CA2261338A1 - Encapsulated low-energy brachytherapy sources - Google Patents
Encapsulated low-energy brachytherapy sources Download PDFInfo
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- CA2261338A1 CA2261338A1 CA002261338A CA2261338A CA2261338A1 CA 2261338 A1 CA2261338 A1 CA 2261338A1 CA 002261338 A CA002261338 A CA 002261338A CA 2261338 A CA2261338 A CA 2261338A CA 2261338 A1 CA2261338 A1 CA 2261338A1
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- source
- annulus
- capsule
- tubes
- outer metal
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- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
- G21G4/00—Radioactive sources
- G21G4/04—Radioactive sources other than neutron sources
- G21G4/06—Radioactive sources other than neutron sources characterised by constructional features
- G21G4/08—Radioactive sources other than neutron sources characterised by constructional features specially adapted for medical application
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
- A61N5/1027—Interstitial radiation therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
- A61N5/1001—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy using radiation sources introduced into or applied onto the body; brachytherapy
- A61N2005/1019—Sources therefor
- A61N2005/1024—Seeds
Abstract
An essentially cylindrical, metal-encapsulated, brachytherapy source including an outer meter capsule, an annulus in a central interior position of said outer metal capsule, and a longitudinally extending heavy metal core in said annulus. The annulus is made of the same metal as said outer metal capsule.
One or more low-profile welds are formed around the central circumference of the outer metal capsule for attaching the outer metal capsule to the annulus and for sealing the outer metal capsule. A plurality of substrate particles each having bound thereto a radioisotope are positioned in the outer metal capsule so that the radioisotope is distributed symmetrically within the source, equally divided between the two ends of the source, and positioned with a strong bias towards the extremes of the two ends of the source.
One or more low-profile welds are formed around the central circumference of the outer metal capsule for attaching the outer metal capsule to the annulus and for sealing the outer metal capsule. A plurality of substrate particles each having bound thereto a radioisotope are positioned in the outer metal capsule so that the radioisotope is distributed symmetrically within the source, equally divided between the two ends of the source, and positioned with a strong bias towards the extremes of the two ends of the source.
Description
ENCAPSULATED hOW-ENERGY BRACHYTHERAPY SOURC$$
BACKGROUND OF THE INVENTION
The invention relates to brachytherapy, ~rhich is a specialty within tha medical field of radiati.en oncology, lore pa~rt~.eularly, it relates to the designs of the small radioactive sources used a,n intexstitial brachytherapy.
Such sources are surgically implanted, temporarily or permanently, in olosa proximity to diseased tissue about to undergo treatment by the radiation emissions from the sources.
Usually, a brt~ehythexapy procedure ~,nvo7.vea many sources impZa:nted thrvughovt the affected tissue mass. (Note: the prefix btetvhy fn the t,~rvrd brachythexapx is from the Greek word btachys, meaning close o~ short).
Interstitial brachytherapy sources may be of solid, uhi~Cary construction ahd entirely composed of bio-eampatible n~ater~.sle, ao or they may be composed of radioactive and other materials sealed inside bio-compatible capsules or coating, outwardly, they are usually metal cylinders with dimensions in the ranges:
1~ngth Z to S millimeters and diameter o.2 to 1 millimeters.
They rely for their effectiveness upon the photon radiations, i.e. X-rays and gamma-rays, emitted by certain radioiaotapes.
The amount o! radioactivity cvntainnd by each aaurce can vary from o.i to 100 millicuries (~nCi) but is usually in the range 0.5 to to xnillicuries.
Hr4chytherapy has boon practiced since early this century, start,ixrg shortly after the distcov~ry of radium by the curies .in 1898_ Many diE!~rant source types have been developed over the i~ntervenin~ years. These have been based upon radioisata~es wid~ly ranging in their half-lives and emission energies, and manufacturing processes have correspondingly varied. Over the last tear decades, most sources have been made by irradiating pre-Pormed, solid, unitary 'seeds" with neutrons in nuclear reactors.
(No~Ce: finished interstitial, brachytherapy sources ready fo=
implant ere often palled seeds, but here the word seed xs~ used in the sense of a preformed solid substrate Which is not yet ode radioaet~.ve to any degree, yr is in the process of being made fully radioactive for purpvsaa of making a f iniehed braChytherapy source). This simple and economical approach yields unencap~ulated radioactive sources in batch sizes oh the order og a0,000 units ready !or use without further procoap~,~ng. The most prevalent of this type have been iridium-192 eouxces, which are made from iridium-plati.z~um alloy seeds. These are generally employed as temporary implants. Although somet~hat in decline because the erlergiee of their emissions are now consider~ad to be higher than desirable for many applications, iridium-19z sources are still used in the largest numbers in interstitial brachythexapy_ Within the last ten yoars, other trends nave become clear~,y apparent. There are 9txong preEerencee developing in Iavox of -z-po~rsnont implant sources and radioisotopes emitting onXy low-energy photon radiations and having half-lives in the to tv 100 day range. x'ho main reasons for the change in outlook are= a) permanent implants involve only a singlQ surgical procedure and result In lower hospital costs because of short patient atay9 with no delays or returns tar implant removals; b) low photon energies mean less penetrating power, leading to legs radiation exposure of healthy tissue surrounding the diseased tissue region, ae well as greatly reduced Cumulative radiation doses to hospital per~onnel; and c) halt-lives in the 10 to 100 day range allow the right amount of radiation to De delivered at a rats close to optimum with respect to therapoutic effect.
The two rosin low-energy sources in camfierrial supply, and now dominating the overall brachyth~rapy source market in monetbry terms) are encapsulated types with radioactive contents sealed inside welded titanium capsules. one type is based on the radioisotope palladium-1o3 (half-life 17 days) and the other on iodine-125 (half-life 60 days). Of a11 radioisotopes, these two appear to be by far the most suited for interstitial brachytherapy applications and are not likely to be easily supplanted. Although these source types do possess the virtues delineated for low-energy sources in the preceding paragraph, both are far from ideal in other important respects: a) both are much more expensive and physically larger than the sources being displaced; b) the encapsulation material strongly attenuates the low-energy radiation output; and c) because they are essentially -3~
quasi line sources (as opposed to theoretical line sources which have length but no thickness) and their emissions are of low-energy, their radiation output distributions are anisotropic (i.e. lacking in equality in a11 directions) and this negatively effects trea'~nt planning and outcome. These deficiencies stem largely from their designs and manufacturing methods.
