WO2000059571A2

WO2000059571A2 - Brachytherapy device and method

Info

Publication number: WO2000059571A2
Application number: PCT/US2000/009076
Authority: WO
Inventors: Malcolm D. Heaven
Original assignee: Imagyn Medical Technologies, Inc.
Priority date: 1999-04-06
Filing date: 2000-04-05
Publication date: 2000-10-12
Also published as: AU4797900A; WO2000059571A3

Abstract

This invention relates to the manufacture of small radioactive seeds used for implantation into tumors to eradicate cancerous cells, and used as an alternative to external radiation therapy such as electron beam irradiation. The seed is produced by inserting at least one image marker (20) and introducing X-124 into the capsule (12). The conversion of non-radioactive Xe-124 to radioactive I-125 occurs in the sealed capsule (12) after welding capsule end (18) and irradiating in a nuclear reactor. The activity of the seed is controlled by varying the pressure and/or the amount of neutron bombardement.

Description

BRACHYTHERAPY DEVICE AND METHOD

Background of the Invention This invention relates to the field of brachytherapy and the manufacture of small radioactive seeds. Brachytherapy involves the implantation of small radioactive seeds, or pellets into tumors to eradicate cancerous cells, and is an alternative to external radiation therapy such as electron beam irradiation.

Brachytherapy has been used in the treatment of numerous types of cancer, including cervical, breast, lung, head and neck, and prostate. As an example of the present invention, the treatment of prostate cancer will be described herein. This is in no way intended to limit the scope of this application, as the use of the invention disclosed herein has general application in the production of the radioactive pellets, or seeds for many other applications as will be apparent to those skilled in the art in view of the disclosure herein.

Treatment of prostate cancer using radioactive seed implantation has been known for some time. Currently either ¹⁰³Palladium or ¹²⁵lodine seeds are used, with apparent activities typically ranging from about 0.25 mcuries to about 1.2 mcuries, depending on the prostate size and aggressiveness of the cancer. Recent advances in ultrasound imaging and other technological advancements have enabled this procedure to become a very viable alternative to other treatments such as external beam irradiation and radical prostatectomy. The procedure involves ultrasound mapping of the prostate gland and size of tumor using a transrectal ultrasound probe. A radiation oncologist will then decide on the number and positioning of the radioactive seeds needed to deliver a sufficient amount of radiation to kill the cancerous cells. The requisite number of radioactive seeds are typically loaded into 18 gauge brachytherapy needles. Needles may contain anywhere from one to seven seeds, usually separated by bio-absorbable spacers of catgut or other suitable suture material. To prevent the seeds and/or the spacers from accidentally falling out of the needle, the distal end of the needle, the tip, is plugged with a small amount of bone-wax. Bone-wax is a medical grade beeswax material. The seeds are prevented from falling out of the proximal or hub end of the needle by a blunt obturator, which is ultimately used to force the seeds from the 18 gauge needle once in position in the prostate. The needles are inserted into the prostate transperineally. An alternative means of delivering the seeds utilizes a mechanical device coupled to a suitably sized needle.

The seeds are fed one at a time, the device being automatically withdrawn a pre-specif ied distance each time a seed is deposited, and further seeds being fed to the needle from a cartridge typically holding 10-15 seeds. Such devices are typified by the MICK Applicator, manufactured by Mick Radio Nuclear Instruments, Inc.

The current accepted processes for producing brachytherapy seeds based on ¹²⁵l have some serious limitations. Of the known ¹²⁵l seeds on the market, it is reasonable to assume that, at some point in their manufacture, the process involves handling ¹²⁵l or its compounds with the attendant risks associated with this highly toxic material. It is also fair to assume, looking at the seed constructions, that a laser or other suitable welding or closing process is used to close the tubular container or capsule once the ^,25l in one form or another has been inserted.

This process in itself has risks, in that it is difficult ensure that the container is welded closed without possibly vaporizing the ¹²⁵l or ¹²⁵l labeled compound contained therein. This leads to significant contamination of equipment, etc., with radioactive species. An additional problem associated with this possible outcome is disposal of the unsatisfactory seeds, plus, in the case of a minute flaw in the weld, potential contamination by leakage at a later stage.

