WO2018022990A1

WO2018022990A1 - Standardized placement apparatus for radiopharmaceutical calibration

Info

Publication number: WO2018022990A1
Application number: PCT/US2017/044367
Authority: WO
Inventors: Adam Kesner; Rafe MCBETH
Original assignee: The Regents Of The University Of Colorado, A Body Corporate
Priority date: 2016-07-29
Filing date: 2017-07-28
Publication date: 2018-02-01

Abstract

The present invention is related to methods and apparatus for standardizing the geometric placement and measurement of a radioactive source relative to a radioactivity measurement device, and can be used in application of clinical radiopharmaceuticals or implants to measure and record relative pre and post treatment radioactivity measurements, which can then be used to determine the fraction of initial activity delivered during treatment. In particular, the invention is related to a device that maintains a reliable distance between a radiation source and a radiation detector and a method of determining the percent of radioactivity delivered by radionuclides (e.g., Y-90 microspheres) during radionuclide therapy, for example, liver brachytherapy. For example, the method can determine the precision and accuracy of several clinically available instruments for the pre- and post-treatment measurement of Y-90 microspheres.

Description

Standardized Placement Apparatus for Radiopharmaceutical Calibration

Field Of The Invention

The present invention is related to methods and apparatus for standardizing the geometric placement and measurement of a radioactive source relative to a radioactivity measurement device, and can be used in application of clinical radiopharmaceuticals or implants to measure and record relative pre and post treatment radioactivity measurements, which can then be used to determine the fraction of initial activity delivered during treatment. In particular, the invention is related to a device mat maintains a reliable distance between a radiation source and a radiation detector and a method of determining the percent of radioactivity delivered by radionuclides (e.g., Y-90 microspheres) during radionuclide therapy, for example, liver brachytherapy. For example, the method can detennine the precision and accuracy of several clinically available instruments for the pre- and post-treatment measurement of Y-90 microspheres. Background

For Y-90 microsphere radionuclide therapy, e.g., brachytherapy of the liver, a

conventional method to detennine the dose delivered to the patient is by taking the difference between an ion chamber measurement of the pre-treatment vial and post-treatment procedure waste (i.e., for example, tubing, gloves, residual vial activity...). However, Ion chamber/GM measurements have inherent error associated with fluctuating readouts. Multiple vial treatments and multiple waste containers could lead to increased error without robust measurement methods. Improved measurement methods will provide physicians with better estimates of treatment and decrease the chance of incorrectly classified misadministrations due to detector errors.

Summary Of The Invention

The present invention is related to methods and apparatus for standardizing the geometric placement and measurement of a radioactive source relative to a radioactivity measurement device, and can be used in application of clinical radiopharmaceuticals or implants to measure and record relative pre and post treatment radioactivity measurements, which can then be used to determine the fraction of initial activity delivered during treatment In particular, die invention is related to a device that maintains a reliable distance between a radiation source and a radiation detector and a method of determining the percent of radioactivity delivered by radionuclides (e.g., Y-90 microspheres) during radionuclide therapy, for example, liver brachymerapy. For example, the method can determine the precision and accuracy of several clinically available instruments for the pre- and post-treatment measurement of Y-90 microspheres.

In one embodiment, the present invention contemplates a device, comprising: a) a spacer having a proximal end and a distal end; b) a radiation detector placed on said distal end; and c) a radiation source chamber at said proximal end. In one embodiment, said radiation detector is a scintillation crystal based thyroid probe system. In one embodiment, said spacer is columnar. In one embodiment, the spacer is hollow. In one embodiment the spacer is solid. In one

embodiment the spacer is solid. In one embodiment, said spacer is a pipe. In one embodiment, said spacer is a pole. In one embodiment, the spacer is a stick. In one embodiment, said columnar spacer is a standardized placement apparatus for radiopharmaceutical calibration spacer. In one embodiment, said radiation source chamber further comprises a radiation source. In one embodiment, said spacer is a known length. In one embodiment, said spacer has a diameter ranging between approximately 5 -25 centimeters. In one embodiment, said spacer is approximately 15 centimeters in diameter. In one embodiment, said proximal end and said distal end. In one embodiment, the length of said spacer ranges between approximately 0.5 to 2 meters. In one embodiment, the length of said spacer is approximately 122 centimeters. In one embodiment, said radiation source is in a container that fits within said radiation source chamber. In one embodiment, said spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal. In one embodiment, said distal end comprises a notch. In one embodiment, said distal end comprises a ridge. In one

embodiment, said distal end comprises a net. In one embodiment, said radiation detector comprises an energy discriminator. In one embodiment, said radiation detector is capable of recording signal in separate energy windows. In one embodiment, said radiation detector comprises an gas chamber type detector. In one embodiment, said radiation detector comprises a solid state type detector.