The secjuestering and encapsulation of radioactive materials in small contains=s for brachytherapy purposes are described in U.S. Patsnt Nos. l,753,287; 3,351,049; 4,323,055; 4,702, r 8;
4,891,165; 4,994,o13; 5,342,283; and 5,405,309, which patents are incorporated herein by reference. with the exception of U.9, P4te~t Nv. 1,753,Z87, these descriptions taken together ou~mariae the technologies developed to date or formally envisioned for the co~ereial, large scale production of low-enexgx bxaehyth~repy eourc~e based o» palladium-103 and fodine~125.
With regar4 to the yore prevalent low~enexgy brachytherapy souroe types, the structures and degrees of anieatropy are indicated in Chapter 1 of the textbook 'Interstitial Braohytherapy ~ Physical, Biological and clinical Considerations", Interstitial Collaborative Working Group, Raven Press, New Yark (i990), 2SHN 0-8816r581-4. This textbook is iDeorporated herein by reference. The output radiation fluxes a=o shown to fall away steeply at the end~ of the sources, caused by abeorptio» of the loo~energy photon radintions within the sources themselves. l~uc~ cf this effect stems from a feature of all real line sources. Descriptively, this feature is the longer average path through the substrate and/or anoapeulaticn materials that must be traveled by the radiation directed tow$rds the ends of real line sources_ In thn eases of currently available encapsulated low-energy brachythsrapy sou=ces, the problem is exacerbated by the fact that the sources are welded at the ends, thereby thickening the capsule walls at these locativna.
It should be noted that anisotropy of radiation output is generally not a problem as Far as treating tissue lying very close to a low-energy brachytherapy source is concerned. At sAort distances from the source in any direction, ~ay less than one source le»gth, suZfieient radiation dose is delivered regardl~es of anisotropy. However, the radiation flux diminishes guiekZy pith diata~co from a couxae and anisotropy becomes aw important factor furthex out from an impZsnted source whore the radiation dose delivered is calculated to be dust adequatt !or that source to play its pact in killing the treated tissue mass.
The problem ig further complicated when there are large uncertainties in planned treatment parameters caused bx variations in the degree of anisotropy between individual sources a0 and uncertainties in the orientation of individual sources within an array o~ sources.
The probleat of anisotropy and the contribution to it by end Welds and ether sorts of seals was appreciated by the patentees of U.S. patent Noe. 3,3A,049 and 4,323,o55 in relation to iodine~lZ5 souroee. These related disclosures envisioned cylindrical metal capsules having clvaed, rounded ends, with the _g_ valla at the' ends being B~nooth and syauaQtric and Having a thickhQSa similar to the aide walls. However, this idealized constsuction was never xealized in rvutinQ practice, the ands of the production souxces being simply scaled by thick bead welds.
Some progress in the area was described in U.S. Patent Nve 4,702,ZZ8 arid 5,405,3o9 rgspe,ctively in relation to palladium~io3 sources. These related disclosures propose the use of metal tube Gt~psules with laser weJ.ded end caps, the tube gall and end oap thieknesses being similar. As well as having thin walled welded la end caps, the radioactivity distribution is not uniform along the length) but is somewhat biased toward$ the ends, which Should also promote isotropy at the ends. Hut again, good isotropy 1s not evident in these sources. Another capsule designed with improved aourco isotropy in mind is described it U.S. Patent No.
d,891,165. Tk~is disclosure describes cylindrical metal capsules formed by press fitting together tWO, three or four tightly inter-fitting sleeves, each with one end open and one end cloaad, to yield finished capsules with laminated walls of essentially uniform thickness a11 around. As disclosed, the capsules wera~
20 designed to have flat closed ends and to be optiv~tally sealed by an adhswivs or by welding. In practice, two slooves are used and the design has beer modified to have rounded ends. The capsule is used with an intexnal iodine-125 substrate that dimtributes the radioactivity uniformly along the lengtlx of the source as described in U.S. Patent No. 4,994,a1.3. The modified design is a means of achievi~r~g an essentially cylindrical capsule that has uniform wall tbick~nees all around and to have rounded, smooth, ay~etrsc, closed ends as originally disclosed in U.S.
Patent No. 3,351,049. Tn practice, the capsule of U_S. Patent 4,891,16g is sealed by performing a cixcumferenCial weld close to one end where the rl~a of the formerly open ee~a of the outer cylinder rQ~cts against the side wall of the inner cylinder. A
study repented in Medical Physics, Vol. 19, No. 4) pp. 92?-931 (1992), incorporated herein by reference, iridioat~~ that a significant improvement in Isotropy is gained by meeans o! this technology, although it is not clear whether welded or non-ve~.dsd oapeulea pexe used in the study. There are perceived problem4 with this technology, however. 8acaue4 of th~ lack ef a heat ~ink behind the vexa area, there is a high potential for ~everely ~reakening or even perforating the capsule wall in perlori4lng the circumferential weld. Another perceived problem due to the lack of a heat ~ink behind the weld area, is the heating of the internal radioactive esubatrates, resulting in releases of volatil~ radioactive iodine and blow-outs during gelding before the seal ~,s complete. Yet another perceived problom isr that the geld is near one and of the source, re~aul,ti»g in some coritri,butlon to source anisotropy because o! attenuation of the lour-en~rgy radiation.
gUl9~ARY OF THE INVENTION
The present invention provides two new dee~igne !or radioactive sources which are meant primarily for implantation within the human body xor puxposes of brachytherapy_ The invention addresses the anisotropy problems associated With encapsulated, generally cylindrical, low-energy sources. The nsw de~igns allow for a highex degree of isotropy of radiation output to be attained relative tv similar sources currently co~nm~~rcially available. This is achieved by pvgitioning the spherical substrate beads carrying the radioactive material close to the thin Walled, rounded ends of a source; and by sealing the source with a weld around the cdntxal circumference.
In accordance with a broad aspect of the invention, there is provided an essentially cylindrical, metal~encapsulated, brachytherapy source comprising an outer metal Capsule, an annulus in a central interior position of the outer metal capsule, and a longitudinally extending heavy metal core in the annulus. The annulus is made of the same metal as the outer metal capsule. ~edns including one or more low-profile welds are provided around the central circumference of the outer metal capsule for attaching the outer metal capsule tv the annulus and for sealing the outer metal capsule. A plurality of substrate particles each having bound thereto a xadxoiavtvpe are positioned in the outer metal capsule so that the radioisotope 18 distributed sy~ometrically within the source, edually divided between the two ends of the source, and positioned With a strong bias towards the extremes of the two ends of the sourco_ Also, the length of the metal core is determined by the Shape, ~ize and number of substrate particles at each end of the source.