It is also typical to deposit on, or react the isotope with, a suitable substrate such as a silver or other suitable high / material wire or sphere which allows for x-ray imaging of the implanted seeds. Subsequent loading of these coated substrates into the outer protective casing is a difficult task, and leads to further contamination of equipment and facilities. Current seeds available are typified by those manufactured by Theragenics Corporation and disclosed in U.S. Patent Nos. 4,784,116 and 5,405,309; Amersham, Inc. under U.S. Patent No. 4,323,055; Best Industries, Inc. under U.S. Patent No. 4,891,165; and Good, U.S. Patent No. 5,342,283, all of which are incorporated in their entireties herein by reference.

Another disadvantage of current processes is associated with obtaining the correct activity from seed-to- seed. Typically for prostate cancer seed apparent activity ranges between 0.25-1.0 mcuries per seed. (1 curie is equivalent to 3.7 x 10¹⁰ becquerels when using ISO units of measure). Activity is critical, as the delivered dose required to kill the cancerous cells needs to be calculated accurately. Slight variations in filling the container, variations in chemistry, etc., all contribute to variability in the apparent activity of the seed. The invention disclosed herein results in more precise control of seed activity.

Thus, notwithstanding the various efforts in the prior art, there remains a need for a method of producing radioactive seeds which minimizes the risk of escape of radioactive material, and improves control over seed-to-seed variations inactivity. Summary of the Invention

There is provided in accordance with one aspect of the present invention, a brachytherapy seed. The seed is produced by the process comprising the steps of loading a capsule with at least one imaging marker, and introducing ^mXe into the capsule. The capsule is sealed to enclose the ^{, 4}Xe therein, and thereafter irradiated with neutrons in a nuclear reactor to convert at least some of the ¹²⁴Xe into radioactive ¹²⁵l. In one embodiment, the capsule is formed by closing one end of a tubular body, prior to the loading step. The amount of ¹²⁴Xe in the capsule is preferably controlled by varying the pressure of the ^{1 4}Xe. The amount of radioactive ^,25l may be controlled by varying the extent of neutron bombardment, and/or the amount of ¹² Xe. In one embodiment the Xe is first adsorbed onto a carrier prior to the loading step. The carrier is preferably selected from the group consisting of zeolites, ion exchange resins, and molecular sieves. In accordance with another aspect of the present invention, there is provided a method of making a radiation source. The method comprises the steps of providing a container, and introducing a gas into the container. The gas is thereafter converted into a radioactive isotope.

In one embodiment, the providing a container step comprises providing a metal tube having at least one open end. The method preferably further comprises the step of sealing the open end after the introducing step and before the converting step. Preferably, the method further comprises the step of introducing at least one imaging marker into the container.

In one embodiment, the gas comprises ¹² Xe. The introducing step comprises introducing the gas under a pressure of at least about one atmosphere. The converting step preferably comprises exposing the gas to neutron bombardment, sufficient to produce a source having an activity within the range of from about 0.25 mcurries and about 2.5 mcurries.

The container generally has a length of from about 2 mm to about 20 mm, and, preferably, between about 4 mm and about 6 mm in a prostate cancer application. In one embodiment, the overall length of the capsule is about 4.5 mm. The container generally has a maximum outside cross section within the range of from about 0.2 mm to about 2.0 mm. Containers intended for use in treating prostate cancer generally have a maximum outside cross section within the range of from about 0.5 mm to about 1.5 mm and, in one specific embodiment of the invention, the outside diameter of the cylindrical container is about 0.8 mm.

Further features and advantages of the present invention will become apparent to those of ordinary skill in the art in view of the detailed description of preferred embodiments which follows, when considered together with the attached drawings and claims.

