PRODUCTS AND METHODS FOR BRAQUITERAPIA
This invention relates to radiotherapy. More particularly, it relates to radioactive sources for use in brachytherapy, and in particular to radioactive sources with improved ultrasound image visibility. Brachytherapy is a medical treatment that covers a general term that includes the placement of a radioactive source near a diseased tissue and may include temporary or permanent insertion or implantation of a radioactive source in a patient's body. The radioactive source is thus located in proximity to the area of the body being treated. This has the advantage that a high dose of radiation can be delivered to the treatment site with relatively low doses of radiation to intervening or surrounding healthy tissue. Brachytherapy has been proposed to be used in the treatment of a variety of conditions, including arthritis and cancer, for example, breast, brain, liver or ovarian cancer and especially prostate cancer in men (see for example JC Blasco et al., The Urological Clinics of North America, 23, 633-652 (1996), and H. Radge et al., Cancer, 80, 442-453 (1997)). Prostate cancer is the most common form of malignancy in men in the U.A., with more than 44,000 deaths in 1995 alone. Treatment may include the temporary implantation of a radioactive source for a calculated period, followed by subsequent removal. Alternatively, the radioactive source can be implanted permanently in the patients and allowed to decay to a
Inert state during a predictable time. The use of temporary or permanent implantation depends on the selected isotope and the duration and intensity of the required treatment. Permanent implants for prostate treatment include radioisotopes with relatively short half-lives and lower energies relative to temporary sources. Examples of permanently implantable sources including iodine-125 or palladium-103 as the radioisotope. The radioisotope is generally encapsulated in a titanium shell to form a "seed" which is then implanted. Temporary implants for the treatment of prostate cancer may include iridium-192 as the radioisotope. Recently, brachytherapy has also been proposed for the treatment of restenosis (for summaries see R. Waksman, Vascular Radiotherapy Monitor, 1998, 1, 10-18 and MedPro Month, January 1998, pages 26-32). Restenosis is a re-narrowing of the blood vessels after the initial treatment of coronary artery disease. Coronary artery disease is a condition that results from narrowing or blockage of the coronary arteries, known as a stenosis, which can be due to many factors including the formation of atherosclerotic plaques inside the arteries. Such blockages or narrowing can be treated by mechanical removal of the plate or by the insertion of forceps to keep the artery open. One of the most common forms of treatment is percutaneous transluminal coronary angioplasty (PTCA), also known as angioplasty.
balloon. Currently, more than half of one million PTCA procedures are carried out annually in the U.A. only. In PTCA, a catheter that has an inflatable balloon at its distant end is inserted into the coronary artery and placed at the site of blockage or narrowing. The balloon is then inflated, which leads to the flattening of the plaque against the arterial wall and the stretching of the artery wall, resulting in an elongation of the lumenal passage and therefore an increase in blood flow. PTCA has a high initial success rate but 30-50% of
patients present by themselves stenotic recurrence of the disease, ie, restenosis, within 6 months. One treatment for restenosis that has been proposed is the use of intraluminal radiation therapy. Several isotopes including iridium-192, strontium-90, yttrium-90, phosphorus-32, rhenium-186 and rhenium-88 have been proposed for use in the
treatment of restenosis. Conventional radioactive sources for use in brachytherapy include the so-called seeds, which are capsules or flat sealed containers of a biocompatible material, for example metals such as titanium or stainless steel, containing a radioisotope
inside a sealed chamber but allowing radiation to exit through the walls of the container / chamber (EU 4323055 and EU 3351049). Such seeds are only suitable for use with radioisotopes that emit radiation that can penetrate the walls of the chamber / container. Therefore, such seeds are generally used
with radioisotopes that emit? -radiation or low energy X-rays, in
place of emission ß-radioisotopes. In brachytherapy, it is vital for the therapeutic result for the medical personnel administering the treatment to know the relative position of the radioactive source in relation to the tissue to be treated, to ensure that the radiation is delivered to the correct tissue and that it is not located during or under the dose. Therefore, current seeds typically incorporate a marker for X-ray imaging such as a radiopaque metal (e.g., silver, gold or lead). The location of the implanted seed is then achieved through X-ray imaging, which exposes the patient to an additional dose of radiation. Such radiopaque markers are typically formed so that imaging gives information about the orientation as well as the location of the seed in the body, since both are necessary for accurate radiation dosimetry calculations. Permanent implantation of radioactive sources of brachytherapy for the treatment of, for example, prostate cancer can be done using an open laparotomy technique with direct visual observation of radioactive sources and tissue. However, the procedure is relatively invasive and often leads to undesirable side effects in the patient. An improved method comprising the insertion of radioactive sources transperineally into predetermined regions of the diseased prostate gland using the external model path to establish a reference point for implantation has been proposed (see for example Grimm, PD, ef al., Atlas of the Urological Clinics of North America, Vol. 2,