_g_ In accordance with another broad aspect of the invantiott, the;e is provided a Foetal-encapsulated brachythsrapy gourte comprising an elongated plug having an es$entially cylindrical portion dmfining an elongated axis; an outer metal capsule including two metal end-tubes aligl~~: along the longitudinal axis with each one d~ the end-tubes h~rvingr ohe closed end facing outwardly of tt~e source and one open end tightly fitted on they plugr and facing ir~vardly. Each one of the erd~tubee are Welded to the plug r~ith a space betweQn the closed ehd thereof and a so respective end of the plug. Also, at least one substrate including at least one Xadioi.rsotope ~,s in the space in each one of the end~tuboe.
Zn accordance with a specific aspect of the invention, the plug comprises an elongated annulus and s heavy metal core within the annulus. Also, the annulus ie made of the same metal as the outer metal capsule.
In accordance With another specific aspect of the invention, there is a plurality of substrate particles in reach ore of the apa~cee in the end-tubes with the sadi.oactivity intensity 20 dacr~aaeing from the outer end to the inner end of each apace. In one embodiment. there are two cubgtrato partielas in oaclx one of the spaces in the end-tub~s with the radioactivity of the outer substrate particle being twice the rxdieactivi.ty et tt~e in»er substrate particle.
A broad object of the invention is to provide safe, effective, cylindrically encapsulated, low-energy brachytherapy sources with improved isotropy of radiation output relative to currently available sources of the same general type.
A specific objective of the invention im to address an~.sotropy by strongly bia9ing the position of the radioeotive components tovarde the ands of the sources, thereby compensating for the radiation attenuation that takes placo in the capsule galls o! currently available sources.
Another spac~,fic objective of the invention is to prov~.de batter symmetry of radiation output, and better reliability of 1o ca8aule integrity. by providing a better situation for the sealing weld of the source capsules relative to other source designs.
aRIBp D~scRZ~zorr o~ THE DRAt~ZNGs FI6_ 1 shove an unwvlded source capsule assembled without contmnts.
FIG. 2 shows detail of the Weld region of the cap~vl~ of FIG) I.
FIG. 3 shows a welded source containing four radioactive 20 substrate beads.
FZG. 4 a~hows a welded source containing two radioactive substrate heeds.
DLSCRIPTIOIJ' 0~' THE PR~~'I~tRFD EMBODTMENZ'$
In a pra~erred embodiment, the capsule materials are tita~niu~a and plat~.nu~n-iridium alloy metals, the substrateB
holding the~radioactive material are spherical beads composed of a zeolite with a binder, and the radioisotope is either palladium-1o3 or iodine~la5.
FIG. 1 shows the assembled but unWelded components o! the ~~tal capsule. The capsule is composed of three parts: two identical titanium end-tubeB 11 with one open end and one cloned rounded end; end one cylindrical, annular titanium plug 1z with a concentric platinum-iridium alloy core 13, onto each end o! which the and-tubes ere press fitted, The annular titanium plug has a central circumferential ridge 14 with a low profile. The ridge serves as a stop and as an alignment axd in the attachment of the and-tubes, aid provides extra titanium at the weld locatian_ FIG. 2 ie a magnified view of the weld region o! the source showing th~ end-tuba walls 21 butted against the ridge Z2 of the annular plug ~3.
FI6. 3 shows a welded source with four zeolfte bead substrates 31. The radioactive ingredient is syanmetrically distributed within the source and is firmly attached to the zeolite beads by chemical Dvnding or physical entrapment. A
single Circuyuterential weld 3Z is performed to secure the end tubes to the a~ulud and to each other, and to hermetically seal the finished source.
FIG. 4 shows a souxce with two zeolite bead substrates 4Z.
The 8lntinum-iridium alloy core 4z length is chosen to limit the free space av$ilabla for the movement eP the zeolite beads within the capsule, depending on wh~ther two or four zsolite beads per -11~
source are used.
TAe titanium annulus i2,23 provides good backing for the weld and thus helps in avoiding Capsule wall perforation in the welding process. The titanium annulus 12,a3 and platinum-iridium alloy core 13,42 together have sufficient bulk to provide a heat einx to curb the temperature excursion experienced by the radioactive compnnehte during source welding. Thus, the probability of volatilizatien and blow-out of certain radioisotopes, such as iodine-125, is reduced. 'fhe location of 1o the Weld 32 mihimires the effect of the weld on sy~nnotry and uniformity of radiation output caused by photon absorption in the weld bead. The heavy platinum~irxdium alloy core 13,42 of the annulus acts as a linear X-ray marker for detection of the source and determination of its orientation from outside the body after implantation. 'fhe uniform Wall thickness of the capsule and the close fit of the spherical bead substrates 31,41 in the end tubes promote symxaetry end stability respectively of the radiation output, xhe heavy poBitional bias of the radioaet~vlty towards the ends of the capsule promotes good isotropy relative similax 2o sources by compensating for attenuation of radiation in the capsule vall_ The option of four substrate beads as opposed to tWO alloys an increase in source strength. Thin option also aliovg for adjustments in the degree of radiation isotropy by changing the ratio of the amount of radioactivity on the inner pair of beads versus the amount on th,e outer pair.
In the matter of dimensions, the sources of FIGS_ 3 and 4 may vary in length between 3 and 7,0 millimeters and in dia~roster between 0. 5 and 7.. S millimeters. The uniform ~ra7,X thickness of the etld tubos~ may very between 0.02 and 0.2 millimQtera. The dimensions of the other compvnsnts are made to a close fit, Generally, the diameter of the spherical substrates may vary between 0.3 and 1.3 millimeters.
z~oi~ites era a olass of crystalline molecular aie~re~ that occur naturally or can be synthesized in powder form. They are thermally ~stabi.a ihoxganic compounds that have an open s,lumino-silicate frame~rdrk that allows them to host other chemical species ~rithin their strueture~r. Their re~.evant properties include. good heat and xadia~tion resistance; catian exchange capacities comparable with organic resins; good capacities For the a;deorption and retention of various radioactive iodine species; lour density and average atomic number of elemental constituents meaning low attenuation of low-energy photons; and with a binder can be formed into durable pellets or spherieal beads 1n appropriate sixes. For comprehensive information on zsail.tas and their applications, the reader is refexxed to the textboox 'Zeolite Molecular Sieves' by Donald W. Hrack, John Wiley arid Sons Ins., New York (1974y, which textbook is ~.ncorporated herein by reference.