In one embodiment, the present invention contemplates a method, comprising: a) providing: i) a radionuclide; and ii) a device, comprising: A) a spacer having a proximal end and a distal end; B) a radiation detector placed on said distal end; and C) a radiation source chamber at said proximal end; and b) obtaining a radioactivity measurement of said radionuclide with said device. In one embodiment, the radioactivity measurement is a first radioactivity measurement In one embodiment, the radioactivity measurement is a second radioactivity measurement. In one embodiment, said radioactivity measurement is a first radioactivity measurement and a second radioactivity measurement In one embodiment, the method further comrpises the step of calculating a percent value of said second radioactivity measurement to said first radioactivity measurement In one embodiment, said radionuclide is attached to a plurality of Y-90

microspheres. In one embodiment, said radionuclide is attached a plurality of Lu-177

microspheres. In one embodiment, said radionuclide is attached to a plurality of 1-131 microspheres. In one embodiment, said radiation detector is a scintillation crystal based thyroid probe system. In one embodiment, said radiation detector comprises an energy discriminator. In one embodiment, said radiation detector acquires signal in multiple energy windows. In one embodiment, said radiation detector comprises an ion chamber type detector. In one

embodiment said radiation detector comprises a solid state type detector. In one embodiment, said spacer is columnar. In one embodiment, the spacer is hollow. In one embodiment the spacer is solid. In one embodiment the spacer is solid. In one embodiment, said spacer is a pipe. In one embodiment, said spacer is a pole. In one embodiment, the spacer is a stick. In one embodiment, said columnar spacer is a standardized placement apparatus for radiopharmaceutical calibration spacer. In one embodiment, said radiation source chamber further comprises a radiation source. In one embodiment, said spacer is a known length. In one embodiment, said spacer has a diameter ranging between approximately 5 -25 centimeters. In one embodiment, said spacer is approximately 15 centimeters in diameter. In one embodiment, said proximal end and said distal end. In one embodiment, the length of said spacer ranges between approximately 0.5 to 2 meters. In one embodiment, the length of said spacer is approximately 122 centimeters. In one embodiment, said radiation source is in a container that fits within said radiation source chamber. In one embodiment, said spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal. In one embodiment, said distal end comprises a notch. In one embodiment, said distal end comprises a ridge. In one

embodiment, said distal end comprises a net.

In one embodiment, the present invention contemplates a method, comprising: a) providing i) a patient; ii) a radionuclide; iii) a device, comprising: A) a spacer having a proximal end and a distal end; B) a radiation detector placed on said distal end; and C) a radiation source chamber at said proximal end; b) obtaining a pre- treatment radioactivity measurement of said plurality of radiolabeled microspheres with said device; c) delivering a therapeutic radioactivity dose to said patient with said radionuclide; d) obtaining a post-treatment radioactivity

measurement of said plurality of radiolabeled microspheres with said device; e) calculating a percent value of said therapeutic delivered radioactive dose to said patient In one embodiment, said radionuclide is attached to a plurality of Y-90 microspheres. In one embodiment, said radionuclide is attached to a plurality of Lu-177 microspheres. In one embodiment, said radionuclide is attached to a plurality of 1-131 microspheres. In one embodiment, said radiation detector is a scintillation crystal based thyroid probe system. In one embodiment, said radiation detector comprises an energy discriminator. In one embodiment, said radiation detector acquires signal in multiple energy windows. In one embodiment, said radiation detector comprises an ion chamber type detector. In one embodiment, said radiation detector comprises a solid state type detector. In one embodiment, said spacer is columnar. In one embodiment, said columnar spacer is a standardized placement apparatus for radiopharmaceutical calibration spacer. In one embodiment, said radiation source chamber further comprises a radiation source. In one embodiment, said spacer is a known length. In one embodiment, said spacer has a diameter ranging between approximately 5 -25 centimeters. In one embodiment, said spacer is approximately 15 centimeters in diameter. In one embodiment, said proximal end and said distal end. In one embodiment, the length of said spacer ranges between approximately 0.5 to 2 meters. In one embodiment, the length of said spacer is approximately 122 centimeters. In one embodiment, said radiation source in a container that fits within said radiation source chamber. In one embodiment, said spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal. In one embodiment, said distal end comprises a notch. In one embodiment, said distal end comprises a ridge. In one embodiment, said distal end comprises a net In one embodiment, the spacer is columnar. In one embodiment the spacer is hollow. In one embodiment the spacer is solid. In one embodiment the spacer is solid. In one embodiment said spacer is a pipe. In one embodiment said spacer is a pole. In one embodiment the spacer is a stick.

In one embodiment the present invention contemplates a system, comprising; a) a spacer aligned between a radiation source chamber and a radiation detector system, wherein said radiation source and said radiation detector system are separated by a replicable distance; and b) a radiation source placed within said radiation source chamber, wherein at least one radiation activity measurement of said radiation source by said radiation detector system correlates with the radiation strength of said radiation source. In one embodiment, said radiation source is a medical isotope. In one embodiment, said medical isotope is a Y-90 isotope. In one

embodiment, said medical isotope is a Lu-177 isotope. In one embodiment, said medical isotope is a 1-131 isotope. In one embodiment, the spacer is hollow. In one embodiment the spacer is solid. In one embodiment, said spacer is a pipe. In one embodiment, said spacer is a pole. In one embodiment, the spacer is a stick. In one embodiment, said spacer is a known length. In one embodiment, said spacer has a diameter ranging between approximately 5 - 25 centimeters. In one embodiment, said spacer is approximately 15 centimeters in diameter. In one embodiment, said proximal end and said distal end. In one embodiment, the length of said spacer ranges between approximately 0.5 to 2 meters. In one embodiment, the length of said spacer is approximately 122 centimeters. In one embodiment, said radiation source is in a container that fits within said radiation source chamber. In one embodiment, said at least one radiation activity measurement comprises a first radiation activity measurement and a second radiation activity measurement. In one embodiment, a percent activity value is determined by comparing said second radiation activity measurement to said first radiation activity measurement. In one embodiment, said percent activity value is confirmed in accordance with pre-established criteria. In one embodiment, said radiation detector system is a scintillation crystal based thyroid probe system. In one embodiment, said radiation detector system is a scintillation type detector. In one embodiment, said radiation detector system is a ion chamber type detector. In one embodiment, said radiation detector system is a solid state type detector.