i?, i.aA? .yÍttí l «, ír-r. and & lÍAyA, yy .. r.,., .. and .... > & H AL% t ^ "« _. -., - "- ¿£ i? *. A - * - ¿tnuT-J- »-« »-y - ^ -? YUr. , No. 2, 1 1 3-125 (1994)). Commonly, these radioactive sources, for example seeds, are inserted by means of a needle device while an external depth indicator is employed with the patient in the dorsal lithotomy position. For the treatment of prostate cancer, typically 50 to 1 20 seeds are administered per patient in a 3-dimensional set derived from multiple, separate, linear seed needle inserts. The dose calculation is based on complex 3-D set, plus the data on the volume of the tumor plus the volume of the prostate, etc. Preferably, the insertion or implantation of a radioactive source for brachytherapy is carried out using minimally invasive techniques such as, for example, techniques including needles and / or catheters. It is possible to calculate a location for each radioactive source that will give the desired radiation dose profile. This can be done using the knowledge of the radioisotope content of each source, the dimensions of the source, an exact knowledge of the dimensions of the tissue or tissues in relation to which the source is placed, as well as an awareness of the position of said relative tissue to a reference point. The dimensions of tissues and organs within the body for use in such dose calculations can be obtained prior to placement of the radioactive source by using conventional diagnostic imaging techniques including X-ray imaging, resonance imaging magnetic resonance imaging (MRI) and ultrasound imaging. However, difficulties may arise during the placement procedure
of the radioactive source that can adversely affect the accuracy of the source placement if only the pre-positioning images are used to guide the placement of the source. The orientation and position of the tissue can change in the patient's body relative to an external or internal reference point selected as a result of for example manipulation during surgical procedures, patient movement or changes in adjacent tissue volume. In this way, it is difficult to achieve the exact placement of sources to achieve a desired dose profile in brachytherapy using only the knowledge of the anatomy of the tissue and position that was obtained before the placement procedure. Therefore, it is advantageous if the real-time display of both the tissue and the radioactive source can be provided. A particularly preferred imaging method due to its safety, easy to use and inexpensive, is the formation of ultrasound images. During placement of the radioactive sources in position, a surgeon can monitor the position of the tissues such as the prostate gland that uses, for example, transrectal ultrasound-echo imaging techniques that offer the advantage of low risk and convenience for both the patient and the surgeon. The surgeon can also monitor the position of the relatively long needle used in the implantation procedures using ultrasound. During the insertion or implantation procedure, the location of the source may be inferred to be close to the tip of the needle or other device used for the procedure. Without
However, the relative location of each separate radioactive source must be evaluated subsequent to the implantation procedure to determine if it is in a desired or unwanted location and to assess the uniformity of the therapeutic radiation dose to the tissue. Radioactive sources can migrate into tissue after implantation. However, the relatively small size of current radioactive sources of brachytherapy and the mirror-like properties of their surfaces makes them very difficult to detect by ultrasound imaging techniques, especially when they are oriented in directions other than substantially orthogonal to the beam. of incident ultrasound. Even very small deviations of 90 ° relative to the incident ultrasound beam cause substantial reductions in the strength of the echo signal. The ultrasound visibility of conventional radioactive seeds is highly dependent on the angular orientation of the seed axis with respect to the ultrasound inductor used for imaging. A flat, smooth surface will generally act as a mirror, reflecting the ultrasound waves in the wrong direction unless the angle between the sound and the surface is 90 °. A smooth cylindrical structure such as a conventional radioactive seed will reflect the waves in a fan-shaped conical pattern that spans a considerable spatial angle but will only give strong ultrasound reflexes when forming images at an angle very close to 90 °. One way to improve the ultrasound visibility of conventional radioactive seeds is therefore to reduce the angular dependence
- ^ í ,. of the reflected ultrasound. * Therefore, there is a need for radioactive sources to be used in brachytherapy with ultrasound imaging visibility, and in particular from sources where the dependence of visibility on the angular orientation of the source axis with respect to the ultrasound transducer is reduced. The ultrasound reflexes can be either mirror (like mirror) or scattered (diffuse). The biological tissue typically reflects ultrasound in a scattered manner, while the devices used tend to be effective ultrasound reflectors. Relatively long smooth surfaces such as those of needles used in medical procedures reflect sound waves in a specular manner. Efforts have been made to increase the ultrasound visibility of relatively long surgical apparatuses, such as surgical needles, solid stylets and cannulas by the proper treatment of their surfaces such as corrugation, striation or chemical attack. In this way, E.U. 4,401, 124 discloses a surgical instrument (a hollow needle device) having a diffraction grating inscribed on the surface to increase the reflection coefficient of the surface. The sound waves that hit the slots defract or disperse as secondary wave fronts in many directions, and a percentage of those waves are detected by the ultrasound transducer. The diffraction grating is provided for use on the guiding edge of a surgical instrument for insertion into a body or for