PROPHETIC EXAMPLE
It is intended to produc~ on~ hundred titanium-encapsulated interstitial brachytherapy sources each cortait~ing six t~illicuriem ~af palladium-10~ xadioact~,v~,ty. The palladium-103 in each source is to be divided between tour zeolite bead substrates di,atxibuted as follows: two millicuries on esoh outer bead arid on~ 1ni11icurie on each itaner bead. The sources are to have dimensions as follows: length 4.5 millimeters; diameter 0.8 Millimeters, and end-tube wall thickness o.05 millimeters.
1~ large batch of 4A type zeolite beads having bead diameters of 0.65 mil~.imeters is previously acquired_ Trarge batches of each of the capsule parts are acquired in the following to dimensions: end-tube, i.2 millimeters in length, 0.8 millitnetarg in outer diaiaeter, 0.05 millimeters in Wall thickness; arrd titaniumjplatinum-iridium alloy annular plugs, 1.'7 ~ailli~eeters irs length, 0.7 teill~.~neter~a in body diameter, core diameter 0.3 millimeters, ridge diameter 0.~5 millimeters, ahd ridge width O.L
millimeters. The annular plugs are sized to fit shugly info the end tubes so that when press fitted the tvo pieces do nvt easily part.
A sub-batch of at least two hundred of the 4A zeolite beads ie suitably inmtersed in and Mixed with rrn aquQOUS solution of 20 palladium-103 in ammonium hydroxide at a pH of l0.5 eo as to evmnly load 2 milliCUries of palladium-103 onto each bead. The beads are then separated from the solution and thoroughly dried in a drying oven, first at 1Z0 degrees Celsius for 1 hour and then tit 350 degrees Celsius for 1 hour. Another sub--batch of at least tWO hundred of the zeolite beads is taken and similarly treated so as to yield dry zeolite beads each loaded with 1 millicurie of palladiummo3.
A zeolite bead loaded with 2 millicuries of palladium-lo3 ie dispensed into each of two hundred titanium end~tubes held in a vertical orientation with the open ends uppermost. xhen a zeolite bead leaded with 1 millicurie of palladium-1p3 is dispensed into each of the same two hundred end-tubes, so that a 1 millicuxie bead rests on top of each 2 m111icurie bead. A titanium annular plug pith a platinum-iridium alloy core is then preened finely into each of the open ends of one hundred of the end-tubes into which the zeolite beads have been dispensed. The pressure usmd ie just sufficient to ensure that the perimeter o! the previously open end of the end-tube rests squarely against the ridge stop vn the annular plug. The one-hundred plugged arid~tubes and they inverted and each is pressed, protruding annular plug first, into one of the remaining one hundred unplugged end-tubes. Each of the one hundred assembled sources is then laser welded under argon atmosph~re to provide a hermetic seal around the circuiaf~rence where the previously open ends of the two end-tub~s and the ridge of the annular plug meet. Ttxs sources are then 2v ready for surtace cleaning, inspection and testing before shipment to medical centers.
Other bio-compgtible materials, such as stainless steal. are useable as material for the construction of the sou=ce capsule.
Other heavy metals) such as gold, silver) to»talum, tungsten ahd the six platfnum eleaments, and alloys of thsvn elements are useable in place or platinum-iridium ahoy as the X~ray marker -~5-matarial_ Other ~oaterials such as carbon, charcoal and ivn~
exchange resino in spherical bead or other particulate form are useable as subotxate ~aatexial for the radioisotope. Other radioisotopes such as cesium-171, samarium~145, terbium-16l and thulium-1,70 are useable.
Variations in design might be advanced to achia~'e the central circumferential weld and a similar distribution of radioactivity ~rithin a similarly shaped source. The invention oonteieplates and encompasses a11 such variations.
i0 Although the invention has bean describ~d in conjunction with specific embodiments, it is evident that many alternatives and variations Will be apparent to those skilled in the art in light of the roragoing description. Accordingly) the invention i.B intended to embrace a11 of the alternatives and variationB
that tall within the spirit and scope of the appended claims.
The above references are hereby incorporated by rgfgrgnce.
-zs-
BACKGROUND OF THE INVENTION
The invention relates to brachytherapy, ~rhich is a specialty within tha medical field of radiati.en oncology, lore pa~rt~.eularly, it relates to the designs of the small radioactive sources used a,n intexstitial brachytherapy.
Such sources are surgically implanted, temporarily or permanently, in olosa proximity to diseased tissue about to undergo treatment by the radiation emissions from the sources.
Usually, a brt~ehythexapy procedure ~,nvo7.vea many sources impZa:nted thrvughovt the affected tissue mass. (Note: the prefix btetvhy fn the t,~rvrd brachythexapx is from the Greek word btachys, meaning close o~ short).
Interstitial brachytherapy sources may be of solid, uhi~Cary construction ahd entirely composed of bio-eampatible n~ater~.sle, ao or they may be composed of radioactive and other materials sealed inside bio-compatible capsules or coating, outwardly, they are usually metal cylinders with dimensions in the ranges:
1~ngth Z to S millimeters and diameter o.2 to 1 millimeters.
They rely for their effectiveness upon the photon radiations, i.e. X-rays and gamma-rays, emitted by certain radioiaotapes.
The amount o! radioactivity cvntainnd by each aaurce can vary from o.i to 100 millicuries (~nCi) but is usually in the range 0.5 to to xnillicuries.
Hr4chytherapy has boon practiced since early this century, start,ixrg shortly after the distcov~ry of radium by the curies .in 1898_ Many diE!~rant source types have been developed over the i~ntervenin~ years. These have been based upon radioisata~es wid~ly ranging in their half-lives and emission energies, and manufacturing processes have correspondingly varied. Over the last tear decades, most sources have been made by irradiating pre-Pormed, solid, unitary 'seeds" with neutrons in nuclear reactors.