Brief Description of the Drawings

The novel features and advantages of the present invention will be more readily understood upon reading the detailed description taken in connection with the accompanying drawings in which:

Figure 1 is a cut-away view of a typical brachytherapy seed device in accordance with the present invention; Figures 2A, 2B, 2C, and 2D are a schematic of the seed preparation process;

Figures 3A and 3B are a schematic showing conversion of Xe via neutron bombardment; and

Figure 4 is a schematic showing an alternative embodiment of the invention.

Detailed Description of Preferred Embodiments

The invention is a novel ¹²⁵l based brachytherapy seed produced by a novel method which overcomes certain deficiencies of the existing processes. Additionally, the novel process results in an even coating of isotope not only on the substrate spheres or other imaging markers, but on the entire inner surface of the containment capsule resulting in a substantially uniform dose distribution. Uniform dose distribution is highly desirable as it simplifies the planning process for seed placement, and is also desirable to ensure a good therapeutic outcome.

While the invention is described using the example of radioactive seeds for use in brachytherapy, it is applicable to the production of a variety of small cylindrical shapes such as pins or needles, or other pre-sealed shapes such as spheres. This illustrative use of radioactive seeds is in no way meant to limit the invention, and other uses will become apparent to one skilled in the art in view of the disclosure herein.

Current prostate brachytherapy seeds generally utilize a titanium capsule, or container. This has the standardized dimensions of approximately 0.8 mm outer diameter, and an overall length of approximately 4.5 mm. Due to the welded ends generally being hemi-spherical or near hemi spherical solid welds, the internal length can be WO 00/59571 PCTYUSOO/09076

assumed to be approximately 4.2mm. The wall thickness is typically 2mil, making the internal diameter 0.7 mm. There is no particular significance to these dimensions, except that they have become the norm over time.

Although titanium outer casings are conventional, any bio-compatible material of low permeability which does not adversely attenuate the radiation and which can successfully contain the radioactive isotope can be utilized. Such materials as stainless steel or high strength engineering polymers such as, but not limited to, polyetheretherketones, polyphenylene oxide, or polyetherketone, for example, may be used. The use of bio-absorbable polymer materials may be particularly advantageous. The use of some such materials entail the use of alternate forming or closure methods such as injection molding, spin welding, heat sealing, solvent or adhesive bonding or other methods known to one skilled in the art. For simplicity of illustration, the conventional outer container of titanium will be used. In one aspect of the invention, the container is formed by first closing one end of titanium tubing such as by welding. Alternatively, a pre formed or deep drawn tube sealed at one end may be used. Then the container is loaded with whatever markers, supports or substrates may be desired to ensure visibility on x-ray or other imaging modalities, and the open end is closed such as by welding to form an enclosed capsule in a pure ¹²⁴Xenon atmosphere. When a deep drawn or pre-formed tube is used, the base of the closed tube is configured so that it matches closely the cross- section of the typical weld closure, so that dose distribution is even throughout the length of the seed. A fixed volume of ¹²⁴Xe at standard temperature and pressure (STP) is thus captured in the sealed capsule. ¹² Xe is the starting material for ^12SI. The whole operation to this point is carried out in any normal clean environment, without concerns regarding toxicity or radiation. Inspection of the sealed capsules can be carried out using any number of convenient test methods without having to take any special precautions. This allows for weld integrity to be verified with certainty before the conversion to radioactive ¹²⁵l, thus avoiding the various situations which can lead to contamination attendant with alternate methods of manufacture.

An alternative to operating in a pure atmosphere of xenon is to adsorb the xenon onto a suitable support or other substance such as an appropriate zeolite, ion exchange resin or molecular sieve, and load this along with whatever markers are used into the capsule. This offers a very precise method of controlling the volume of xenon captured.

The next step in the process is the neutron bombardment of the sealed capsules in which the following reaction occurs:

+ n

900 barns

13.0 days

Using regular sampling and assaying, the neutron bombardment is stopped at the appropriate time known in the art required to yield the desired activity. This is a major advantage over previous methods, where coating levels, process variables such as incident light, etc., lead to wide distributions in activity. Calculations show that there is sufficient Xe present at STP to yield more than the required ^{1 5}l in a brachytherapy seed of conventional size for use in prostate treatment. The invention makes it possible to increase the pressure and hence the amount of Xe available within the capsule, thus producing higher activity and longer storage life.