It is used along a surface of an object, the position of which is monitored while it is in the body. US Patent 4,869,259 discloses a medical needle device having a portion of its surface injected with particles to produce a uniformly corrugated surface that disperses the incident ultrasound so that a portion of the scattered waves is detected by an ultrasound transducer. U.S. Patent 5,081,997 describes surgical instruments with sound reflecting particles embedded in a portion of the surface. The particles diffuse incident sound, and a portion is detected by an ultrasound transducer. The U.S. Patent No. 4,977,897 discloses a tubular cannula device comprising a needle and an inner stylet in which one or more holes are punched transversely perpendicular to the axis of the needle to improve the visibility of the ultrasound. The solid inner stylet can be corrugated or marked to increase the sonographic visibility of the stylus / stylet combination. WO 98/27888 describes an economically enhanced medical device in which a non-conductive epoxy-containing ink-printing pattern mask is transferred-coated to the surface of the device, dried instantaneously and then thermally degraded. The portions of the needle not protected by the mask are removed by etching in an electropolishing step to leave a pattern of substantially square depressions in the simple metal, and the coated ink is removed with a solvent and cleaning
mechanics. The depressions provide the device with increased echogenicity under ultrasound. The Patent of E. U. 4,805,628 discloses a device that is inserted or implanted for long-term residence in the body, such a device becomes more visible to ultrasound by providing a space in the device having a wall substantially impervious to gas, such a space filling with a gas or mixture of gases. The invention is directed to IUDs (intrauterine devices), pro-aesthetic devices, and pacemakers, and the like. McGahan, J. P. in "Laboratory assessment of ultrasonic needle and catheter visualized" JOURNAL OF ULTRASOUND IN MEDICINE, 5 (7), 373-7 (July 1986) evaluates seven different catheter materials for in vitro sonographic visualization. While five of the seven catheter materials have good to excellent sonographic detection, nylon and polyethylene catheters were poorly visualized. Additionally, several improved needle visualization methods were tested. The sonographic needle visualization was assisted by a variety of methods including either corrugation or marking of the outer needle or inner stylet and placement of a guidewire through the needle. However, none of the above-mentioned prior art describes or suggests methods to improve the ultrasound visibility of radioactive sources for use in brachytherapy, including the relatively much smaller radioactive sources or seeds to be used in permanent implants, nor the needle to provide
jj? ^ L? MS ^ tiJSfaM f-v ítmmíim? á ultrasound visibility of such sources. Indeed, there is a propensity in the field of brachytherapy against the change in the design of the seed capsule, since it has not essentially changed and has remained commercially successful for 20 years, together with the fact that none of these changes it may have regulatory or nuclear safety implications, and therefore would typically be avoided. In addition, any change could be observed as the increase in the probability of problems with the seeds that are 'stuck' in the seeds etc. , that is, it is observed so highly desirable that the seeds move flatly within the needles, cannulas, etc. The "sticking" of the seeds inside the loading devices is a known problem for clinicians and may present a safety risk. In this wayIf undue pressure is applied to move a stuck seed, it is known that the seed capsule can be broken with consequent radioactive release, contamination, etc. Therefore, there is a propensity in the matter towards making seeds more flat (or at least having less friction) instead of apparently the other round way. Once implanted, the seeds are proposed to remain permanently at the implantation site. However, individual seeds may occasionally be rare to migrate into a patient's body away from the initial site of implantation or insertion. This is highly undesirable from a clinical perspective, for example it can lead to overdose of a tumor or other diseased tissue and / or exposure of healthy tissue to radiation. Therefore, there is also a need for radioactive sources to be used in brachytherapy that
they show a reduced tendency to migrate within a patient's body when compared to conventional brachytherapy seeds. According to one aspect of the present invention there is thus provided a radioactive source for use in brachytherapy comprising a radioisotope within a sealed biocompatible container, wherein at least a portion of a container surface is corrugated, shaped or Another way is treated in such a way that it is no longer flat. The treatment of the surface can increase the ultrasound visibility of the source and / or reduce the tendency of the source to migrate once implanted in a patient's body. Radioisotopes suitable for use in the radioactive brachytherapy sources of the invention are known in the art. Particularly preferred radioisotopes include palladium-103 and iodine-125. Suitable vehicles for the radioisotope within the biocompatible container may comprise materials such as plastics, graphite, zeolites, ceramics, glasses, metals, polymeric matrices, ion exchange resins or other, preferably porous materials. Alternatively, the vehicle can be made of metal, e.g., silver, or it can comprise a layer of metal placed on a suitable substrate. Suitable substrate materials include a second metal such as gold, copper or iron, or solid plastics such as polypropylene, polystyrene, polyurethane, polyvinyl alcohol, polycarbonate, Teflon ™, nylon, delrin and Keviar ™. Suitable methods of electroplating are known in the art and include chemical deposition,
electronic methods, ion electroplating techniques, chemoplasty and electrodeposition. The material of the vehicle can be in the form of a bead, wire, filament or rod. Such vehicle materials can be encapsulated in a hollow sealed container, for example a metal container, to provide a sealed source or "seed", or the vehicle can be coated with an electroplated shell, for example a layer of a metal such as silver or nickel . The radioisotope can be physically captured in or in the vehicle, for example by absorption, or it can be chemically bound to it in some way. Alternatively, the source may comprise a hollow sealed container that directly encapsulates the radioisotope without the need for a vehicle. Suitable biocompatible container materials include metals or metal alloys such as titanium, gold, platinum, and stainless steel, plastics such as polyesters and vinyl polymers, and polymers of polyurethane, polyethylene and poly (vini) acetate), plastics being coated with a layer of a biocompatible metal; compounds such as graphite compounds, and glass such as matrices comprising silicone oxide. The container can also be electroplated on the outside with a biocompatible metal, for example gold or platinum. Titanium and stainless steel are the preferred metals for such containers, especially titanium. The radioisotope can also be incorporated in a polymer matrix, or a ceramic or plastic composite, and / or may be part of a wall of the container. For example, if a metal alloy is used