In one embodiment, the present invention contemplates a method, comprising: a) providing: i) a patient comprising a tissue in need of a radiographic scan; ii) a plurality of radiolabeled microspheres; iii) a device, comprising: A) a spacer having a proximal end and a distal end; B) a radiation detector placed on said distal end; and C) a radiation source chamber at said proximal end; b) administering said radiolabeled microspheres to said tissue; c) detecting said tissue radiolabeled microspheres using said device to perform said radiographic scan; and d) calculating a percent-delivered value of said administered plurality of radiolabeled microspheres wherein said percent-delivered value comprises an accuracy standard deviation of less than five percent. In one embodiment, said radiolabeled microspheres are Y-90 microspheres. In one embodiment, said plurality of radiolabeled microspheres is a plurality of Lu-177 microspheres. In one embodiment, said plurality of radiolabeled microspheres is a plurality of 1-131

microspheres. In one embodiment, said tissue is a liver tissue. In one embodiment, said thyroid probe comprises an energy window having channels 0 -1023 KeV. In one embodiment, the method further comprises the step of obtaining a pre-treatment radioactivity measurement of said plurality of radiolabeled microspheres with said device. In one embodiment, the method further comprises the step of obtaining a post-treatment radioactivity measurement of said plurality of radiolabeled microspheres with said device. In one embodiment, said radiation detector is a scintillation crystal based thyroid probe system. In one embodiment, said radiation detector comprises an energy discriminator. In one embodiment, said radiation detector comprises multiple energy window. In one embodiment, said radiation detector comprises an ion chamber type detector. In one embodiment, said radiation detector comprises a solid state type detector. In one embodiment, said hollow spacer is columnar. In one embodiment, the spacer is hollow. In one embodiment the spacer is solid. In one embodiment the spacer is solid. In one embodiment, said spacer is a pipe. In one embodiment, said spacer is a pole. In one embodiment, the spacer is a stick. In one embodiment, said columnar spacer is a standardized placement apparatus for radiopharmaceutical calibration spacer. In one embodiment, said radiation source chamber further comprises a radiation source. In one embodiment, said spacer is a known length. In one embodiment, said spacer has a diameter ranging between approximately 5 -25 centimeters. In one embodiment, said spacer is approximately 15 centimeters in diameter. In one embodiment, said proximal end and said distal end. In one embodiment, the length of said spacer ranges between approximately 0.5 to 2 meters. In one embodiment, the length of said spacer is approximately 122 centimeters. In one embodiment, said radiation source is in a container that fits within said radiation source chamber. In one embodiment, said spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal. In one embodiment, said distal end comprises a notch. In one embodiment, said distal end comprises a ridge. In one embodiment, said distal end comprises a net.

In one embodiment, the present invention contemplates a device, comprising a hollow spacer configured to be aligned between a radiation source chamber and a radiation detector system, wherein said hollow spacer ensures that said radiation source chamber and said radiation detector system are separated by a replicable distance; and wherein said hollow spacer ensures that at least one radiation activity measurement of a radiation source by said radiation detector system correlates with the radiation strength of said radiation source. In one embodiment, said radiation detector is a scintillation crystal based thyroid probe system. In one embodiment, said spacer is columnar. In one embodiment, the spacer is hollow. In one embodiment, said spacer is a hollow pipe. In one embodiment, said hollow spacer is a standardized placement apparatus for radiopharmaceuti cal calibration spacer. In one embodiment, said radiation source chamber further comprises a radiation source. In one embodiment, said radiation source is a Y-90 isotope. In one embodiment, said radiation source is a Lu-177 isotope. In one embodiment, said radiation source is a 1-131 isotope, In one embodiment, said hollow spacer is a known length. In one embodiment, said spacer has a diameter ranging between approximately 5 - 25 centimeters. In one embodiment, said spacer is approximately 15 centimeters in diameter. In one embodiment, said proximal end and said distal end. In one embodiment, the length of said spacer ranges between approximately 0.5 to 2 meters. In one embodiment, the length of said spacer is approximately 122 centimeters. In one embodiment, said radiation source is in a container that fits within said radiation source chamber. In one embodiment, said hollow spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal. In one embodiment, said distal end comprises a notch. In one

embodiment, said distal end comprises a ridge. In one embodiment, said distal end comprises a net. In one embodiment, said radiation detector comprises an energy discriminator. In one embodiment, said radiation detector is capable of recording signal in separate energy windows. In one embodiment, said radiation detector comprises an gas chamber type detector. In one embodiment, said radiation detector comprises a solid state type detector. In one embodiment, said radiation source is attached to a plurality of microspheres.

Definitions

To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as "a", "an" and "the" are not intended to refer to only a singular entity but also plural entities and also includes the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

The term "about" as used herein, in the context of any of any assay measurements refers to +/- 5% of a given measurement

The term "substitute for" as used herein, refers to the switching the administration of a first compound or drug to a subject for a second compound or drug to the subject

The term "suspected of having", as used herein, refers a medical condition or set of medical conditions (e.g., preliminary symptoms) exhibited by a patient mat is insufficient to provide a differential diagnosis. Nonetheless, the exhibited condition(s) would justify further testing (e.g., autoantibody testing) to obtain further information on which to base a diagnosis.

The term "at risk for" as used herein, refers to a medical condition or set of medical conditions exhibited by a patient which may predispose the patient to a particular disease or affliction. For example, these conditions may result from influences that include, but are not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.