(No~Ce: finished interstitial, brachytherapy sources ready fo=
implant ere often palled seeds, but here the word seed xs~ used in the sense of a preformed solid substrate Which is not yet ode radioaet~.ve to any degree, yr is in the process of being made fully radioactive for purpvsaa of making a f iniehed braChytherapy source). This simple and economical approach yields unencap~ulated radioactive sources in batch sizes oh the order og a0,000 units ready !or use without further procoap~,~ng. The most prevalent of this type have been iridium-192 eouxces, which are made from iridium-plati.z~um alloy seeds. These are generally employed as temporary implants. Although somet~hat in decline because the erlergiee of their emissions are now consider~ad to be higher than desirable for many applications, iridium-19z sources are still used in the largest numbers in interstitial brachythexapy_ Within the last ten yoars, other trends nave become clear~,y apparent. There are 9txong preEerencee developing in Iavox of -z-po~rsnont implant sources and radioisotopes emitting onXy low-energy photon radiations and having half-lives in the to tv 100 day range. x'ho main reasons for the change in outlook are= a) permanent implants involve only a singlQ surgical procedure and result In lower hospital costs because of short patient atay9 with no delays or returns tar implant removals; b) low photon energies mean less penetrating power, leading to legs radiation exposure of healthy tissue surrounding the diseased tissue region, ae well as greatly reduced Cumulative radiation doses to hospital per~onnel; and c) halt-lives in the 10 to 100 day range allow the right amount of radiation to De delivered at a rats close to optimum with respect to therapoutic effect.
The two rosin low-energy sources in camfierrial supply, and now dominating the overall brachyth~rapy source market in monetbry terms) are encapsulated types with radioactive contents sealed inside welded titanium capsules. one type is based on the radioisotope palladium-1o3 (half-life 17 days) and the other on iodine-125 (half-life 60 days). Of a11 radioisotopes, these two appear to be by far the most suited for interstitial brachytherapy applications and are not likely to be easily supplanted. Although these source types do possess the virtues delineated for low-energy sources in the preceding paragraph, both are far from ideal in other important respects: a) both are much more expensive and physically larger than the sources being displaced; b) the encapsulation material strongly attenuates the low-energy radiation output; and c) because they are essentially -3~
quasi line sources (as opposed to theoretical line sources which have length but no thickness) and their emissions are of low-energy, their radiation output distributions are anisotropic (i.e. lacking in equality in a11 directions) and this negatively effects trea'~nt planning and outcome. These deficiencies stem largely from their designs and manufacturing methods.
The secjuestering and encapsulation of radioactive materials in small contains=s for brachytherapy purposes are described in U.S. Patsnt Nos. l,753,287; 3,351,049; 4,323,055; 4,702, r 8;
4,891,165; 4,994,o13; 5,342,283; and 5,405,309, which patents are incorporated herein by reference. with the exception of U.9, P4te~t Nv. 1,753,Z87, these descriptions taken together ou~mariae the technologies developed to date or formally envisioned for the co~ereial, large scale production of low-enexgx bxaehyth~repy eourc~e based o» palladium-103 and fodine~125.
With regar4 to the yore prevalent low~enexgy brachytherapy souroe types, the structures and degrees of anieatropy are indicated in Chapter 1 of the textbook 'Interstitial Braohytherapy ~ Physical, Biological and clinical Considerations", Interstitial Collaborative Working Group, Raven Press, New Yark (i990), 2SHN 0-8816r581-4. This textbook is iDeorporated herein by reference. The output radiation fluxes a=o shown to fall away steeply at the end~ of the sources, caused by abeorptio» of the loo~energy photon radintions within the sources themselves. l~uc~ cf this effect stems from a feature of all real line sources. Descriptively, this feature is the longer average path through the substrate and/or anoapeulaticn materials that must be traveled by the radiation directed tow$rds the ends of real line sources_ In thn eases of currently available encapsulated low-energy brachythsrapy sou=ces, the problem is exacerbated by the fact that the sources are welded at the ends, thereby thickening the capsule walls at these locativna.
It should be noted that anisotropy of radiation output is generally not a problem as Far as treating tissue lying very close to a low-energy brachytherapy source is concerned. At sAort distances from the source in any direction, ~ay less than one source le»gth, suZfieient radiation dose is delivered regardl~es of anisotropy. However, the radiation flux diminishes guiekZy pith diata~co from a couxae and anisotropy becomes aw important factor furthex out from an impZsnted source whore the radiation dose delivered is calculated to be dust adequatt !or that source to play its pact in killing the treated tissue mass.
The problem ig further complicated when there are large uncertainties in planned treatment parameters caused bx variations in the degree of anisotropy between individual sources a0 and uncertainties in the orientation of individual sources within an array o~ sources.
The probleat of anisotropy and the contribution to it by end Welds and ether sorts of seals was appreciated by the patentees of U.S. patent Noe. 3,3A,049 and 4,323,o55 in relation to iodine~lZ5 souroee. These related disclosures envisioned cylindrical metal capsules having clvaed, rounded ends, with the _g_ valla at the' ends being B~nooth and syauaQtric and Having a thickhQSa similar to the aide walls. However, this idealized constsuction was never xealized in rvutinQ practice, the ands of the production souxces being simply scaled by thick bead welds.
Some progress in the area was described in U.S. Patent Nve 4,702,ZZ8 arid 5,405,3o9 rgspe,ctively in relation to palladium~io3 sources. These related disclosures propose the use of metal tube Gt~psules with laser weJ.ded end caps, the tube gall and end oap thieknesses being similar. As well as having thin walled welded la end caps, the radioactivity distribution is not uniform along the length) but is somewhat biased toward$ the ends, which Should also promote isotropy at the ends. Hut again, good isotropy 1s not evident in these sources. Another capsule designed with improved aourco isotropy in mind is described it U.S. Patent No.
d,891,165. Tk~is disclosure describes cylindrical metal capsules formed by press fitting together tWO, three or four tightly inter-fitting sleeves, each with one end open and one end cloaad, to yield finished capsules with laminated walls of essentially uniform thickness a11 around. As disclosed, the capsules wera~
20 designed to have flat closed ends and to be optiv~tally sealed by an adhswivs or by welding. In practice, two slooves are used and the design has beer modified to have rounded ends. The capsule is used with an intexnal iodine-125 substrate that dimtributes the radioactivity uniformly along the lengtlx of the source as described in U.S. Patent No. 4,994,a1.3. The modified design is a means of achievi~r~g an essentially cylindrical capsule that has uniform wall tbick~nees all around and to have rounded, smooth, ay~etrsc, closed ends as originally disclosed in U.S.