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to form a container, then a component of the alloy can be a suitable radioisotope. If a container is made of a composite material, a component of the compound can be a suitable radioisotope. The source must be of adequate size and size for its proposed use. For example, these total dimensions are preferably such that the source can be delivered to the treatment site using conventional techniques, for example using a hollow needle or a catheter. Seeds for use in the treatment of prostate cancer are, for example, typically substantially cylindrical in shape and approximately 4.5 mm long with a diameter of approximately 0.8 mm., so that they can be delivered to the treatment site using a hypodermic needle. For use in the treatment of restenosis, a source must be of suitable dimensions for insertion into a coronary artery, for example with a length of approximately 10 mm and a diameter of approximately 1 mm, preferably a length of approximately 5 mm and a diameter of about 0.8 mm, and more preferably with a length of about 3 mm and a diameter of about 0.6 mm. Sources for use in the treatment of restenosis are typically delivered to the treatment site using conventional catheter methodology. The sources of the invention may also be substantially spherical in shape. The sources of the invention can be used as permanent implants or for temporary insertion in a patient. The choice of
li - ..? J l .a - B.L-v- i. . . j & aa radioisotope and type of source, plus the method of treatment using, depends in part on the condition to be treated. As used herein, the term "corrugated, formed or otherwise treated" means a surface or part of the surface that is not flat and polished as in conventional or regular brachytherapy sources, but which comprises irregularities or discontinuities of some kind of. The irregularities or discontinuities can be installed in a regular pattern or they can be random, or they can present a mixture of regular and random regions. The irregularities or discontinuities can take the form of grooves, scratches, abrasions, depressions or the like, cut, pressed, stamped, attacked or otherwise marked on a surface. Irregularities or discontinuities may also take the form of edges, protuberances, corrugations or the like projecting from the surface. If a source with improved ultrasound visibility is required, the corrugation, formation or other treatment must be on a sufficient portion of the surface of the container that the scattering of the ultrasound by the source is substantially omnidirectional. The corrugation, formation or other treatment may occur on substantially the entire surface of the container, at one or both ends, in the center or on any other portion of the surface. Preferably, the corrugation, formation or other treatment is such that the source will be visible to the ultrasound in substantially all orientations relative to the incident beam. For improved sound visibility, the size of the irregularities or discontinuities on the surface of the containers (such as rods, spheroids, containers, seeds and the like) should be such that the visibility of ultrasound imaging of the sources is improved above that of a similar source with a flat surface. Preferably, each individual irregularity reflects and / or scatters ultrasound in an omnidirectional manner. Typically, the irregularities will be from an amplitude up to about a quarter of a wavelength of the ultrasound included in water. At an ultrasound frequency of 7.5 MHz, this is approximately 50 μm for example 40-60 μm. Depending on the frequency of the ultrasound, amplitudes of approximately 30 to approximately 90 μm may be adequate. Within this size range, longer irregularities are preferred due to an increase in reflected energy. Lower amplitudes, for example below approximately 20 μm, may not provide significant increase in ultrasound visibility. The corrugation, form or other treatment can take the form of production of grooves, depressions, scratches or similar on the surface of the container. The slots, etc. they can be installed randomly on the surface or in more regular patterns, for example in patterns and geometric shapes such as squares or circles, or as lines passing substantially parallel or perpendicular to the axis of a source, or in a helical installation. Preferably, the slots, etc., are not installed in a pattern that repeats highly with more than 1 repetition per quarter wavelength since patterns can act as optical gratings and lead to a loss of omnidirectionality in the
echo return The corrugation, formation or other treatment will depend in part on the exact size and shape of the radioactive source concerned, and can be easily determined using trial and error experiments. Preferably, the irregularities and discontinuities are in the form of a helical groove (e.g. with a sinusoidal profile) or on the surface of the container. The slope of the helix can be chosen from five of maximum order in the intensity of ultrasound reflected at a specific angle with respect to the orthogonal orientation. For example, for a conventional radioactive seed 4.5 mm long and 0.8 mm in diameter, a slope of approximately 0.6 mm will give a maximum at 10 ° C of orthogonal with 7.5 MHz of ultrasound, while a slope of approximately 0.3 mm will give a maximum of 20 ° of orthogonal. For such seed the depth of the groove from the peak to the top should be approximately 40 to 60 μm. The spacing of the repetitive grooves along one axis of the source should not be too closed, otherwise a minimum of ultrasound diffusion can occur at angles close to 90 ° (ie, orthogonal). Preferably, the source will comprise a radiopaque substance, for example silver and another metal, so that the sources can be visualized using X-ray imaging techniques in addition to ultrasound imaging. The preferred sources of the invention are sources comprising a metal container or capsule that encapsulates a radioisotope, with or without a vehicle, which can be visualized both by