The term "effective amount" as used herein, refers to a particular amount of a

pharmaceutical composition comprising a therapeutic agent that achieves a clinically beneficial result (i.e., for example, a reduction of symptoms). Toxicity and therapeutic efficacy of such compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD₅₀/ED₅₀. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

The term "symptom", as used herein, refers to any subjective or objective evidence of disease or physical disturbance observed by the patient For example, subjective evidence is usually based upon patient self-reporting and may include, but is not limited to, pain, headache, visual disturbances, nausea and/or vomiting. Alternatively, objective evidence is usually a result of medical testing including, but not limited to, body temperature, complete blood count, lipid panels, thyroid panels, blood pressure, heart rate, electrocardiogram, tissue and/or body imaging scans.

The term "disease" or "medical condition", as used herein, refers to any impairment of the normal state of the living animal or plant body or one of its parts mat interrupts or modifies the performance of the vital functions. Typically manifested by distinguishing signs and symptoms, it is usually a response to: i) environmental factors (as malnutrition, industrial hazards, or climate); ii) specific infective agents (as worms, bacteria, or viruses); iii) inherent defects of the organism (as genetic anomalies); and/or iv) combinations of these factors.

The terms "reduce,'' "inhibit," "diminish," "suppress," "decrease," "prevent" and grammatical equivalents (including "lower," "smaller," etc.) when in reference to the expression of any symptom in an untreated subject relative to a treated subject, mean that the quantity and/or magnitude of the symptoms in the treated subject is lower man in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel. In one embodiment, the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.

The term "administered" or "administering¹¹, as used herein, refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient. An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.

The term "patient" or "subject", as used herein, is a human or animal and need not be hospitalized. For example, out-patients, persons in nursing homes are "patients." A patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (z'.e., children). It is not intended that the term "patient" connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of experimentation whether clinical or in support of basic science studies. The term "pharmaceutically" or "pharmacologically acceptable", as used herein, refer to molecular entities and compositions mat do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.

The term, "pharmaceutically acceptable carrier", as used herein, includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.

Brief Description Of The Figures

Figure 1 illustrates one embodiment of a tubular placer system for radiation measurement comprising a spacer 1.

Figure 2 illustrates one embodiment of a tubular placer system for radiation measurement comprising a spacer 1, a radiation detector 2 and a radiation source 3.

Figure 3 presents one illustration of a flow chart for generating a measurement using a tubular placer system as described herein.

Figure 4 presents one embodiment of a SPARC spacer 4.

Figure 5 presents an illustrative clinical SPARC spacer 4 setup with a thyroid probe 7 and an Y-90 radiation source 6. In mis embodiment, the radiation source 3 is depicted next to the proximal end of the SPARC spacer 4 for clarity, but would be placed within the proximal end SPARC spacer 4 during measurement operations.

Figure 6 presents exemplary data showing measured % standard deviations for forty- three (43) Y-90 radiation measurement samples using different measurement systems. Source radiation activity levels ranging between approximately 0.08 - 7.0 GBq.

Figure 7 presents exemplary validation data for forty-three (43) Y-90 samples using different measurement systems.

Figure 7A: Correlations with factory calibrations.

Figure 7B: Performance evaluation across radioactivity ranges between approximately 0.08 - 7.0 GBq. Figure 8 presents exemplary data showing a projected probability of incorrectly measuring a misadministration calculated in a Y-90 procedure when using different

measurement methods. Figure 9 presents exemplary data showing the distribution of standard deviation in accurate measurement among a variety of instruments. Radioactivity ranging between approximately 0.08 - 7.0 GBq.

Figure 10 presents exemplary data showing the standard deviation percentage of factory calibrated measurements for several radiation detectors relative to activity level of source.

Figure 11 presents representative embodiments of the types of devices mat can be used in one embodiment of the present invention.

Figure 11 A: Factory NIST traceable calibration

Figure 1 IB: In-house dose calibrator

Figure 11C: Thyroid probe with 5 energy windows. Nalgene containing vial placed inside standardized holder.

Figure 11 D: GM with factory template.4 averaged measurements at 0, 90, 180 and 270 degrees

Figure 1 IE: Ion chamber with factory template.4 averaged measurements at 0,

90, 180 and 270 degrees

Figure 1 IF: Gamma camera with 2 detectors and 6 energy windows. Detailed Description Of The Invention

The present invention is related to methods and apparatus for standardizing the geometric placement and measurement of a radioactive source relative to a radioactivity measurement device, and can be used in application of clinical radiopharmaceuticals or implants to measure and record relative pre and post treatment radioactivity measurements, which can then be used to determine the fraction of initial activity delivered during treatment. In particular, the invention is related to a device that maintains a reliable distance between a radiation source and a radiation detector and a method of determining the percent of radioactivity delivered by radionuclides (e.g., Y-90 microspheres) during radionuclide therapy, for example, liver brachytherapy. For example, the method can determine the precision and accuracy of several clinically available instruments for the pre- and post-treatment measurement of Y-90 microspheres. I. Y-90 Microsphere Brachytherapy

The subject matter disclosed herein relates generally to clinical isotopes, and more particularly to a method and apparatus for determining the percent of Y-90 delivered during Y- 90 liver brachytherapy.

Y-90 microsphere brachytherapy is increasingly being used to treat primary cancers or metastasis in the liver. The treatments are based on injecting microspheres into the liver arteries, as described with careful vendors recommended protocols, with the aim of selectively implanting them within tumor tissue. In this way, the treatment targets tumor tissue with destructive radiation, while maintaining low radiation doses to healthy liver tissue.