The following calculations illustrate an example of target seed apparent activity. This calculation uses the current standard configuration for a prostate implant seed. The x-ray imaging markers are microspheres of silver, tungsten, or some other suitable high / material. For this example they are 635 microns in diameter.

Calculation of Seed Apparent Activity

Volume of empty container - π 1 - π0.352*4.2 = 1.616559 cu.mm - 1.61656E-06 L. However, assuming that marker spheres are still required (for strength and crush resistance if nothing else) the available volume is less: Sphere diameter - 00.635 mm

Sphere volume - 4/3πr³ - 0.0001341 L

5 Spheres volume - 0.0006703 cc - 6.703E-07 L

Available container volume - 9.46E-07 L

From Avogadro's Law 1 mole of an ideal gas at STP occupies 22,414 ml. (At the conditions prevailing it can be assumed that the Xe acts as an ideal gas).

Avogadro also states that this same volume contains 6.022E+ 10²³ molecules. (Avogadro's Number, N„). Hence:

1 mole (124 g) of ¹²⁴Xe - 22.414 L - 6.022E+ 10²³ molecules

Volume of capsule - 9.46E-07 L Weight of Xe - 124*9.46E-07/22.414 - 5.234-06 g

Number of molecules ^» (6.022E + 23/124)* 5.234E-06 - 2.543E + 16

Activity calculation:

Using a typical target activity at T„ of 0.5 mCi, the following can now be calculated: The activity, A, can be calculated from the following: A - λN, where A is the activity in becquerel, λ is the decay constant and N is the number of nuclei present. Chosen activity, A - 0.5mCi. 1 Ci - 3.7E + 10 Bq, therefore 0.5 mCi - 1.85E+07 Bq. The decay constant, λ, can be calculated from the following formula: λ - 0.693/Ty.,, where Ty, is the half-life in seconds. Hence: λ - 0.693/59.4^*24^*3600 - 0.693/5132160 - 1.35E-07

The number of nuclei required to yield this activity can now be calculated as follows:

N - A/λ - 1.85E+07/1.35E-07 - 1.37E+ 14 nuclei.

These are now ¹²⁵l nuclei, and the weight of ¹²⁵l can be calculated as follows: 1 mole of ¹² l weights 125 grams, and also represents N₀, or 6.022E+23 molecules. Hence, 1.37E+ 14 nuclei weight:

125* (1.37E+ 14/6.022E+23) - 2.844E-08 grams.

Using the assumption that the difference between the atomic mass of the Xe and the I are insignificant for the purposes of this calculation, it can be seen that: 5.234E-06 grams of ¹²⁴Xe yielded 2.844E-08 grams of ¹²⁵l. This translates roughly to a conversion of

0.54%. Theoretically this means that a seed could be produced with an activity of approximately 92.6 mCi without using anything other than STP conditions.

Note, no account has been taken of the competing conversion of ¹²⁵l to ¹²⁶l, which would be present as a contaminant, as it is in all current methods of manufacture of ¹²⁵l. However, the short half like of ¹²⁶l of 13.11 days, versus 59.408 days for ¹²⁵l allows manufacturers to let the ¹²⁶l decay to acceptable levels before shipping. ¹²⁶l has an undesirable decay energy.

Referring now to the drawings, a brachytherapy seed 10 illustrative of the invention is shown. The brachytherapy seed 10 comprises a tubular body 12 defining a cavity 14 therein. The cavity 14 is enclosed by a first end 16 and a second end 18. The overall length, cross section, and volume of the seed 10 can be varied widely, depending upon the intended application of the brachytherapy device. In general, the device 10 will be configured for insertion into soft tissue, such as in the form of pins or seeds. The device 10 may be a self contained, independent device, as illustrated, or may be a portion of a larger device such as a distal portion of an elongate needle, useful for percutaneous or other insertion into a treatment site.