X-ray imaging and ultrasound imaging techniques. An advantage of using the sources of the invention in brachytherapy is that the ultrasound and imaging signal can be read, measured and analyzed by adequate computer software fast enough to allow a physician to plan dosimetry in real time. This is an advantage from a clinical point of view for both the patient and the medical staff. However, the sources of the invention can be used in processes that include any type of dosimetry mapping that uses the information obtained due to the ultrasound visibility of the sources. In addition, a physician can use the same imaging technique, ie, ultrasound, instead of during surgery to confirm both the position (eg, prostate) and the size of the organ, and placement of the source. This could allow a doctor to calculate if additional sources need to be inserted, for example, in situations where the dose pattern needs to be recalculated based on the "real" position of the seeds. The radioactive sources of the invention can be delivered into a substantially linear biodegradable material, for example as in the product RAPIDStrand ™, available from Medi-Physics, Inc. of Illinois, E. U.A. Preferably, the sources are uniformly separated (eg 100 mm apart in RAPIDStrand ™) to allow even / uniform radiation dosimetry and the dimensions of the assembly are such that the whole can be loaded onto a needle for administration to a patient. The biodegradable material can be a suture or a layer
adequate biocompatible. The corrugated, formed or otherwise treated surface of a source of the invention can be produced by a variety of different methods. In a further aspect of the invention, there is provided a method for increasing the ultrasound visibility of a radioactive source for use in brachytherapy comprising a radioisotope and a sealed biocompatible container, the method comprising corrugation, forming or otherwise treating a surface or part of a surface of the container to provide irregularities or discontinuities of dimensions and efficient installation to increase the reflection of the ultrasound to facilitate the detection of them. For example, if the source comprises a radioisotope encapsulated in an essentially cylindrical container or an encapsulation material, then the outer surface of the container or encapsulation material may be corrugated or formed by forcing the source through a serrated or flanged nozzle or a Threading device to impart grooves on the surface. A similar effect can be produced by grinding. The surface may also be corrugated as a result of mechanical friction, for example by the use of a wire brush or a paperboard, or an appropriate degree of sandpaper, for example, rough grade. The outer surface can also be attacked, for example using a laser or water jet cutter or by electrolytic attack. The deformation, for example cleaning by sand spraying, can also be used. The deformation can be done dry or
^ -lL,. ^ é iTl'ill l. "-Mi i i? mitf? wet as a water jet cleaning. If the source comprises an electroplated support, the electroplating process itself can lead to a sufficiently corrugated surface for the purpose of the invention. The manufacture of radioactive seeds comprising a radioisotope within a sealed metal or metal alloy container usually includes the provision of a suitable metal tube, one end of which is sealed, for example, by welding to form a container. The radioisotope is then introduced into the container and the other end is also sealed for example by welding to provide a sealed seed or source. Alternatively, a container or container can be formed by stamping a metal core or melting, casting or forming a molten metal core, or machining or drilling a stock of solid metal core, or melting and reforming and solidifying a metal stock or attaching a cover to the end of a pipe by means such as welding or threading, or by the use of heat to expand and then contract the cover in cooling. The outer surface of the container can be corrugated, formed or otherwise processed at any stage of the manufacturing process. For ease of fabrication, corrugation, forming and other treatment process occurs preferably before loading the container with the radioisotope, more preferably in the non-radioactive metal tube before sealing either end, and more preferably in a long section of pipe metal before it is cut into short segments suitable for use in forming containers. Corrugation, formation or other
Treatment must not be such that the integrity of the container is compromised. Preferably, the wall thickness of the container is maintained although the total shape after the treatment is such that the surface is no longer flat. In a still further aspect of the invention, there is provided a method for the preparation of a radioactive source comprising a radioisotope and a biocompatible sealed container at least a portion of the surface from which it is corrugated, shaped or otherwise treated, in a manner which is no longer flat, the method comprising corrugating, forming or otherwise treating an outer surface or part of an outer surface of the biocompatible container of the source to thereby provide irregularities or discontinuities in the outer surface. In still another additional aspect of the invention, there is provided an additional method for the preparation of a radioactive source comprising a radioisotope of a radioactive source comprising a radioisotope and a biocompatible container sealed at least a portion of the surface from which it is corrugated, form or otherwise treat in a manner that is no longer planar, the method comprising (') corrugating, forming or otherwise treating a surface or part of a surface of a biocompatible container material to provide irregularities or discontinuities of dimensions; (ü) charging a radioisotope into the biocompatible container material of step (i); Y