Y-90 microsphere implantation treatments are administered using multidisciplinary teams of specialized physicians, technologists, and physicists. Treatments are performed in IR suits, so the fluoroscopy can be utilized for catheter placement Unlike external beam radiation therapy the therapeutic radiation is delivered using implanted radioactive spheres, so the specific radiation dose is difficult to control. Also, unlike traditional brachytherapy procedures which are usually based on sources the size of plant seed (e.g., prostate brachytherapy implants), Y-90 microspheres are approximately 20-60 microns in diameter and delivered in quantities on the order of millions.

For these reasons, Y-90 treatments are administered in a similar manner to nuclear medicine procedures where they are injected as if they were radiolabeled pharmaceuticals. More specifically, the doses are injected through vendor approved apparatuses.

Just as with any type of radiation treatment, ensuring that proper quantities of radiation are delivered is of large importance, both for the sake of the patient, as well as to ensure compliance with federal and state regulations. However, there is no way to directly measure the amount of radioactivity/sphere' s deposited during treatment. Several methods of utilizing Y-90 PET or SPECT imaging have been proposed, but vendor recommendations and FDA approved protocols provide the art-accepted foundation for a clinically used method to use surrogate measures to project dosimetry.

Specifically, biodistribution is assumed to correlate closely with Tc-99m MAA distributions which are acquired using gamma cameras on days prior to treatment. The magnitude of the radioactivity apportioned to the biodistribution is calculated by measuring pre- administered and post administration activity measurements as measured with a handheld ion chamber, and using the relative value of those measurements to project the activity in the patient If the amount of activity delivered to the patient differs from the prescribed activity or prescribed absorbed dose (as projected using vendor calculators) by more than 20% men mis is a reportable misadministration, as defined by the Nuclear Regulatory Commission (NRC).

Misadministrations necessarily require follow up action and can have negative, often punitive, consequences for staff, clinics, and patients. It is therefore important that the % delivered calculations, based of pre- and post- treatment measurements, be precise and reproducible. Furthermore improved measurement methods will decrease the chance of misadministration due to detector errors.

There are currently two vendors that provide FDA approved Y-90 microsphere treatment devices (e.g., Theraspheres^® and Sirspheres^®). Both vendors recommend similar protocols of measuring pre-administration and post-administration activities using a standard geometry and ion chamber counting device, as a means of calculating the dose delivered. This system does not use a calibrated measurement, but instead is based on relative exposure values, and this is done for practical reasons. It is based on the assumption that all of the activity measured pre treatment will either go into the patient, or reside in the treatment waste (tubing and other sealed system components) and show up in the post-treatment waste measurement The % delivered can then be calculated using equation (1):

Where for pre and post treatment the measurements have units associated with whatever measurement device is used. The % delivered number is a unitless ratio.

Most all radiation dosimeters have some level of error associated with them. For example, handheld ion chambers and Geiger counters are both capable of providing relative exposure measurements, and are what is used in today's practice. These types of radiation detectors are based on measurements of liberated ions in a small volume of air or gas. These detectors measure instantaneous exposure rates, require operator's to read measurements that may be fluctuating and susceptible to operator error. II. Scintillation-Based Microsphere Brachytherapy

In one embodiment, the present invention contemplates a device comprising a scintillation-based radiation detector that provides greater Y-90 microsphere detection precision man conventional radiation dosimeters. In one embodiment, the device comprises a gamma camera and a thyroid uptake probe. Although it is not necessary to understand the mechanism of an invention it is believed that the gamma camera and thyroid uptake probe can make bom pre- and post- treatment measurements.

It is further believed that these scintillation-based radiation detection instruments may have several physical and practical advantages over conventional radiation dosimeters. In terms of radiation detection, scintillation detectors are denser and thus more sensitive, can cliscrirninate energies, and can integrate signal (i.e. not limited to instantaneous measurements). Practically speaking, thyroid probes and gamma cameras can be used in almost completely operator independent protocols and require no measurement interpretation by the operator. Furthermore, all measurements are recorded and thus available if later verification is required, i.e. if a misadministration investigation needs to be pursued.

A. Standardized Placement Apparatus For Radlop hannaceutical Calibration Spacer

In one embodiment, the present invention contemplates a spacer. In one embodiment, the spacer comprises a standardized placement apparatus for radiopharmaceutical calibration (SPARC) spacer. In one embodiment the SPARC spacer comprises a scintillation-based radiation detector. In one embodiment, the SPARC spacer can be used to standardize the placement of pre- and post-treatment radioactive doses relative to a radiation detector system. In one embodiment, the SPARC spacer comprises at least one solid state detector. In one embodiment, the solid state detector is a scintiallation crystal-based thyroid probe detector. In one embodiment, the SPARC spacer is used in a clinical measurement process providing an improved accuracy and precision into the measurement process as compared to conventional radiation dosimeters thereby simplifying the clinical workflow.

Although it is not necessary to understand the mechanism of an invention, it is believed that the SPARC spacer is used to produce a rerjroducWe setup for me measurement of a radioactivity sample. This reproducible setup can be used to measure pre- and post-treatment radioactivity measurements and determine the percent activity delivered during treatment. In one embodiment, the SPARC spacer comprises a hollow pipe. In one embodiment, the hollow pipe is of a standard size. In one embodiment the spacer is solid. In one embodiment, said spacer is a pipe. In one embodiment, said spacer is a pole. In one embodiment, the spacer is a stick.