Patent No. 3,351,049. Tn practice, the capsule of U_S. Patent 4,891,16g is sealed by performing a cixcumferenCial weld close to one end where the rl~a of the formerly open ee~a of the outer cylinder rQ~cts against the side wall of the inner cylinder. A
study repented in Medical Physics, Vol. 19, No. 4) pp. 92?-931 (1992), incorporated herein by reference, iridioat~~ that a significant improvement in Isotropy is gained by meeans o! this technology, although it is not clear whether welded or non-ve~.dsd oapeulea pexe used in the study. There are perceived problem4 with this technology, however. 8acaue4 of th~ lack ef a heat ~ink behind the vexa area, there is a high potential for ~everely ~reakening or even perforating the capsule wall in perlori4lng the circumferential weld. Another perceived problem due to the lack of a heat ~ink behind the weld area, is the heating of the internal radioactive esubatrates, resulting in releases of volatil~ radioactive iodine and blow-outs during gelding before the seal ~,s complete. Yet another perceived problom isr that the geld is near one and of the source, re~aul,ti»g in some coritri,butlon to source anisotropy because o! attenuation of the lour-en~rgy radiation.
gUl9~ARY OF THE INVENTION
The present invention provides two new dee~igne !or radioactive sources which are meant primarily for implantation within the human body xor puxposes of brachytherapy_ The invention addresses the anisotropy problems associated With encapsulated, generally cylindrical, low-energy sources. The nsw de~igns allow for a highex degree of isotropy of radiation output to be attained relative tv similar sources currently co~nm~~rcially available. This is achieved by pvgitioning the spherical substrate beads carrying the radioactive material close to the thin Walled, rounded ends of a source; and by sealing the source with a weld around the cdntxal circumference.
In accordance with a broad aspect of the invention, there is provided an essentially cylindrical, metal~encapsulated, brachytherapy source comprising an outer metal Capsule, an annulus in a central interior position of the outer metal capsule, and a longitudinally extending heavy metal core in the annulus. The annulus is made of the same metal as the outer metal capsule. ~edns including one or more low-profile welds are provided around the central circumference of the outer metal capsule for attaching the outer metal capsule tv the annulus and for sealing the outer metal capsule. A plurality of substrate particles each having bound thereto a xadxoiavtvpe are positioned in the outer metal capsule so that the radioisotope 18 distributed sy~ometrically within the source, edually divided between the two ends of the source, and positioned With a strong bias towards the extremes of the two ends of the sourco_ Also, the length of the metal core is determined by the Shape, ~ize and number of substrate particles at each end of the source.
_g_ In accordance with another broad aspect of the invantiott, the;e is provided a Foetal-encapsulated brachythsrapy gourte comprising an elongated plug having an es$entially cylindrical portion dmfining an elongated axis; an outer metal capsule including two metal end-tubes aligl~~: along the longitudinal axis with each one d~ the end-tubes h~rvingr ohe closed end facing outwardly of tt~e source and one open end tightly fitted on they plugr and facing ir~vardly. Each one of the erd~tubee are Welded to the plug r~ith a space betweQn the closed ehd thereof and a so respective end of the plug. Also, at least one substrate including at least one Xadioi.rsotope ~,s in the space in each one of the end~tuboe.
Zn accordance with a specific aspect of the invention, the plug comprises an elongated annulus and s heavy metal core within the annulus. Also, the annulus ie made of the same metal as the outer metal capsule.
In accordance With another specific aspect of the invention, there is a plurality of substrate particles in reach ore of the apa~cee in the end-tubes with the sadi.oactivity intensity 20 dacr~aaeing from the outer end to the inner end of each apace. In one embodiment. there are two cubgtrato partielas in oaclx one of the spaces in the end-tub~s with the radioactivity of the outer substrate particle being twice the rxdieactivi.ty et tt~e in»er substrate particle.
A broad object of the invention is to provide safe, effective, cylindrically encapsulated, low-energy brachytherapy sources with improved isotropy of radiation output relative to currently available sources of the same general type.
A specific objective of the invention im to address an~.sotropy by strongly bia9ing the position of the radioeotive components tovarde the ands of the sources, thereby compensating for the radiation attenuation that takes placo in the capsule galls o! currently available sources.
Another spac~,fic objective of the invention is to prov~.de batter symmetry of radiation output, and better reliability of 1o ca8aule integrity. by providing a better situation for the sealing weld of the source capsules relative to other source designs.
aRIBp D~scRZ~zorr o~ THE DRAt~ZNGs FI6_ 1 shove an unwvlded source capsule assembled without contmnts.
FIG. 2 shows detail of the Weld region of the cap~vl~ of FIG) I.
FIG. 3 shows a welded source containing four radioactive 20 substrate beads.
FZG. 4 a~hows a welded source containing two radioactive substrate heeds.
DLSCRIPTIOIJ' 0~' THE PR~~'I~tRFD EMBODTMENZ'$
In a pra~erred embodiment, the capsule materials are tita~niu~a and plat~.nu~n-iridium alloy metals, the substrateB
holding the~radioactive material are spherical beads composed of a zeolite with a binder, and the radioisotope is either palladium-1o3 or iodine~la5.
FIG. 1 shows the assembled but unWelded components o! the ~~tal capsule. The capsule is composed of three parts: two identical titanium end-tubeB 11 with one open end and one cloned rounded end; end one cylindrical, annular titanium plug 1z with a concentric platinum-iridium alloy core 13, onto each end o! which the and-tubes ere press fitted, The annular titanium plug has a central circumferential ridge 14 with a low profile. The ridge serves as a stop and as an alignment axd in the attachment of the and-tubes, aid provides extra titanium at the weld locatian_ FIG. 2 ie a magnified view of the weld region o! the source showing th~ end-tuba walls 21 butted against the ridge Z2 of the annular plug ~3.
FI6. 3 shows a welded source with four zeolfte bead substrates 31. The radioactive ingredient is syanmetrically distributed within the source and is firmly attached to the zeolite beads by chemical Dvnding or physical entrapment. A
single Circuyuterential weld 3Z is performed to secure the end tubes to the a~ulud and to each other, and to hermetically seal the finished source.
FIG. 4 shows a souxce with two zeolite bead substrates 4Z.
The 8lntinum-iridium alloy core 4z length is chosen to limit the free space av$ilabla for the movement eP the zeolite beads within the capsule, depending on wh~ther two or four zsolite beads per -11~
source are used.
TAe titanium annulus i2,23 provides good backing for the weld and thus helps in avoiding Capsule wall perforation in the welding process. The titanium annulus 12,a3 and platinum-iridium alloy core 13,42 together have sufficient bulk to provide a heat einx to curb the temperature excursion experienced by the radioactive compnnehte during source welding. Thus, the probability of volatilizatien and blow-out of certain radioisotopes, such as iodine-125, is reduced. 'fhe location of 1o the Weld 32 mihimires the effect of the weld on sy~nnotry and uniformity of radiation output caused by photon absorption in the weld bead. The heavy platinum~irxdium alloy core 13,42 of the annulus acts as a linear X-ray marker for detection of the source and determination of its orientation from outside the body after implantation. 'fhe uniform Wall thickness of the capsule and the close fit of the spherical bead substrates 31,41 in the end tubes promote symxaetry end stability respectively of the radiation output, xhe heavy poBitional bias of the radioaet~vlty towards the ends of the capsule promotes good isotropy relative similax 2o sources by compensating for attenuation of radiation in the capsule vall_ The option of four substrate beads as opposed to tWO alloys an increase in source strength. Thin option also aliovg for adjustments in the degree of radiation isotropy by changing the ratio of the amount of radioactivity on the inner pair of beads versus the amount on th,e outer pair.