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(iii) sealing the biocompatible container For example, a suitable thin-walled metal tube such as a titanium metal tube can be mechanically deformed prior to the insertion of the radioactive material and welded the ends to form a sealed source. A flat helical groove can be produced both on the inner and outer surface of the tube without affecting the thickness of the wall by the use of a suitable folding process. A support tool of cylindrical shape and with external threads of a suitable depth and slope can be inserted first into the metal tube. The support tool should fit snugly inside the tube. A crease tool can then be forcedly applied to the outer surface of the tube. The shape of the crease tool must equal that of the support tool. The folding tool can consist of two or more parts, each part covering a different sector of the tube surface. Following the folding operation, the support tool can be removed by simple twisting due to its helical threaded shape. One or more helical grooves can also be produced by gently pressing a sharp metal edge to the surface of a container while the container is rolled onto a solid surface at a slight angle, either before or after the container is sealed to form a radioactive source. If the improved ultrasound visibility of a source is desired, alternatively or additionally to corrugate, form or treat the outer surface, the inner surface of the container can be corrugated,
Í.? .LÁ? Á.? A > .t-. < -... l. * X * -fe-. ... iAy b, At ^ Ji-i.- form or otherwise be treated before the introduction of the radioisotope. For example, a corrugated or non-uniform surface inside a container can be introduced by means of a plug to create screw or screw threads inside the container. The cap can flute, mark or drill a threaded pattern as it is turned into the container. The space of the threads inside a container can be set to any desired dimension obtainable by covering the interior of the container. The cap can be made before one end is sealed (i.e., in a tubular precursor to the container) or after one end is sealed (i.e., in a can). Preferably, the tube is marked before it is sealed at one end. If the inside surface of a container is corrugatedIn this way, the total thickness of the wall of the container must not be too good that no ultrasound penetrates into the interior of the container and is reflected from it. The proper thickness can be easily determined by experimentation. A thickness of the container wall up to approximately 0.1 mm is adequate. The thickness of the wall of a container encapsulating a radioisotope is dependent on at least the energy of the radioisotope and the nature of the vehicle. For example, conventional 1 5l sources use 50 μm thick titanium cylinders for containment, which are sufficient to block the beta particles emitted by the 25l while allowing enough gamma rays and low energy X-rays through the impact therapeutic. However, if an aluminum container is used, the thickness of the wall would need to change in order to properly capture any beta particles emitted. Correspondingly, if a polymeric container is used, it would need to be coated, for example with a "paint" of titanium oxide or electroplated with a metal to modify or block the emissions of beta particles if the plastic by itself does not capture them. Higher energy sources can be used with vehicles that are thicker than lower energy sources. The number of helical or helical grooves, threads or edges or the like on an inner or outer surface of a container can be, for example, in the range of from about 1 to about 100 per mm of container body length. The tube or container can be cut with at least one edge, thread or groove pattern and optionally with more than one such pattern of different helical threads or spirals in advance which may be in the same or opposite sense of handleability. The thickness or depth of each edge, thread or groove can vary from about 1 μm to about half the thickness of the wall of the container if desired. Two or more edges, threads or slots of different spaces, different workability, and / or different thickness or depths can be covered in the container to give a wide variety of marking patterns on the inner surface thereof or cut on the outer surface of the container. container to give a wide variety of marking patterns on the outside of them. The thickness of the wall of the container can be preferably within the specifications established for seeds and radioactive sources of conventional brachytherapy, or it can be selected as the optimum useful in brachytherapy through clinical experimentation. Optionally, the wall of the container can be thicker than what is finally desired at the beginning of the corrugation, formation and other treatment procedure, and the excess thickness can be removed during the procedure, for example during the packing of the interior of the container. The corrugation or formation on the outer surface of a container according to the invention may take the form of indentations on the surface. The indentations can be found in the form of teeth, steps, notches or projections on the surface of the container. Such indentations may be grouped in part of the surface to form a container, and / or may be set in rows on part of the surface. A meshed tooth has an edge subtended from the surface that is longer than a second edge that also subtends from the surface, the two edges meeting in a peak or common point. The direction of the indented tooth is defined as the direction in the plof the shortest edge. In another aspect, the edges of the teeth may be of similar length, and the teeth may be substantially symmetrical in two dimensions. In another aspect, the teeth can be conical, pyramidal or trigonal or of another geometric shape where a point is achieved. The teeth can be of a uniform or non-uniform size, and the teeth can comprise more than one indentation. When more than one set of indentations is