In one embodiment, the present invention contemplates a method comprising measuring a known radioactivity source placed upon a surface (i.e., a floor or counter top), placing a SPARC spacer over the known radioactivity source, and moving a radiation measurement probe to standardization position located at the top of the SPARC spacer. In one embodiment, the standardization position creates a known source/detector geometry that can be consistent for each subsequent measurement.

Although it is not necessary to understand the mechanism of an invention, it is believed that the SPARC spacer apparatus and/or system has several advantages and benefits over the art: a) The SPARC spacer apparatus and/or system is easier to use in clinical workflows than existing procedures:

i) it enables a simple and easily reproducible measurement setup;

ii) only one single measurement is required as compared to at least four (4) as in current Y-90 microsphere measurement protocols; and

SPARC spacer methods demand less handling of radioactivity and thus reduce radiation exposure to staff.

b) The system is more reliable than existing procedures:

i) measurements are (virtually) operator independent and reproducible; ii) measurements are recorded electronically and documented (for example, by a thyroid probe);

reader error is absent, and

the sensitivity of the solid state detector allowed for a greater distance between source and detectors and therefore minimizes geometric errors caused by geometrically diffuse source distributions.

c) The system is more accurate and has less errors than currently used systems: i) radiation measurements taken with solid state detectors are more reliable than gas chamber detectors (current standard); solid state detector systems allow measurements to be integrated over time and are thus more accurate than instantaneous readout systems;

solid state detectors allow for the option of discriminating counted signal by energy of the detected by radiation;

measurements taken with the probe have been shown to be more accurate and more precise than with current measurement systems.

Although it is not necessary to understand the mechanism of an invention, it is believed that an increased precision enabled by a SPARC spacer measurement apparatus and/or system reduces the instances of incorrectly measured clinical misadministrations and/or that close-calls are less likely to manifest as an out-of acceptance range reading. In summary, a SPARC spacer as contemplated herein can be used to simplify Y90 microsphere treatment protocols, while providing more reliable measurements.

The foregoing summary, as well as the following detailed, description of various embodiments, will be better understood, when read in conjunction with the appended drawings. Various embodiments described herein provide a method and system for generating

measurement of radioactivity acquired in a standardized geometry.

In various embodiments, the method includes placing a contained radioactive source on a surface, and using a tubular placer system to position a detector at a certain distance away from the source. In one embodiment, the tubular placer system comprises a spacer 1. See, Figure 1. In one embodiment, the spacer 1 is a SPARC spacer. Given this reproducible setup, a radiation measurement can be made. In one embodiment, the tubular placer system further comprises a radiation detector at the distal end of the spacer 1 that is aligned with a radiation source 3. See, Figure 2. In one embodiment, the measurement process of using the tubular placer system may follow a workflow. See, Figure 3.

In one embodiment, the spacer 1 is hollow. For example, the spacer 1 may be constructed of a polyvinyl chloride (PVC) pipe. In one embodiment, the spacer 1 is

approximately 15 cm in diameter. In one embodiment, the spacer 1 is approximately 122 cm in length. Although it is not necessary to understand the mechanism of an invention, it is believed that one embodiment of the spacer 1 fits around an approximate 12-15 cm diameter container that may contain a radiation source. In one embodiment, the spacer 1 is a SPARC spacer 4. See, Figure 4.

In one embodiment, the spacer 1 can be made of any rigid material including, but not limited to, plastic, plexiglas, glass, PVC piping, cardboard, metal, etc. In another embodiment, the spacer 1 comprises a distal end, wherein the distal end comprises a notch, ridge or net In one embodiment, the notch, ridge or net is configured for a rep eatable placement of a radiation detector 2. For example, a radiation detector can be lowered until it rests upon a net 9. See, Figure 4.

In one embodiment, a SPARC spacer 4 is used in a clinical setting with a Y-90 radiation source 6, a scintillation-based radiation detector 2 in communication with a thyroid probe 7 with a data cable 8. This image shows the equipment required for a measurement - to perform the measurement one would place the radiation source inside the spacer. In one embodiment, the spacer device comprises a hollow spacer with a diameter that closely approximates the diameter of the radiation sample container 10 such that it can fit within the radiation source chamber 11. . See, Figure S.

Measurement error observed during radiation sampling was characterized as a % standard deviation of different radiation detection systems and defined by differences between normalized measurements and decay corrected factory calibration activities, derived from a population of forty-three (43) measurements of radioactive Y90 samples. See, Figure 6. The systems presented include a dose calibrator, a Geiger-Mueller counter, a ion chamber, a SPARC spacer 4 setup with thyroid probe detector 7 acquired for 2 minutes with energy windows of 0- 1023 KeV, 50-250 KeV, 2S0 - 500 KeV, and 500-750 KeV, a gamma camera acquisition acquired for 2 minutes with a low energy collimator and wide energy windows on two heads using different size regions of interest. These data compare the relative precision between the different measurement systems.

A correlation between normalized activity measurements was developed for different radiation detector systems and the decay corrected factory calibration activities, derived from a population of forty-three (43) measurements of radioactive Y90 samples. See, Figure 7A. The data was further analyzed for device performance over several different radioactivity levels. See, Figure 7B. The systems presented include a dose calibrator, a Geiger-Mueller counter, a ion chamber, a SPARC spacer setup with thyroid probe detector acquired for 2 minutes with energy windows of 0-1023 KeV, 50-250 KeV, 2S0 - 500 KeV, and 500-750 KeV, a gamma camera acquisition acquired for 2 minutes with a low energy collimator and wide energy windows on two heads using different size regions of interest. These data compare the relative accuracy between the different measurement systems.

