Treatment methods for central nervous system tumors

Abstract

To provide a method for treating central nervous system tumors such as gliomas.SOLUTION: The method comprises delivering a β-emitting radionuclide-containing composition to a tumor via the cerebral vasculature.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the treatment of central nervous system (CNS) tumors using beta-emitting radionuclides, particularly when delivered via the cerebrovascular system. In particular, the present invention relates to the use of injectable compositions containing radionuclide-containing substances in the treatment of CNS tumors, more particularly high-grade axial brain tumors, including hypervascular tumors such as gliomas. [Background technology]

[0002] Central nervous system (CNS) cancers can be extremely difficult to treat, and high-grade gliomas are often difficult to surgically remove and are frequently resistant to radiation therapy and chemotherapy. Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. [Overview of the Initiative] [Problems that the invention aims to solve]

[0003] The current standard treatment is external beam radiation therapy (EBRT) combined with chemotherapy, and the outcomes are relatively poor. [Means for solving the problem]

[0004] The present invention relates to the treatment of central nervous system (CNS) tumors using beta-emitting radionuclides, particularly when delivered via the cerebrovascular system. In various embodiments, the present disclosure provides a method for treating patients requiring treatment of CNS tumors, comprising the step of selectively administering a β-radioactive composition to the cerebrovascular system. In some embodiments, the CNS tumor may be a glioma. In some embodiments, the CNS tumor may be an intraaxial brain tumor. In some embodiments, the CNS tumor may be a meningioma. In some embodiments, the CNS tumor may 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 region of the brain. In this regard, localization in the T2 hyperintense region 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 area 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-emitting composition 89 , 59 , 14 , 131 , 90 , , 47 , 32 , 3 , 153 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-emitting composition can include particles that, among other things, have an average diameter of 1 to 100 μm and contain a radionuclide that emits β-rays. In certain embodiments, the particles are oil, glass, or polymer particles that contain a radionuclide that emits β-rays and have an average diameter of 1 to 100 μm. 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-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 It contains one or more radionuclides selected from Er.

[0009] In some embodiments that can be used in combination with any of the above embodiments and models, the beta-ray emitting particles are glass particles or polymer particles. In some embodiments that can be used in conjunction with any of the above embodiments and models, the beta-ray emitting particles are alumina silicate glass particles containing yttrium, for example, the glass particles may be formed from glass obtained from a mixture of 35-45% Y2O3, 15-25% Al2O3, and 35-45% SiO2, for example, 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 may be released by exposure to radiation. 90 It is converted to Y.

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

[0011] In other embodiments, the Disclosure provides an injectable composition containing a suspension of a beta-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 It contains one or more radionuclides selected from Er.

[0012] In some embodiments, the substance may include particles such as oil, glass, or polymer particles having an average diameter of, among other possible values, 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 It is a beta-emitting particle containing one or more radionuclides selected from Er.

[0013] In some embodiments, the particles are yttrium 90 as an integral component of the glass. 90 The material comprises insoluble glass microspheres having Y), which may have a diameter in the range of 20 to 30 μm, among other possible values. In certain embodiments, the material may contain 22,000 to 73,000 microspheres per milligram of 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 with sterile, pyrogen-free water.

[0014] Additional aspects and embodiments will become apparent to those skilled in the art by considering the following detailed description. [Brief explanation of the drawing]

[0015] [Figure 1] Angiographic image showing contrast agent injected into the left middle cerebral artery of a healthy test dog. [Figure 2]A) Pre-treatment MRI image, and B) Post-treatment Y90 PET / CT image fused with the pre-treatment MRI. The fused image shows the correlation between MRI T2 enhancement peripherals and Y90 PET deposition in the first brain tumor-affected dog that received treatment. [Figure 3] A) T2 FLAIR MRI image one month before treatment, B) T2 FLAIR MRI image one month after treatment, C) T1 contrast-enhanced MRI image one month before treatment, D) T1 contrast-enhanced MRI image one month after treatment. One month after treatment, edema around the lesion resolved, contrast enhancement was not observed, and the size of the lesion decreased. Resolution of midline shift without evidence of cortical atrophy was also observed. [Modes for carrying out the invention]

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

[0017] In preferred embodiments, the disclosure also relates to the use of injectable compositions containing radionuclide-containing substances in the treatment of CNS tumors, more particularly (1) intraaxial brain tumors (including but not limited to primary axial brain tumors), including astrocytoma, primary CNS lymphoma, glioblastoma, and glioma (such as glioma or oligodendroglioma), (2) extraaxial tumors such as meningioma, and (3) secondary brain tumors (i.e., brain metastases) occurring elsewhere in the body.