In the matter of dimensions, the sources of FIGS_ 3 and 4 may vary in length between 3 and 7,0 millimeters and in dia~roster between 0. 5 and 7.. S millimeters. The uniform ~ra7,X thickness of the etld tubos~ may very between 0.02 and 0.2 millimQtera. The dimensions of the other compvnsnts are made to a close fit, Generally, the diameter of the spherical substrates may vary between 0.3 and 1.3 millimeters.
z~oi~ites era a olass of crystalline molecular aie~re~ that occur naturally or can be synthesized in powder form. They are thermally ~stabi.a ihoxganic compounds that have an open s,lumino-silicate frame~rdrk that allows them to host other chemical species ~rithin their strueture~r. Their re~.evant properties include. good heat and xadia~tion resistance; catian exchange capacities comparable with organic resins; good capacities For the a;deorption and retention of various radioactive iodine species; lour density and average atomic number of elemental constituents meaning low attenuation of low-energy photons; and with a binder can be formed into durable pellets or spherieal beads 1n appropriate sixes. For comprehensive information on zsail.tas and their applications, the reader is refexxed to the textboox 'Zeolite Molecular Sieves' by Donald W. Hrack, John Wiley arid Sons Ins., New York (1974y, which textbook is ~.ncorporated herein by reference.
PROPHETIC EXAMPLE
It is intended to produc~ on~ hundred titanium-encapsulated interstitial brachytherapy sources each cortait~ing six t~illicuriem ~af palladium-10~ xadioact~,v~,ty. The palladium-103 in each source is to be divided between tour zeolite bead substrates di,atxibuted as follows: two millicuries on esoh outer bead arid on~ 1ni11icurie on each itaner bead. The sources are to have dimensions as follows: length 4.5 millimeters; diameter 0.8 Millimeters, and end-tube wall thickness o.05 millimeters.
1~ large batch of 4A type zeolite beads having bead diameters of 0.65 mil~.imeters is previously acquired_ Trarge batches of each of the capsule parts are acquired in the following to dimensions: end-tube, i.2 millimeters in length, 0.8 millitnetarg in outer diaiaeter, 0.05 millimeters in Wall thickness; arrd titaniumjplatinum-iridium alloy annular plugs, 1.'7 ~ailli~eeters irs length, 0.7 teill~.~neter~a in body diameter, core diameter 0.3 millimeters, ridge diameter 0.~5 millimeters, ahd ridge width O.L
millimeters. The annular plugs are sized to fit shugly info the end tubes so that when press fitted the tvo pieces do nvt easily part.
A sub-batch of at least two hundred of the 4A zeolite beads ie suitably inmtersed in and Mixed with rrn aquQOUS solution of 20 palladium-103 in ammonium hydroxide at a pH of l0.5 eo as to evmnly load 2 milliCUries of palladium-103 onto each bead. The beads are then separated from the solution and thoroughly dried in a drying oven, first at 1Z0 degrees Celsius for 1 hour and then tit 350 degrees Celsius for 1 hour. Another sub--batch of at least tWO hundred of the zeolite beads is taken and similarly treated so as to yield dry zeolite beads each loaded with 1 millicurie of palladiummo3.
A zeolite bead loaded with 2 millicuries of palladium-lo3 ie dispensed into each of two hundred titanium end~tubes held in a vertical orientation with the open ends uppermost. xhen a zeolite bead leaded with 1 millicurie of palladium-1p3 is dispensed into each of the same two hundred end-tubes, so that a 1 millicuxie bead rests on top of each 2 m111icurie bead. A titanium annular plug pith a platinum-iridium alloy core is then preened finely into each of the open ends of one hundred of the end-tubes into which the zeolite beads have been dispensed. The pressure usmd ie just sufficient to ensure that the perimeter o! the previously open end of the end-tube rests squarely against the ridge stop vn the annular plug. The one-hundred plugged arid~tubes and they inverted and each is pressed, protruding annular plug first, into one of the remaining one hundred unplugged end-tubes. Each of the one hundred assembled sources is then laser welded under argon atmosph~re to provide a hermetic seal around the circuiaf~rence where the previously open ends of the two end-tub~s and the ridge of the annular plug meet. Ttxs sources are then 2v ready for surtace cleaning, inspection and testing before shipment to medical centers.
Other bio-compgtible materials, such as stainless steal. are useable as material for the construction of the sou=ce capsule.
Other heavy metals) such as gold, silver) to»talum, tungsten ahd the six platfnum eleaments, and alloys of thsvn elements are useable in place or platinum-iridium ahoy as the X~ray marker -~5-matarial_ Other ~oaterials such as carbon, charcoal and ivn~
exchange resino in spherical bead or other particulate form are useable as subotxate ~aatexial for the radioisotope. Other radioisotopes such as cesium-171, samarium~145, terbium-16l and thulium-1,70 are useable.
Variations in design might be advanced to achia~'e the central circumferential weld and a similar distribution of radioactivity ~rithin a similarly shaped source. The invention oonteieplates and encompasses a11 such variations.
i0 Although the invention has bean describ~d in conjunction with specific embodiments, it is evident that many alternatives and variations Will be apparent to those skilled in the art in light of the roragoing description. Accordingly) the invention i.B intended to embrace a11 of the alternatives and variationB
that tall within the spirit and scope of the appended claims.
The above references are hereby incorporated by rgfgrgnce.