A projected probability of measuring a misadministration - defined as less than 80% delivered - in a given Y90 microsphere treatment for difference true % administered activities was compared between different measurement systems. See, Figure 8. These systems included a Geiger-M ueller counter, a ion chamber, a SPARC spacer setup with thyroid probe detector acquired for 2 minutes with an energy windows of 0-1023 KeV, and a gamma camera acquisition acquired for 2 minutes with a low energy collimator and wide energy windows on two heads using different size regions of interest

The above data demonstrates how the use of a SPARC spacer 4 can improve workflows by decreasing the number of falsely measured misadministrations, and increasing the sensitivity to true measured misadministrations. In particular; i) the thyroid probe (wide window) and ion chamber linearity correlated best with factory activities; ii) the thyroid probe (wide window) had the smallest % standard deviation in regards to precision; iii) the thyroid probe (wide window) performs the best across different activity ranges in regards to precision; and iv) the thyroid probe performs similar to a does calibrator in regards to the probability of incorrectly measuring a misadministration and outperforms all other tested measurement systems. m. Device Callbrations

A variety of devices were tested where factory calibration measurements were considered "truth" and the data plotted as a distribution of a standard deviation percentage of accurate measurements. See, Figure 9. All measurements were decay corrected to dose preparation time and normalized by their (decay corrected) factory calibration for comparison. The mean percent standard deviation of the corrected/normalized data was calculated for each measurement modality. The results show that GM and Ion chambers have overall standard deviation of 15% and 8% respectively. The dose calibrator had the lowest % standard deviation but is unusable for post treatment measurements. A thyroid probe with wide (energy) window was shown to be the most accurate measurement technique. The percent standard deviation was also determined to nave a trend of increased accuracy for all measurement modalities. See, Figure 10 and Table 1.

Table 1: Performance Percent Standard Deviation Across Radioactivity Levels

These data showed a distinct advantage of the thyroid probe for low activity measurements typical of post treatment waste. For example, GM, ion chamber and gamma camera had large percent standard deviation at low activities.

Current standard of practice for determining percent-delivered measurements of a radioisotope dose can be improved by using a thyroid probe to acquire the pre- and post- treatment measurements of Y-90 microspheres. The wide energy window for the thyroid probe, channel 0 -1023, gave the most precise measurement results, likely because this window contained the most statistics. Measurements taken with the thyroid probe and standardized holder are robust and provide a high level of reproducibility.

Clinical workflow and documentation can be streamlined using the thyroid probe.

Advantages of this method include, but are not limited to, requiring only single measurement, measurements are quick having a minimal effect on clinical workflow, measurements include spectral information, and measurements are printed/saved thereby eliminating human recording error.

Experimental

Multiple samples of varying activity, to represent both pre and post treatment activities, were taken (n=38) using multiple measurement methods and compared:

Measurement methods:

Factory NIST traceable calibration. See, Figure 11 A.

In-house dose calibrator See, Figure 1 IB.

Thyroid probe with 5 energy windows. Nalgene containing vial placed inside standardized holder. See, Figure 11C.

GM with factory template.4 averaged measurements at 0, 90, 180 and 270 degrees. See, Figure 11D.

Ion chamber with factory template.4 averaged measurements at 0, 90, 180 and 270 degrees. See, Figure HE.

Gamma camera with 2 detectors and 6 energy windows. See, Figure 1 IF.

Claims

Claims We claim:

1. A device, comprising:

a) a spacer having a proximal end and a distal end;

b) a radiation detector placed on said distal end; and

c) a radiation source chamber at said proximal end.

2. The device of Claim 1 , wherein said radiation detector is a scintillation crystal based thyroid probe detector.

3. The device of Claim 1 , wherein said spacer is columnar.

4. The device of Claim 3, wherein said columnar spacer is a standardized placement

apparatus for radiopharmaceutical calibration spacer.

5. The device of Claim 1 , wherein said radiation source chamber further comprises a

radiation source.

6. The device of Claim 1, wherein said spacer is a known length.

7. The device of Claim 1 , wherein the diameter of said spacer ranges between

approximately 5 - 25 centimeters.

8. The device of Claim 1 , wherein the length of said spacer ranges between approximately 0.5 to 2 meters.

9. The device of Claim 5, wherein said radiation source is in a container that fits within said radiation source chamber.

10. The device of Claim 1, wherein said spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal.

11. The device of Claim 1 , wherein said distal end comprises a notch.

12. The device of Claim 1, wherein said distal end comprises a ridge.

13. The device of Claim 1 , wherein said distal end comprises a net.

14. The device of Claim 1, wherein said radiation detector comprises an energy

discriminator.

15. The device of Claim 1 , wherein said radiation detector comprises multiple energy

window.

16. The device of Claim 1 , wherein said radiation detector comprises an ion chamber type detector.

17. The device of Claim 1, wherein said radiation detector comprises a solid state type

detector.

18. A method, comprising:

a). providing:

i) a patient;

ii) a radionuclide;

iii) a device, comprising:

A) a spacer having a proximal end and a distal end;

B) a radiation detector placed on said distal end; and

C) a radiation source chamber at said proximal end. b) obtaining a pre-treatment radioactivity measurement of radionuclide with said device;

c) delivering a therapeutic radioactivity dose to said patient with said

radionuclide;

d) obtaining a post-treatment radioactivity measurement of radionuclide with said device;

e) calculating a percent value of said therapeutic delivered radioactive dose to said patient

19. The method of Claim 18, wherein said radionuclide is a plurality of Y-90 microspheres.

20. The method of Claim 18, wherein said radiation detector is a scintillation crystal based thyroid probe detector.

21. The method of Claim 18, wherein said radiation detector comprises an energy

discriminator.

22. The method of Claim 18, wherein said radiation detector comprises multiple energy window.

23. The device of Claim 18, wherein said radiation detector comprises an ion chamber type detector.

24. The device of Claim 18, wherein said radiation detector comprises a solid state type detector.

25. A system, comprising;

a) a spacer aligned between a radiation source chamber and a radiation

detector system, wherein said radiation source and said radiation detector system are separated by a replicable distance; b) a radiation source placed within said radiation source chamber, wherein at least one radiation activity measurement of said radiation source by said radiation detector system correlates with the radiation strength of said radiation source.

26. The system of claim 25, wherein said radiation source is a medical isotope.

27. The system of Claim 26, wherein said medical isotope is a Y-90 isotope.

28. The system of Claim 25, wherein the spacer is a hollow pipe.

29. The system of Claim 25, wherein the spacer is a solid pole or solid stick.

30. The system of Claim 25, wherein said at least one radiation activity measurement

comprises a first radiation activity measurement and a second radiation activity measurement.

31. The system of Claim 30, wherein a percent activity value is determined by comparing said second radiation activity measurement to said first radiation activity measurement.

32. The system of Claim 31 , wherein said percent activity value is confirmed as a pre- established criteria.

33. The system of claim 21, wherein said radiation detector system is a scintillation crystal based thyroid probe detector.

34. The system of Claim 21, wherein said radiation detector system is a scintillation type detector system.

35. The system of Claim 21, wherein said radiation detector system is a ion chamber type detector system.

36. The system of Claim 21 , wherein said radiation detector system is a solid state type detector system.

37. A method, comprising:

a) providing:

i) a patient comprising a tissue in need of a radiographic scan;

ii) a plurality of radiolabeled microspheres;

iii) a device, comprising:

A) a spacer having a proximal end and a distal end;

B) a radiation detector placed on said distal end; and

C) a radiation source chamber at said proximal end

b) administering said radiolabeled microspheres to said tissue; c) detecting said tissue radiolabeled microspheres using said device to

perform said radiographic scan; and

d) calculating a percent-delivered value of said administered plurality of radiolabeled microspheres wherein said percent-delivered value comprises an accuracy standard deviation of less than five percent

38. The method of Claim 37, wherein said radiolabeled microspheres are Y-90 microspheres.

39. The method of Claim 37, wherein said tissue is a liver tissue.

40. The method of Claim 37, wherein said thyroid probe comprises an energy window having channels 0 -1023 KeV.

41. The method of Claim 37, further comprising the step of obtaining a pre-treatment

radioactivity measurement of said plurality of radiolabeled microspheres with said device.

42. The method of Claim 37, further comprising the step of obtaining a post-treatment radioactivity measurement of said plurality of radiolabeled microspheres with said device.

43. The method of Claim 37, wherein said radiation detector is a scintillation crystal based thyroid probe system.

44. The method of Claim 37, wherein said radiation detector comprises an energy

discriminator.

45. The method of Claim 37, wherein said radiation detector comprises multiple energy window.

46. The method of Claim 37, wherein said radiation detector comprises an ion chamber type detector.

47. The method of Claim 37, wherein said radiation detector comprises a solid state type detector.

48. The method of Claim 37, wherein said spacer is columnar.

49. The method of Claim 48, wherein said columnar spacer is a standardized placement apparatus for radiopharmaceutical calibration spacer.

50. The method of Claim 37, wherein said radiation source chamber further comprises a radiation source.

51. The method of Claim 37, wherein said spacer is a known length.

52. The device of Claim 1, wherein the diameter of said spacer ranges between

approximately 5 - 25 centimeters.

53. The device of Claim 1 , wherein the length of said spacer ranges between approximately 0.5 to 2 meters.

54. The method of Claim 37, wherein said radiation source is in a container that fits within said radiation source chamber.

55. The method of Claim 37, wherein said spacer comprises a material selected from the group consisting of plastic, plexiglas, glass, polyvinylchloride, cardboard and metal.

56. The method of Claim 37, wherein said distal end comprises a notch.

57. The method of Claim 37, wherein said distal end comprises a ridge.

58. The method of Claim 37, wherein said distal end comprises a net

59. A device, comprising a hollow spacer configured to be aligned between a radiation

source chamber and a radiation detector system, wherein said hollow spacer ensures that said radiation source chamber and said radiation detector system are separated by a replicable distance; and wherein said hollow spacer ensures that at least one radiation activity measurement of a radiation source by said radiation detector system correlates with the radiation strength of said radiation source.

60. A method, comprising:

a) providing:

i) a radionucleotide; and

a device, comprising:

A) a spacer having a proximal end and a distal end;

B) a radiation detector placed on said distal end; and

C) a radiation source chamber at said proximal end; and

b) obtaining a radioactivity measurement of said radionuclide with said device.

61. The method of Claim 60, where said radioactivity measurement is a first radioactivity measurement.

62. The method of Claim 60, wherein said radioactivity measurement is a second

radioactivity measurement 63. The method of Claim 60, wherein said radioactivity measurement is a first radioactivity measurement and a second radioactivity measurement 64. The method of Claim 63, wherein said method further comprises the step of calculating a percent value of said second radioactivity measurement to said first radioactivity measurement 65. The method of Claim 63, wherein said radionucleotide is attached to a pluarlity of

microspheres.