[0018] CNS cancers can be extremely difficult to treat, and high-grade gliomas are often difficult to surgically remove and are frequently resistant to radiotherapy and chemotherapy. Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. The current standard of treatment is external beam radiation therapy (EBRT) combined with chemotherapy, with relatively poor outcomes. Researchers at the Johns Hopkins Comprehensive Brain Tumor Center have developed the GliaSite® radiotherapy system (RTS), which delivers radiation through the opening created by the surgical removal of a malignant brain tumor. "Proximity radiation therapy," which uses manually inserted encapsulated gamma emitters, is an established treatment for cancers of tissues such as the prostate and is being tested against GBM.

[0019] GBM is a hypervascular tumor and always contains an invasive tumor component. This prevents surgical cure in virtually all cases, making the treatment of GBM extremely difficult. 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 surgical treatment options for GBM, the standard treatment is subdivided external beam radiation therapy (EBRT).

[0020] Typically, EBRT consists of 35 fractions of 1.8 Gy per day, delivering a total of 63 Gy, including a 1-2 cm margin from the tumor and marginal enhancement. Radiotherapy has been used to treat GBM since the 1940s, and a preliminary radiobiological threshold identified in the 1970s shows a moderate 2.3-fold increase in survival at 60 Gy. Modern EBRT treatments using stereotactic techniques and dose escalation protocols have not shown a reproducible effect on improving survival (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, alkylating agents) has been the standard treatment since 2002, following data from 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] Apart from EBRT, manual low-dose-rate close-range brachytherapy has been considered for the treatment of GBM. 125I and, more recently, 131Cs close-range brachytherapy have been used in combination with standard external beam radiation therapy for salvage after relapse. Regarding new diagnoses of 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 close-range radiotherapy using low-energy gamma emitters involve high doses of radiation to healthy brain parenchyma, leading to a high frequency of neurotoxicity. To counteract neurotoxicity, advanced techniques such as proton or X-ray microchannels that use a microbeam field to irradiate tumors have shown potential to preserve parenchyma not involved in cancer (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 glioma is, by definition, characterized by enhanced hypervascularity in mirabilis (MR), which distinguishes low-grade (WHO I, II) and high-grade (WHO III, IV) gliomas. Numerous angiogenic factors have been identified in relation to the various classifications of high-grade gliomas (see Hanif, F., Muzaffar, K., Perveen, K., Malhi, SM & Simjee, SU 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, enhancing the tumor. In fact, contrast enhancement on CT can be more than 20 times greater in the tumor compared to a normal parabronchial tumor (Figure 1). A challenging aspect of GBM therapy is the consistently present, relatively low-cellular, invasive disease. While the invasive component presents therapeutic challenges, recurrence after EBRT usually occurs in the center, within 1-2 cm of the original margin of tumor enhancement.

[0025] The dose-response relationship between GBM and radiotherapy is well-explained. Proximity brachytherapy, which places sealed radioactive sources near the tumor, has shown efficacy in several reports, but heterogeneous overall survival rates reflect a nearly 50% neurotoxicity rate. High neurotoxicity in manual brachytherapy may be due to wide dose margins resulting from the use of low-energy gamma emitters. This toxicity can be partially mitigated 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 inventors hypothesized that transarterial radioembolization (TARE), an established treatment for liver tumors, could potentially be a viable improved treatment for central nervous system cancers of the brain. GBM has a well-documented dose-response relationship with radiotherapy, and although the brain does not have a dual blood supply like the liver, GBM is by definition hypervascular (10:1 contrast enhancement is possible in GMB). This limits the concentration of arterially administered substances in normal brain parenchyma, and since modern EBRT has achieved some success in improving responses, particularly by targeting high-dose hypervascular areas, a similar effect could be expected with TARE.

[0027] Manual proximity irradiation using low-energy gamma emitters (125I, 131Cs) is known as GBM, but high doses result in high neurotoxicity to nearby nerve structures. To mitigate such effects, the inventors hypothesized that radiation emitted from radionuclides positioned within a cancerous vascular system with a limited determinant range would limit the dose and damage to normal tissue. In particular, they determined that radionuclides emitting beta rays may have the correct profile for limiting the dose to nearby normal tissue, especially if they are shaped appropriately for TARE.

[0028] Superselective angiography of GBM was described nearly 20 years ago and has been reported numerous 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), delivered in combination with pharmaceuticals, has been used with some success (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 this invention have developed a technology used in manual close-range irradiation therapy. 125 I, 131 We hypothesized that, compared to gamma-ray emitters such as Cs, the dose deposition margin for beta rays is much narrower, and therefore they may not harm soft tissues that are not involved in cancer. 90 Y is the highest energy pure beta emitter commonly used in radionuclide therapy. 131 I or 177 Lu, etc. 90 Substitutes for Y have low-energy beta radiation and may not harm the surrounding tissue of the ring-enhanced GBM, but if the margin is low, they may not be able to effectively treat the cellular and / or acellular invasive tumor components that are often present. Therefore, we believe that the use of any beta-emitting radionuclide is within the scope of this disclosure, in particular materials containing high-energy radionuclides, especially 90 Y and 166 It is intended to be used with substances such as Ho, which are used in TARE.

[0030] In recent years, a modified EBRT algorithm has shown promise. This technique assumes that areas with the highest vascular distribution represent areas with high cellularity, and therefore delivers a higher dose to the enhancing tumor component. A lower dose is administered to the T2 / FLAIR high signal area, assuming this reflects an invasive tumor or hypocellular edema. The modified EBRT protocol treats the enhancing area with a high dose (100-130 Gy) to improve the response without significantly increasing the absorbed dose to normal parenchyma associated with high-dose treatment of the entire tumor. The inventors believe that, 90 We hypothesized that higher-energy beta radiation emitters, such as those from Y radionuclides, could be comparable to or even improve upon this. 90 Y has been shown to irradiate the highly vascularized tumor area with a large absorbed dose (~1000 Gy) in biopsy specimens after liver cancer treatment, and in this respect, it may improve EBRT.

[0031] Other EBRT techniques that do not harm brain parenchyma not involved in cancer, such as X-rays and proton microchannels, are glass 90 When comparing Y microspheres with EBRT, it has been shown to reduce neurotoxicity, similar to comparisons made in relation to differences in toxicity in liver treatment (which can be 3-5 times greater). In particular, glass in normal brain parenchyma. 90 The sparse distribution of Y microspheres may preserve this tissue and may function mechanically, similar to X-ray and proton microchannels, which are currently important subjects of research in EBRT.

[0032] Particularly preferred compositions for use in the methods of this disclosure include radionuclide-containing materials whose form is minimally embolic, such as oils, polymers, or glass microspheres, and the minimally embolic beta-emitting radionuclides, including particles, 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 radionuclides selected from Er. More preferably, 89 Sr, 166 Ho, 153 Sm, 177 Lu, 169 Mark and 90 A relatively pure β-emitter selected from Y. Optimally, in the form of glass or polymer microspheres. 90 Y is a radioactive nuclide. In some cases, iodine is produced using lipiodol, etc. 131 Oil can also be used.

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

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

[0035] Superselective delivery of beta-emitting substances, such as oils 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 cerebral vascular supply and perfusion compared to the anatomy of hepatic vascular systems treated with conventional methods. Superselective delivery also has the advantage of further restricting 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, pronounced Cerasphere or Terrasphere), available from Bio-Compatibles UK Limited, contains yttrium-90. 90 Yttrium is composed of insoluble glass microspheres, which are an essential component of glass. The glass is an aluminosilicate glass containing yttrium, obtained from a mixture of 35-45% Y2O3, 15-25% Al2O3, and 35-45% SiO2, more specifically, from about 40% Y2O3, about 20% Al2O3, and about 40% SiO2. At least some of the yttrium in the glass is removed by exposure to radiation. 90 It has been converted to Y.

[0037] The average diameter of the spheres ranges from 20 to 30 μm. Each milligram contains 22,000 to 73,000 microspheres. TheraSphere® is supplied as 0.6 mL of pyrogen-free sterile water in a 1.0 mL V-bottom vial, secured within a clear acrylic vial shield. TheraSphere® 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, a smaller dose size is used, or a portion of the above dose sizes is used. In a preferred embodiment, the dose may be 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, the dose may be 5%, 10%, 15%, 20%, 25%, or 30% of any of the above dose sizes. In the optimal embodiment, the dose may be 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 referred to as day 0, the days from 1 to 7 following the calibration day are referred to as week 1, and the days from 8 to 12 are referred to as week 2. In one embodiment, calibration refers to day 0 at time zero. In one embodiment, time zero on day 0 is noon Eastern Standard Time.

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

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

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

[0043] Microspheres are delivered to the target via a catheter placed in an artery supplying blood to the tumor. Unable to pass through the vascular system due to capillary occlusion of arterioles, the microspheres become trapped in the tumor, exerting a localized radiotherapy effect while simultaneously causing some damage to the surrounding normal tissue. See Campbell, AM, Bailey, IH & Burton, MA. Tumour dosimetry in human liver following hepatic yttrium-90 microsphere therapy. Phys Med Biol 46, 487-498 (2001).

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

[0045] Other beta-emitting materials include SIR-spheres(registered trademark), 90 The present invention includes ion exchange resin beads containing the radionuclide Y. These beads have a diameter of 20–60 μm and are available from Certex Medical. SIR-spheres may be envisioned for use in this disclosure. In one embodiment, the SIR-spheres would be modified to increase their specific activity in order to enhance the therapeutic effect exhibited during their use. In a preferred embodiment, this increase in specific activity is applied to the resin. 90 This can be achieved by increasing the amount of Y filled.

[0046] Further beta-emitting materials 131 It is I-iodized lipiodol, whose use is described in a monograph by the European Society of Nuclear Medicine, and lipiodol 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, composed 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 in the brain. Beta-emitting particles theoretically may also generate other radiations, similar to radionuclides such as 3 H, 14 C, 32 P, 59 Fe, 47 Ca, etc., but the inventors assume that 89 Sr, 166 Ho, 153 Sm, 177 Lu7, 169 Er, and 90 Y, optimally, 90 particles containing Y provide the most appropriate treatment.

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

[0050] These particles are optimally and conveniently supplied as an aqueous suspension, for example, a suspension in sterile water or saline. Particle administration is preferably initiated with a steroid, for example, with an initial dose of prednisone at 4 mg / kg (IV or PO), followed by, for example, 2 mg / kg PO per day, which may be started on the day of cerebral artery radioembolization and then continued gradually at 2–4 mg / kg until the clinician feels it is safe to discontinue (based on post-treatment MRI).

[0051] The method of this disclosure involves, in particular, deploying a catheter in a cerebral artery supplying a central nervous system cancer, such as a tumor. If the tumor is located in one of the cerebral hemispheres or localized in this subzone, it is more preferable to place the catheter in a specific branch of the cerebral artery supplying the tumor.

[0052] In a preferred embodiment, the method of the present disclosure involves deploying a catheter through the radial artery. Typically, the guide catheter is advanced on a wire and inserted into the aorta, for example, via the femoral artery, and then advanced into the carotid artery, often using fluoroscopy.

[0053] Preferably, angiographic evaluation using a contrast agent is performed, for example, by deploying an iodized contrast agent, and the cerebral artery branches that primarily supply blood to the tumor are identified and accessed in that manner. The catheter is preferably a microcatheter, and an example of a suitable microcatheter is provided by Stryker, Excersior SL-10 1.7F (0.6 mm in diameter). The suitable catheter does not use a balloon to isolate the vascular system during administration of the beta-ray radionuclide-containing composition. In some situations, a balloon, such as that associated with a balloon catheter, may be preferred by clinicians. However, the inventors believe this is unnecessary if particles of the appropriate size containing the composition are used.

[0054] Preferably, the microcatheter is advanced as close as possible to the tumor without causing physical damage to the blood vessels. This allows for the placement of the β-ray composition to be as selective as possible, for example, preferably primarily providing localization and preferably providing some embolus formation to the tumor with limited perfusion of normal brain parenchyma. The antivascosmodic agent is preferably administered by intraarterial injection to prevent vasospasm during selective arterial catheter insertion, for example, nitroprusside (100 mcg).

[0055] In one embodiment, it is preferable to review pre-treatment MRI to determine the tumor volume before treatment. The research physicist executes a treatment plan with a preferred expected 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 microspheres is complete, the wire, catheter, and sheath are removed. For closure, manual pressure is maintained until hemostasis is achieved or a closure device is utilized.

[0056] In one embodiment, the targeted therapeutic dose is understood to be the area perfused by the administration. In one embodiment, this targeted therapeutic dose includes both tumor tissue and normal tissue. In one embodiment, the healthcare provider may use anatomical imaging and / or cone-beam computed tomography (CBCT) in the procedure with contrast enhancement to determine the targeted therapeutic dose.

[0057] In one embodiment, a research physicist executes a treatment plan with expected therapeutic volume doses of 10–1000 Gy, preferably 50–200 Gy, more preferably 80–180 Gy, and optimally 100–150 Gy. As those skilled in the art will understand, tumor absorbed doses are expected to be higher than normal tissue absorbed doses. Not bound by theory, this may be due to the hypervascularity of tumors.

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

[0059] In one embodiment, the desired absorbed dose, expressed in Gray (Gy), can be calculated based on the target therapeutic dose using the MIRD schema. In another embodiment, the desired absorbed dose, expressed in Gray (Gy), can be calculated based on the target therapeutic dose using software similar to TheraSphere® iDOC® or Therapeutic Window Illustrator software.

[0060] In one embodiment, the desired absolute activity, expressed in becquerels (Bq) or gigabecquerels (GBq), can be calculated based on the target therapeutic dose using the MIRD schema. In one embodiment, the desired absolute activity (Bq or GBq) can be calculated based on the target therapeutic dose using software similar to TheraSphereiDOC® or Therapeutic Window Illustrator software. After occlusion and hemostasis are achieved, the subject is preferably transferred to PET / CT for scanning. Anesthesia is maintained, for example, with an IV bolus of propofol. The PET-CT scan is performed under general anesthesia of isoflurane with the use of a ventilator. PET / CT detects radiation emissions from 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 returns. 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 hours). After radiosafety assessment, the subject may be allowed to go home when awake and at normal body temperature. After treatment and imaging, the subject may be discharged on the same day. The clinician should look for behavioral changes or signs of seizures for follow-up, and depending on the severity of these problems, a clinical decision regarding the possibility of a herniation is made based on the subject's behavior, presence of seizures, cranial nerve defects, and physical appearance, and the investigator may recommend treatment to reduce intracranial pressure.

[0062] Subjects typically undergo post-treatment MRI imaging under anesthesia, preferably within one week after treatment, at least once a week, to assess for signs of inflammation, edema, and other neurological changes. Sedation and anesthesia are as described for cerebral artery radioembolization. In one embodiment, imaging can be performed without anesthesia.

[0063] (Examples) This disclosure will be described by reference to the following non-limiting illustrative examples. In light of these, further embodiments will arise for those skilled in the art.

[0064] Experimental evidence: There is no suitable large-scale research animal model for glioblastoma pleomorphism (GMB), which exhibits characteristics of human brain tumors. These tumors occur spontaneously in humans, but are also common in several dog breeds. Canine cancer models with spontaneously occurring, high-grade axial brain tumors, including GBM, are clinically highly relevant to human cancers 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 domesticated animals with spontaneously developing tumors can potentially benefit the domesticated animals while minimizing the use of research animals. Animals were evaluated for their disease before enrollment in the study, following standard treatment at the Johns Hopkins Medical Center for Image-Guided Animal Therapy. The evaluation included (i) veterinary neurological examination, (ii) blood tests (CBC, chemical panel), and MRI with contrast.

[0066] Participation in this study involves an MRI review and 90 The approach depended on identifying tumor characteristics suitable for Y therapy. These characteristics included tumors perfused primarily from a single vascular region, with no involvement from both hemispheres.

[0067] Research dogs were used as safety controls, and dogs with spontaneously occurring canine gliomas in one hemisphere were presented to the clinic. Pet dogs were used only in the aggressive treatment group.

[0068] result: Treatment of the research dogs proceeded well, with a significant absorbed dose delivered to a normal brain. Overall, the research dogs tolerated the treatment well.

[0069] Two cases of glioma were treated by the date of this patent application, and both experiences were similar in terms of the impression of the imaging of the procedure. The tumor was treated via the carotid artery, with the aim of covering half of the brain (right / left) containing the tumor. Some perfusion crosses the midline, so it is slightly more than half. Angiography was unremarkable. Although hypervascularization or redness of the tumor was expected, the tumor could not be easily identified. 90 Post-Y PET showed good uptake in the T2 high-signal (flare image) regions of the brain surrounding the tumor and in the tumor itself. Based on the angiography, it was remarkable to achieve such high localization to this tumor region of the brain.

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

[0071] The first test dog was introduced on Thursday of the second week. 90 A dog treated with Y TheraSphere® (low dose of radiation - 2 weeks postpartum) experienced a transient ischemic attack (TIA) after treatment. A second dog was treated with approximately twice the activity and approximately twice the number of microspheres at the dose administered on Friday of the first week. Dogs with higher activity and fewer beads did not experience significant TIA after treatment. Higher specific activity microspheres may limit the embolic / ischemic effect in the brain. In this regard, embolus formation in the cerebrovascular system is generally considered negative because it can cause a TIA or stroke. The risk of adverse effects from embolus formation should be mitigated by using smaller, fewer microspheres while still delivering therapeutic levels of radiation. This can be achieved by using small, high specific activity (activity per gram) microspheres.

[0072] 90By the time of the PET scan following dog Y, the tumor dose in dog 1 was 35 Gy, while the normal tissue dose was 18.6 Gy. Due to limitations in the spatial resolution of PET, the tumor dose may be higher. The tumor dose in dog 2 was 115 Gy, while the normal tissue dose was 23.5 Gy. This separation of tumor and normal tissue by dog ​​2 is excellent and may be far better than what is typically achieved with external beam radiation. The target tumor dose for external beam radiation is approximately 60 Gy. The short penetration of beta rays and the relatively large tumor-to-normal ratio should prevent the normal tissue from receiving a high absorbed dose. Dog 1 showed a full response approximately one month after treatment. Dog 2 has shown no symptoms for 11 days.

Claims

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

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 one or more radionuclides selected from Er, the injectable composition according to claim 1.

3. The aforementioned particles, 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, which is a beta-ray emitting particle containing one or more radionuclides selected from Er.

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

5. The particle is a beta-ray emitting particle, and the beta-ray 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 aforementioned pure beta-emitting radionuclide ９０ The injectable composition according to claim 5, wherein Y.

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

8. The aforementioned particles are 35-45% Y ２ O ３ , 15-25% Al ２ O ３ , and 35-45% SiO ２ The injectable composition according to claim 1, formed from glass obtained from a mixture of the following.

9. The aforementioned particles are approximately 40% Y ２ O ３ Approximately 20% Al ２ O ３ , and about 40% SiO ２ The injectable composition according to claim 1, formed from glass obtained from a mixture of the following.

10. The aforementioned particles are yttrium 90 as an integral component of glass. ９０ The injectable composition according to claim 1, comprising insoluble glass microspheres having Y).

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

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

13. The injectable composition according to claim 1, wherein the CNS tumor is a highly malignant axial tumor.

14. The injectable composition according to claim 1, wherein the CNS tumor is an intraaxial brain tumor.

15. The injectable composition according to claim 1, wherein the CNS tumor is a meningioma.

16. The injectable composition according to claim 1, wherein the CNS tumor is a brain metastasis.

17. The injectable composition according to claim 1, wherein the beta-ray emitting composition is localized to the T2 high-signal region of the brain.

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