-zs-
Claims (24)
1. Ate essentially cylindrical, metal-encapsulated, brachytherapy source comprising:
an outer metal capsule, an annulus in a central interior position of said outer metal capsule, and a longitudinally extending heavy metal core in said annulus; said annulus being made of the same metal as said outer metal capsule;
means including one or more low-profile welds around the central circumference of said outer metal capsule for attaching said outer metal capsule to said annulus and for sealing said outer metal capsule;
a plurality of substrate particles each having bound thereto a radioisotope, said substrate particles being positioned in said outer metal capsule so that the radioisotope is distributed symmetrically within the source, equally divided between the two ends of the source, and positioned with a strong bias towards the extremes of the two ends of the source; and the length of said metal core being determined by the shape, size and number of substrate particles at each end of the source.
an outer metal capsule, an annulus in a central interior position of said outer metal capsule, and a longitudinally extending heavy metal core in said annulus; said annulus being made of the same metal as said outer metal capsule;
means including one or more low-profile welds around the central circumference of said outer metal capsule for attaching said outer metal capsule to said annulus and for sealing said outer metal capsule;
a plurality of substrate particles each having bound thereto a radioisotope, said substrate particles being positioned in said outer metal capsule so that the radioisotope is distributed symmetrically within the source, equally divided between the two ends of the source, and positioned with a strong bias towards the extremes of the two ends of the source; and the length of said metal core being determined by the shape, size and number of substrate particles at each end of the source.
2. The source of claim 1 wherein said outer metal capsule and said annulus is formed of titanium or a titanium alloy.
3. The source of claim 1, wherein said core of said annulus is made or platinum-iridium alloy metal.
4. The source of claim 1 wherein said substrate particles are two zeolite spheres.
5. The source of claim 1 wherein said substrate particles are tour zeolite spheres.
6. The source of claim 1 wherein said radioisotope is palladium-103.
7. The source of claim 1 wherein said radioisotope is iodine-125.
8. A metal-encapsulated brachytherapy source comprising;
an elongated plug having an essentially cylindrical portion defining an elongated axis;
are outer metal capsule including two metal end-tubes aligned along said longitudinal axis with each one of the end-tubes having one closed end facing outwardly of said source and one open end tightly fitted on said plug end facing inwardly, each one of the end-tubes being welded to said plug with a space between the closed end thereof and a respective end of said plug;
and at least one substrate including at least one radioisotope is in the space in each one of the end-tubes.
an elongated plug having an essentially cylindrical portion defining an elongated axis;
are outer metal capsule including two metal end-tubes aligned along said longitudinal axis with each one of the end-tubes having one closed end facing outwardly of said source and one open end tightly fitted on said plug end facing inwardly, each one of the end-tubes being welded to said plug with a space between the closed end thereof and a respective end of said plug;
and at least one substrate including at least one radioisotope is in the space in each one of the end-tubes.
9. The source of claim 8 wherein both of the open ends are bonded to said plug by a single circumferential weld.
10. The source of claim 8 wherein the closed ends of the end-tubes are rounded.
11. The source of claim 8 wherein said plug comprises an elongated annulus and a heavy metal core within the annulus.
12. The source of Claim 11 wherein said annulus is made of the same metal as said outer metal capsule.
13. The source of claim 8 wherein each one of the two end-tubes are sealed to said plug by one or more low-profile welds around the circumference of each one of the two end-tubes.
14. The source of claim 8 wherein each substrate has the radioisotope bound thereto such that the radioisotope is distributed symmetrically within the source, equally divided between the two ends of the source, and positioned with a strong bias towards the extremes of the two ends of the source.
15. The source of claim 11 wherein said annulus and said outer metal capsule are titanium or a titanium alloy.
16. The source of claim 15 wherein said core is made of a material selected from the group consisting of platinum-iridium alloy metal, gold, silver, tantalum, tungsten, the six platinum elements, and alloys thereof.
17. The source of claim 8 wherein each one of the spaces has one substrate of a zeolite sphere.
18. The source of claim 8 wherein each one of the spaces has two substrates of zeolite spheres.
19. The source of claim 8 wherein said radioisotope is palladium-103.
20. The source of claim a wherein said radioisotope is iodine-125.
21. The source of claim 16 wherein said annulus has a central circumferential ridge with a low profile (1) for serving as a stop and as an alignment aid when attaching the end-tubes, and (2) for providing extra titanium during welding.
22. The source of claim 11 wherein said annulus is formed of the same material as said outer metal capsule.
23. The source of claim 8 wherein there is a plurality of substrate particles in each one of the spaces in the end-tubes with the radioactivity intensity decreasing from the outer end to the inner and of each space.
24. The source of claim 8 wherein there are two substrate particles in each one of the spaces in the end-tubes with the radioactivity of the outer substrate particle being twice the radioactivity of the inner substrate particle.
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| US4323055A (en) | 1980-04-08 | 1982-04-06 | Minnesota Mining And Manufacturing Company | Radioactive iodine seed |
| US4702228A (en) | 1985-01-24 | 1987-10-27 | Theragenics Corporation | X-ray-emitting interstitial implants |
| US4891165A (en) * | 1988-07-28 | 1990-01-02 | Best Industries, Inc. | Device and method for encapsulating radioactive materials |
| US4994013A (en) | 1988-07-28 | 1991-02-19 | Best Industries, Inc. | Pellet for a radioactive seed |
| US5342283A (en) | 1990-08-13 | 1994-08-30 | Good Roger R | Endocurietherapy |
| US5405309A (en) * | 1993-04-28 | 1995-04-11 | Theragenics Corporation | X-ray emitting interstitial implants |
| US6007475A (en) * | 1998-08-12 | 1999-12-28 | Cns Technology, Inc. | Radioactive therapeutic seeds |
-
1999
- 1999-02-09 AU AU25058/99A patent/AU745288B2/en not_active Ceased
- 1999-02-09 WO PCT/CA1999/000112 patent/WO1999040970A1/en active IP Right Grant
- 1999-02-09 CN CNB998049743A patent/CN1198668C/en not_active Expired - Fee Related
- 1999-02-09 EP EP99904644A patent/EP1054707B1/en not_active Expired - Lifetime
- 1999-02-09 JP JP2000531221A patent/JP2002502676A/en active Pending
- 1999-02-09 CA CA002261338A patent/CA2261338A1/en not_active Abandoned
- 1999-02-09 DE DE69924973T patent/DE69924973T2/en not_active Expired - Fee Related
- 1999-02-11 US US09/248,099 patent/US6099458A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1329512A (en) | 2002-01-02 |
| AU745288B2 (en) | 2002-03-21 |
| EP1054707A1 (en) | 2000-11-29 |
| EP1054707B1 (en) | 2005-04-27 |
| CN1198668C (en) | 2005-04-27 |
| DE69924973T2 (en) | 2006-03-09 |
| DE69924973D1 (en) | 2005-06-02 |
| JP2002502676A (en) | 2002-01-29 |
| US6099458A (en) | 2000-08-08 |
| AU2505899A (en) | 1999-08-30 |
| WO1999040970A1 (en) | 1999-08-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |