharmaceutical composition comprising beta-emitting particles, for example, consisting of liquid, polymer or glass, in an aqueous carrier such as saline or sterile water. In one embodiment, the carrier is any injectable medium. In one embodiment, the carrier is 5% dextrose in water or includes it. In one embodiment, the carrier is ethanol or includes ethanol. In one embodiment, the carrier is an iodinated contrast agent or includes it.

[0048] More preferably, the method involves administering the above composition to the vasculature supplying a CNS tumor of the brain. Beta-emitting particles can theoretically also produce other radiations, similar to radionuclides such as 3 H, 14 C, 32 P, 59 Fe, 47 Ca, etc. However, the inventors assume that 89 Sr, 166 Ho, 153 Sm, 177 Lu7, 169 Er, and 90 Y, and most preferably 90 particles containing Y provide the most appropriate treatment.

[0049] Compositions containing the 90 Y radionuclide in glass or polymer are preferred, most preferably as glass particles, and more preferably having an average diameter of 1 to 100 μm. More preferably, the particles should have an average diameter of 10 to 50 μm, and more preferably an average diameter of 15 to 35 μm, for example 20 to 30 μm.

[0050] These particles are most preferably and conveniently supplied as an aqueous suspension, for example, a suspension in sterile water or saline. Administration of the particles is preferably initiated with steroids, for example, prednisone is administered at 4 mg / kg (IV or PO) first, followed by, for example, PO at 2 mg / kg per day starting on the day of transarterial radioembolization of the cerebral arteries, and then continued while gradually varying the dose at 2 - 4 mg / kg until the clinician feels it is safe to discontinue (based on post-treatment MRI).

[0051] The method of the present disclosure particularly deploys a catheter into the cerebral artery supplying a cancer of the central nervous system, such as a tumor. When the tumor is in or localized in one of the cerebral hemispheres, it is more preferred that the catheter be placed in a specific branch of the cerebral artery supplying the tumor.

[0052] In a preferred embodiment, the method of the present disclosure deploys the catheter through the radial artery. Typically, the guiding catheter is advanced over a wire, inserted, for example, into the aorta through the femoral artery, and advanced to the carotid artery, such as by using fluoroscopy.

[0053] Preferably, an angiographic evaluation using a contrast agent, for example, an iodinated contrast agent, is deployed to identify and access the cerebral artery branches mainly supplying blood to the tumor. The catheter is preferably a microcatheter, and an example of a suitable microcatheter is provided by Stryker, Excersior SL-10 1.7F (diameter 0.6 mm). The preferred catheter does not use a balloon to isolate the vascular system during administration of the β-emitting radionuclide-containing composition. In some situations, a balloon such as that associated with a balloon catheter may be preferred by the clinician. However, the inventors believe this is not necessary if appropriately sized particles containing the composition are used.

[0054] Preferably, the microcatheter advances as close as possible to the tumor without causing physical damage to the blood vessel. This allows the placement of the beta-ray composition to be as selective as possible, for example, preferably providing mainly localization and preferably providing some embolization to tumors with limited perfusion of normal brain parenchyma. An anti-vascular spasm drug is preferably administered, for example, by injection into the artery to prevent vasospasm during selective arterial catheterization, such as nitroprusside (100 mcg).

[0055] In one embodiment, prior to treatment, it is preferred to review the pre-treatment MRI to determine the volume of the tumor. The research physicist performs a treatment plan with an expected preferred tumor absorbed dose of 30 - 200 Gy, preferably 50 - 200 Gy, more preferably 80 - 180 Gy, and optimally 100 - 150 Gy. This treatment dose is injected into the tumor via a microcatheter. After the injection of the microspheres is complete, the wire, catheter, and sheath are removed. Manual pressure is maintained until hemostasis is achieved or a closure device is utilized for closure.

[0056] In one embodiment, the target treatment dose is understood to be the area perfused by the administration. In one embodiment, this target treatment dose includes both tumor tissue and normal tissue. In one embodiment, the medical practitioner can use contrast-enhanced, anatomical imaging and / or cone-beam computed tomography (CBCT) during the procedure to determine the target treatment dose.

[0057] In one embodiment, the research physicist performs a treatment plan with an expected treatment volume dose of 10 - 1000 Gy, preferably 50 - 200 Gy, more preferably 80 - 180 Gy, and optimally 100 - 150 Gy. As will be understood by those skilled in the art, the tumor absorbed dose is expected to be higher than the normal tissue absorbed dose. Without being bound by theory, this may be due to the hypervascularity of the tumor.

[0058] In one embodiment, the desired dose indicated in gray (Gy) can be calculated based on the target volume using software similar to that of TheraSphere™ iDOC™, using a treatment window illustrator, or using the MIRD schema. In one embodiment, the desired dose indicated in gray (Gy) can be calculated based on the target treatment dose using software similar to that of TheraSphere™ iDOC™, using a treatment window illustrator, or using the MIRD schema.

[0059] In one embodiment, the desired absorbed dose indicated in gray (Gy) can be calculated based on the target treatment dose using the MIRD schema. In one embodiment, the desired absorbed dose indicated in gray (Gy) can be calculated based on the target treatment dose using software similar to that of TheraSphere™ iDOC™ or the treatment window illustrator.

[0060] In one embodiment, the desired absolute activity indicated in becquerels (Bq) or gigabecquerels (GBq) can be calculated based on the target treatment dose using the MIRD schema. In one embodiment, the desired absolute activity (Bq or GBq) can be calculated based on the target treatment dose using software similar to that of TheraSphere iDOC™ or the treatment window illustrator. After closure and hemostasis are achieved, the subject is preferably transferred to a PET / CT for scanning. Anesthesia is maintained, for example, with an IV bolus of propofol. The PET-CT scan is performed under general anesthesia with isoflurane while using a ventilator. PET / CT detects the radiation emission from the administered particles and no additional injection of radioactive material is required. In one embodiment, the scan can be performed without anesthesia.

[0061] After PET / CT, the subject is extubated when the swallowing reflex has returned. Potential postoperative pain is managed, for example, by subcutaneous / intramuscular injection of analgesics, such as buprenorphine (0.005 - 0.02 mg / kg q 8 - 12 h) injection. The subject may be permitted to go home when awake and at normal body temperature after the radiation safety examination. After treatment and imaging, the subject may be discharged on the same day. The clinician needs to look for changes in behavior or signs of seizures for follow-up, and depending on the severity of these problems, a clinical decision about the possibility of hernia is made based on the subject's behavior, the presence of seizures, cranial nerve deficits, and physical appearance, and the investigator may recommend treatment to reduce intracranial pressure.

[0062] The subject typically undergoes post-treatment MRI imaging under anesthesia, preferably within 1 week after treatment and no more than once a week, to evaluate signs of inflammation, edema, and other neurological changes. Sedation and anesthesia are the same as those described for the above-mentioned radiosembolization of cerebral arteries. In one embodiment, the imaging can be performed without anesthesia.

[0063] (Example) The present disclosure is illustrated by reference to the following non-limiting exemplary examples. In light of these, additional examples will occur to those skilled in the art.

[0064] Experimental basis: There is no large animal model suitable for glioblastoma multiforme (GBM), which represents the characteristics of human brain tumors. These tumors occur spontaneously in humans but are also common in some dog breeds. Canine cancer models with spontaneous high-grade axial brain tumors, including GBM, are clinically highly relevant to human cancer and exhibit typical histopathological features such as pseudoparalytic necrosis, angiogenesis, endothelial proliferation, and inflammatory cell infiltration. See 10. Schiffman JD, Breen M: Comparative oncology: what dogs and other species can teach us about humans with cancer. Philos Trans R Soc Lond B Biol Sci 2015, 370.

[0065] Advantageously, the use of breeding animals with spontaneously occurring tumors can potentially benefit the breeding animals while minimizing the use of research animals. Disease evaluations were performed on the animals before enrolling them in the study according to the standard treatment at the Johns Hopkins Medicine Image-Guided Animal Therapy Center. The evaluations included (i) a veterinary neurological examination, (ii) blood tests (CBC, chemistry panel), and MRI with contrast.

[0066] Participation in this study was dependent on the identification of tumor characteristics suitable for Y therapy. Such characteristics included tumors perfused mainly from one vascular region and no involvement of both hemispheres. 90

[0067] Research dogs were used as safety controls, and breeding dogs presenting spontaneous gliomas in one hemisphere to the clinic were used only in the active treatment group.

[0068] Results: The treatment of the research dogs proceeded well with significant absorbed doses delivered to the normal brain. Overall, the research dogs tolerated the treatment well.

[0069] ​Two cases of glioma had completed treatment by the filing date of this patent application, and both experiences were similar with respect to the impression of the imaging of the procedure. The tumor was treated from the carotid artery with the aim of covering half (right / left) of the brain containing the tumor. Some perfusion crosses the midline, resulting in more than half. The angiograms were unremarkable. Although hypervascularity or blushing of the tumor was expected, the tumor could not be easily identified. 90 PET after Y showed good uptake in the T2 hyperintense (fluid-attenuated inversion recovery (FLAIR) image) area of the brain surrounding the tumor and in the tumor itself. Based on the angiograms, it was surprising to achieve this much localization in this tumor area of the brain.

[0070] In the following example, TheraSphere® was calibrated to have a specific activity of 0.11 GBq (±10%) at calibration, with Sunday noon (Eastern Standard Time in the United States) of this day being day zero.

[0071] The first test dog was 90 treated with Y TheraSphere® (low radiation - two weeks postpartum) and experienced a transient ischemic attack after treatment. The second dog was treated with a dose on Friday of the first week, with approximately twice the activity and approximately half the number of microspheres. The dog with higher activity and fewer beads did not experience a significant transient ischemic attack after treatment. Higher specific activity microspheres may limit the embolization / ischemic effect in the brain. In this regard, embolization of the cerebral vasculature is generally considered negative as it can cause a transient ischemic attack or stroke. The risk of the adverse effects of embolization needs to be reduced by using smaller and fewer microspheres while irradiating at the therapeutic level of radiation. This can be achieved by using small and high specific activity (activity per gram) microspheres.

[0072] 90By the time of the post-treatment PET, the tumor dose in Dog 1 was 35 Gy and the normal tissue was 18.6 Gy. Due to the constraints of the spatial resolution of the PET, there is a possibility that the tumor dose could be higher. The tumor dose in Dog 2 was 115 Gy and the normal tissue was 23.5 Gy. This separation of tumor and normal tissue in Dog 2 is excellent and may be far superior to what can typically be achieved with external beam radiation. The target tumor dose for external beam is approximately 60 Gy. The short penetration of the beta rays and the relatively large tumor-to-normal ratio should spare the normal tissue from high absorbed doses. Dog 1 showed a complete response at approximately 1 month post-treatment. Dog 2 has been symptom-free for 11 days.

Claims

1. An injectable composition comprising a suspension of beta-emitting minimally embolic glass particles in an aqueous liquid for use in the treatment of CNS tumors by selectively administering an effective amount of the particles to the cerebrovascular system, wherein the beta-emitting composition is administered at an expected tumor absorbed dose of 30 to 200 Gy, the CNS tumor is a glioma, the particles have an average diameter of 10 to 50 μm, the particles contain 22,000 to 73,000 microspheres per milligram, and the particles have a specific activity in the range of 0.05 to 0.005 GBq / mg.

2. The particles are ３ H, １４ C, ３２ P, ５９ Fe, ４７ Ca, ８９ Sr, ９０ Y, １３１ I, １５３ Sm, １７７ Lu7, １６６ Ho, and １６９ the injectable composition according to claim 1, comprising one or more radionuclides selected from Er.

3. The particles are ３ H, １４ C, ３２ P, ５９ Fe, ４７ Ca, ８９ Sr, ９０ Y, １３１ I, １５３ Sm, １７７ Lu7, １６６ Ho, and １６９ β-ray emitting particles containing one or more radionuclides selected from Er, the injectable composition according to claim 1.

4. The injectable composition according to claim 1, wherein the particles are pure beta-emitting particles that emit substantially 100% beta rays.

5. wherein the beta-emitting particle is ８９ Sr, １６６ Ho, １５３ Sm, １７７ Lu, １６９ Er and ９０ The injectable composition according to claim 1, comprising a pure beta-emitting radionuclide selected from Y.

6. The injectable composition according to claim 5, wherein the pure β-ray emitting radionuclide is ９０ Y.

7. The injectable composition according to claim 1, wherein the glass particles are alumina silicate glass particles containing yttrium.

8. The glass particles are 35 to 45% Y ２ O ３ , 15 to 25% Al ２ O ３ , and 35 to 45% SiO ２ The injectable composition according to claim 1, formed from a glass obtained from a mixture of 9. The glass particles are about 40% Y ２ O ３ , about 20% Al ２ O ３ , and about 40% SiO ２ The injectable composition according to claim 1, formed from a glass obtained from a mixture of 10. The glass particles include insoluble glass microspheres having yttrium 90 ( ９０ Y) as an integral component of the glass, the injectable composition according to claim 1.

11. The injectable composition according to claim 1, wherein the diameter of the glass microspheres is in the range of 20 to 30 μm.

12. The injectable composition according to claim 1, wherein the beta-emitting particles are supplied in sterile pyrogen-free water.

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