In preferred application of the invention, the seed 10 is configured for implantation with a prostate. In general, the seed 10 will have an axial length of from about 2 mm to about 20 mm, and, preferably, between about 4 mm and about 6 mm. In one embodiment, the seed 10 has an axial length of about 4.5 mm.

Preferably, the tubular body 12 is substantially cylindrical, although other noncircular cross sections may also be used. The maximum outside cross section or diameter through the seed 10 is generally within the range of from about 0.2 mm to about 2.0 mm. Preferably, in the context of brachytherapy seeds intended for prostate cancer treatment, the tubular body 12 has an outside diameter within the range of from about 0.5 mm to about 1.5 mm. In one specific embodiment, the outside diameter of the cylindrical body 12 is about 0.8 mm. Construction materials for the tubular body 12 have been discussed elsewhere herein.

A plurality of imaging markers 20 may be provided within the cavity 14. Imaging markers 20 comprise any of a variety of known materials which facilitate visualization of the device 10 using conventional visualization techniques. Thus, materials such as silver, tungsten or other high z elements may be used as will be understood by those of skill in the art. The imaging markers 20 may be in the form of spheres, as illustrated, or other shapes such as irregular shapes or powder, depending upon the desired surface area for attachment of an isotope coating 22. As has been discussed, isotope coating 22 is formed by the conversion of ¹² Xe into ^,25l upon neutron bombardment.

The device is produced by first sealing such as by welding a first end 16 of a section of titanium tubing to produce a container such as tubular body 12. Then the container is loaded with whatever markers 20 or substrates may be desired to ensure visibility on imaging modalities. An end weld 18 is made to close the capsule in a pure ¹²⁴Xe atmosphere, thus capturing ¹²⁴Xe inside the capsule. Finally, the sealed capsule is exposed to neutron bombardment in a nuclear reactor to convert the ¹² Xe into radioactive ¹²⁵l.

Thus, referring to Figures 2A through 2D, the tubular body 12 preferably having a closed end 16 thereon is loaded with a plurality of imaging markers 20 illustrated as spherical elements. Although the number of imaging markers can be varied widely, depending upon the volume of cavity 14 and size of the markers 20, anywhere from about 2 to about 20 spherical imaging markers are preferably utilized. In the illustrated embodiment, 6 spherical imaging markers 20 are used, each having a sphere volume of about 1.34 x 10⁴ liters.

The tubular body 12 having the imaging markers 20 therein is positioned within a chamber 24 defined by housing 26 for containing a gas environment. A source (not illustrated) of ¹² Xe gas 28 is placed in communication with the chamber 24 by way of an input port 30. In this manner, an environment of pure or substantially pure ^{1 4}Xe can be maintained in the chamber 24. The amount of ¹² Xe gas introduced into the cavity 14 can be varied as desired for a particular target activity, as well s to optimize other process parameters. In the previously described theoretical calculation, approximately 4.23 x 10 ^B moles ^,24Xe were introduced. Generally, it is believed that in excess of about 1 x 10⁸ moles, occasionally in excess of about 1 x 10⁷ moles, and in some embodiments in excess of about 1 x 10⁶ moles will be used, depending upon other process parameters. The chamber 24 may be placed under vacuum or otherwise flushed prior to the assembly procedure using techniques known in the art, to enhance the partial pressure of ¹²⁴Xe gas.

As a consequence of the open end 32 and interstitial spaces 34 between imaging markers 20, as well as the use of imaging markers 20 having a cross section which is less than the inside diameter of the chamber 14, ¹²⁴Xe gas is able to permeate throughout the interstitial spaces 34 between or among imaging markers 20. The amount of ¹²⁴Xe enclosed in the capsule can be controlled by varying the atmospheric pressure. Generally, pressures of at least about 1 ATM (e.g. STP), in some applications at least about 2 ATM and at least about 4 ATM up to as much as 10 ATM or more may be used in other applications, depending upon the desired initial activity and neutron activation parameters. Therefore, the final radioactivity of the device can be controlled. In addition, the amount of radioactive ¹²⁵l produced can be controlled by varying the amount of neutron bombardment. Flux rate and exposure time considerations are disclosed, for example, in the U.S. Patent No. 6,010,445, the disclosure of which is incorporated in its entirety herein by reference. WO 00/59571 PCTVUSOO/09076

The housing 26 is further provided with a laser window 36 for enabling a laser 38 to direct a beam of energy at the open end 32 of the tubular housing 12. In this manner, an end weld 18 may be formed to entrap the ¹²⁴Xe atmosphere within the chamber 14 of brachytherapy device 10.

In another embodiment of the invention the capsule is made of materials as stainless steel or high strength engineering polymers such as, but not limited to, polyetheretherketones, polyphenylene oxide, or polyetherketone, for example; and entail forming and closure methods such as injection molding, spin welding, heat sealing, solvent or adhesive bonding or other methods known to one skilled in the art.

In yet another embodiment of the invention the capsule is made of bioabsorbable polymer materials.

In another embodiment the container or capsule is pre-formed or pre-welded of a suitable material. The container may comprise a suitably radiopaque material or additive, or the container or capsule may be loaded with whatever markers or substrates are desired to ensure visibility on imaging modalities. The end is welded, or otherwise closed. The pre-formed end is formed such that it approximates in cross-section the final closed, opposite end to ensure uniform dose distribution.

In another embodiment of the invention the ¹²⁴Xe is first absorbed onto a suitable carrier 40 such as a zeolite, ion exchange resin, or molecular sieve, to the desired level before it is added to the capsule. See Figure 4.

Alternatively, the ¹²⁴Xe may be dissolved at high pressure into a suitable polymer based pre-form. This could be done in a continuous process wherein the gas is forced to dissolve under high pressure into a continuous filament of a suitable polymer, such as, for example, an EVA or a polyethylene. Alternatively, the polymer strands, which are of a suitable diameter to fit into the capsule formed by enclosing the tubular body 12 could be chopped into discrete pieces and fed into the titanium casing following impregnation of the fiber, this would give a convenient way of getting a volume of gas into the "seed" with minimal loss. The polymer bulk properties should be such that, on releasing the pressure used to force the gas to dissolve into the polymer, the polymer does not foam. The process could be done at room temperature, or may be advantageously carried out in the polymer melt with subsequent cooling prior to de- pressurization. It may also be advantageous to incorporate radiopaque markers into the polymer substrate. One possible approach could be to use a silver wire which has an extruded covering of the desired polymer on it. Alternatively the polymer could be extruded with microspheres or particles of the radiopaque marker buried in it. It could be further advantageous to inject the ^,2 Xe into the polymer melt during this process, thus accomplishing impregnation simultaneously. The coated wire, or microsphere construction, would be cooled rapidly prior to exiting the extrusion die in order to prevent foaming and loss of ¹² Xe.

Although exemplary embodiments of the invention have been shown and described, many changes, modifications and substitutions may be made by one having ordinary skill in the art without necessarily departing from the spirit and scope of this invention.

Claims

WHAT IS CLAIMED IS:

1. A brachytherapy seed device produced by the process comprising: loading a capsule with at least one imaging marker; introducing ¹²⁴Xe into the capsule; sealing the capsule to enclose the ¹² Xe therein; and irradiating the capsule with neutrons in a nuclear reactor to convert the ¹² Xe into radioactive ^{1 5}l.

2. A device produced by the process according to Claim 1, wherein the capsule is formed by welding one end of a tubular body closed.

3. A device produced by the process according to Claim 1, wherein the amount of ¹²⁴Xe in the capsule is controlled by varying the pressure.

4. A device produced by the process according to Claim 1, wherein the amount of radioactive ¹²⁵l in the capsule is controlled by varying the amount of neutron bombardment.

5. A device as in Claim 1, wherein the ¹²⁴Xe has been first adsorbed onto a carrier selected from the group consisting of zeolites, ion exchange resins, and molecular sieves, to a desired level before it is added to the capsule.

6. A device as in Claim 1, wherein the capsule comprises titanium.

7. A device as in Claim 1, wherein the capsule comprises stainless steel.

8. A device as in Claim 1, wherein the capsule comprises a polymer.

9. A device as in Claim 8, wherein the polymer is bio-absorbable.

10. A device as in Claim 1 , wherein the capsule comprises a pre-formed end.

11. A device as in Claim 10, wherein the pre-formed end is formed such that it approximates in cross- section to the final welded, or otherwise closed, opposite end.

12. A device as in Claim 1, wherein the capsule comprises a sealed tubular construction.

13. A device as in Claim 1 , wherein the capsule comprises a sealed spherical construction.

14. A device as in Claim 1, wherein the introducing step comprises introducing a polymer containing

¹²⁴Xe carried therein.

15. A device as in Claim 14, wherein the ¹²⁴Xe is dissolved into the polymer.

16. A method of making a radiation source, comprising the steps of: providing a container; introducing a gas into the container; and converting the gas into a radioactive isotope.

17. A method of making a radiation source as in Claim 16, wherein the providing a container step comprises providing a metal tube having at least one open end.

18. A method of making a radiation source as in Claim 17, further comprising the step of sealing the open end after the introducing step and before the converting step.

19. A method of making a radiation source as in Claim 16, further comprising the step of introducing at least one imaging marker into the container.

20. A method of making a radiation source as in Claim 16, wherein the gas comprises ^,24Xe .

21. A method of making a radiation source as in Claim 16, wherein the gas consists essentially of ¹²⁴Xe

22. A method of making a radiation source as in Claim 20, wherein the introducing step comprises introducing at least about 1x10⁸ moles of ¹²⁴Xe .

23. A method of making a radiation source as in Claim 20, wherein the introducing step comprises introducing ¹²⁴Xe under a pressure of at least about 1 ATM.

24. A method of making a radiation source as in Claim 16, wherein the container has a volume in the range of from about 1 x 10⁴ liters to about 1 x 10⁸ liters.

25. A method of making a radiation source as in Claim 16, wherein the container has a volume in the range of from about 1 x 10⁵ liters to about 1 x 10⁷ liters.

26. A method of making a radiation source as in Claim 16, wherein the converting step comprises exposing the gas to neutron bombardment.

27. A method of making a radiation source as in Claim 16, wherein the introducing and converting steps are accomplished to produce a source having an activity within the range of from about 0.25 mcuries and about 2.5 mcuries.

28. A method of making a radiation source as in Claim 16, wherein the container has a length within the range of from about 2 mm to about 20 mm.

29. A method of making a radiation source as in Claim 28, wherein the container has a length within the range of from about 4 mm to about 6 mm.

30. A method of making a radiation source as in Claim 28, wherein the container has a maximum outside cross section within the range of from about 0.2 mm to about 2.0 mm.

31. A method of making a radiation source as in Claim 28, wherein the container has a maximum outside cross section within the range of from about 0.5 mm to about 1.5 mm.

32. A method of making a radiation source as in Claim 16, wherein the introducing step comprising introducing a polymer containing the gas.

33. A method of making a radiation source as in Claim 32, wherein the polymer comprises a portion of a polymer strand.

34. A method of making a radiation source as in Claim 32, wherein the polymer further comprises a radiopaque marker.

35. A cold brachytherapy seed, for conversion into a radioactive source by neutron bombardment, comprising a container having a length of no greater than about 20 mm and a cross section of no greater than about 2 mm, and a gas in the container which is capable of conversion into a radioactive isotope upon exposure to a neutron source.

36. A cold brachytherapy seed as in Claim 35, wherein the gas comprises Xe.

37. A cold brachytherapy seed as in Claim 35, wherein the container has a length within the range of from about 4 mm to about 6 mm

38. A cold brachytherapy seed as in Claim 37, wherein the container has a cross section within the range of from about 0.2 mm to about 2 mm.

39. A cold brachytherapy seed as in Claim 35, further comprising at least one radiopaque marker.