Í Aa ,,. Ti. *.! **** • '• *. «Fcfct. If the source and they should not pass, there will be two sets of more preferably passing in opposite directions. The corrugation, formation or other treatment of an exterior surface of the source of the invention can reduce the tendency of the sources to migrate or move once implanted within a patient when compared to conventional flat seeds. The serrations on two or more portions of the surface of a source are particularly suitable in this regard. Such indentations can also lacerate the tissue during implantation, resulting in the formation of scar tissue that can also serve to keep the implanted source in place. Preferably, corrugation, formation or other treatment is sufficient to reduce the tendency of a source to migrate but is not such that the sources can not be supplied to the treatment site using conventional methodology and management techniques. An adequate degree of corrugation, etc. it can be found by trial and error experimentation. If the source comprises a container comprising a composite material, then the outer surface of the container can be corrugated by exploiting the differences in physical properties of the materials comprised in the composite. For example, if the compound comprises a mixture of polymers that are separated by phase in the mixture and have different solubility properties in a particular solvent, then the surface may corrugate upon exposure to that solvent and
i - 27 -causing so that part of the mixture dissolves. Alternatively, if the compound comprises a polymer and a salt, then exposure to a suitable solvent can dissolve the salt but not the polymer and therefore cause the corrugation of the surface. A container comprising a ceramic or polymer can be "corrugated" by introducing particles of water-soluble materials into the container material. For example, sodium chloride particles that are substantially insoluble in most polymer blends could be included in a polymeric container. After exposure to water or simply by placement within the tissue of interest, the sodium chloride particles can dissolve leaving a "corrugated" surface to the container. The resulting hypersomatic effect around the source can also produce a physiological response, which can help serve to fix the source to a greater degree than normal and thus prevent subsequent movement of the source. A ceramic composite container could be prepared from two or more different but compatible ceramic materials in such a way that the exposure of the container to acid or base could electively dissolve one or more of the components of the vehicle thus leading to a suitable corrugated surface. For example, a combination of aluminum oxide and titanium oxide could provide selective dissolution in strongly basic solutions since aluminum is soluble at very high pH while the passive titanium does not dissolve in such a medium. Alternatively, a container may be exposed to a
j j | a¿t .. »> .á.t. < . JiMfcrU. - '•? -. ^ j- ^ j -..., JM-.i. , M | - "tA *« ^ - corrosive solution so that the surface corrodes in a non-uniform manner to lead to a properly corrugated surface.For example, stainless steel is susceptible to corrosion by cracks by the action of chloride ion in a Oxidation environment at lower pH values Any source of conventional brachytherapy can be corrugated, formed or otherwise treated using the method of the invention to improve its visibility of ultrasound imaging For example, the ultrasound visibility of the seeds described in EU 5,404,309, EU 4,784, 116 and EU 4,702,228 could be improved.These seeds comprise a capsule and two radioactive pellets separated by a radiopaque marker within the capsule.The opaque label imparts detectability by X-ray imaging of the The corrugation of the surface of such capsules could be achieved for example by scraping or liming. abrasive adura of the surface. further, the abrasive corrugation could be done exclusively in the region of the capsule next to the opaque marker in each design to impart increased detectability of ultrasound to the capsule in addition to the detectability by X-ray imaging. The capsule region found Next to the radioactive pellets may not corrugate, so that the thickness of the capsule wall remains substantially uniform around the radioactive pellets. The radiation dose received from such partially corrugated capsule when implanted in a patient can therefore be found substantially without changing the radiation dose of a
conventional capsule substantially not corrugated. The calculation and administration of the radiation dose can then be independent of the depth or degree of the surface corrugation in the region of the opaque marker. Corrugation in the region of the marker can likewise be done at depths and at degrees that can change the thickness of the capsule wall without substantially altering the profile of the radiation dose received by the patient. In a further aspect, the invention also provides a method of treating a condition that is responsive to radiation therapy, for example cancer, arthritis or restenosis, comprising the temporary or permanent placement of a radioactive source comprising a radioisotope within a sealed biocompatible container, wherein at least a portion of a container surface is corrugated, shaped or otherwise treated to provide irregularities or discontinuities, at the site to be treated within a patient for a sufficient period of time to supply a therapeutically effective dose. The invention will be further illustrated, by way of example, with reference to the following drawings. Figure 1 illustrates a modality of a radioactive source according to the invention; Figure 2 illustrates another embodiment of a radioactive source according to the invention; Figure 3 illustrates a metal tube suitable for use in the production of a modality of a radioactive source according to the invention;
Figure 4 illustrates a cross-sectional view of the metal tube of Figure 3 during the fold; Figures 5 and 6A to D are ultrasound images of a metallic wire and corrugated metal tubes using embodiments of the methods of the invention. Figure 7A is a photograph of a conventional titanium seed envelope and Figures 7B and 7C are photographers of similar corrugated seed coatings using the embodiments of the method of the invention. Figure 7D graphically shows the backscattered intensity as a function of the angle of the seed axis relative to the ultrasound beam for the seed envelopes of Figures 7A to C. Figure 8 shows a graphical form of the backscattered intensity as a function of the angle of the seed axis in relation to the ultrasound beam for a conventional seed coat and two modified seed coatings according to the invention. Figure 1 is a schematic illustration of part of a source 1 with indented edges 2, the serrations passing in opposite directions at opposite edges. Figure 2 is a schematic illustration of a sealed source 3 according to one embodiment of the invention. The source comprises a metal, for example titanium, the container 4 is sealed at both ends 5. The interior and / or exterior in the container has a screw thread 6 attacked thereon. The container contains a silver rod 7 coated with a plate of avocado iodine containing 125 l. The silver rod 7 is detectable by techniques of formation of
X-ray images. Figure 3 illustrates a metal tube (eg, titanium) 8 that has been subjected to a folding operation to form helical grooves 9 on the outside and inside thereof. Such a tube is suitable for use in the production of a sealed radioactive source according to the invention. Figure 4 schematically illustrates a cross section through the metal tube 8 of Figure 3 during the folding operation. The tube is folded between a support tool 10 and a folding tool 1 1, made of four different segments. Figures 5 and 6A through D are ultrasound images that are discussed in more detail in the following Examples. Figures 7A to D and 8 will also be discussed in more detail in the Examples. The invention will be further illustrated with reference to the non-limiting examples: Examples Example 1 A 12 mm long section of a 0.8 mm diameter copper wire is mechanically corrugated using tweezers with a meshed fork, but no material was removed from the wire . The visibility of the ultrasound was compared to that of a non-corrugated, flat portion of the same wire. The results are shown in Figure 5, which is a sample of the ultrasound image of B-mode of the
wire in a water tank obtained using a Ving ed explorer CFM-750 at 5 MHz. In Figure 5, 12 is a 12 mm long corrugated portion of the wire; 1 3 is the bottom edge of the water tank used in the experiment; 14 is a flat portion of the wire and 15 is a mirror reflection from the section of the flat wire at a 90 ° angle to the incident ultrasound. The lighter region of the wire in the ultrasound image is the corrugated portion, which illustrates that the corrugation of the invention greatly increases the ultrasound visibility. Similar results are obtained if the surface of the conventional titanium seed container is corrugated in the same manner. Example 2 A thin, single filament (0.1 mm diameter), straight nylon wire was mounted in a water bath, and imaged with a Vingmed CFM-750 ultrasound scanner at 7.5 MHz. The wire was installed for pass diagonally through the image, at an angle of 45 ° C with respect to the direction of the sound beam in the center of the image sector. This wire served as a support for parts of the titanium pipe that could move in and out of the central image field. The titanium tubes were those used to form conventional containers for the production of brachytherapy seeds (length of 5 mm, diameter of 0.8 mm, wall thickness of 0.05 mm), but without welded ends and radioactive insertion. Images of pipe pieces with different surface modifications were made
in the exact same location, and without changing the geometry or the facilities of the instrument. A common feature of all the tube segments formed in images are the diffraction artifacts at the unclosed ends. Valid execution comparisons in this way can only be made by studying the central regions of the tubes. Also, a clear halo was observed in the images behind the tubes, most likely caused by acoustic reverberations within the tube structure. The following surface modifications were made: a) fine abrasive grinding; b) rough abrasive grinding, c) rough deformation without loss of material, and d) no modification to the original surface. Figure 6A to D show the resulting ultrasound images. All modifications resulted in improved visibility of the central portion of the seeds when compared to the unmodified case d). The best performance was observed with fine grinding a). Example 3 Established measurement A 7.5 MHz wideband transducer (Panametrics
V320) was mounted on the wall of the measuring chamber. With a transducer diameter of 13 mm and a focal length of 50 mm, this transducer has an acoustic field similar to a typical in-phase transducer used in clinical TRUS applications. A brachytherapy seed was mounted on a fastener that could be rotated at defined angles relative to the direction of the ultrasound beam. The seed was stuck on the tip of a needle protruding from the specimen holder with cyanoacrylate glue so that the center of gravity of the seed coincides with the rotational axis of the fastener. The angular rotation could be established with half an accuracy of degree, which is of greater importance given the high angular dependence of the US backscatter. The fastener could also be adjusted by translation to place the seed in the focal point of the transducer and to be fixed by all the experiments. The transducer was excited with a wideband pulse from a Panametrics 5800 impeller. The received signal was acquired with a LeCroy 9310 oscilloscope and digitized. The sampled radio frequency (RF) signal (fs = 50 MHz) was then transferred to a computer for further processing. Three different seeds were tested; an unmodified seed and two different modified seeds. The unmodified seed (A) was identical to a standard seed except that it was not loaded with radioactive iodine. The dimensions of the seed were 0.8 x 4.2 mm and the thickness of the titanium tube wall was 50 microns. Two similar seeds were modified by gently pressing a pointed metal edge to the surface of the seed while the seed coiled on a solid surface at a slight angle. The resulting deformation one or more helical grooves that pass along the entire length of the seed. One of the modified seeds (B) was placed on a very thin paper towel for friction during deformation and a
t. i ^ ...? .. yy, .y .., lll¡ £ 3¡ • t "a- -Jri -.... ** - J-.« aAfaAAi iiatütL heffcoidal groove 0.058 mm deep, 0.1 mm wide and approximately 0.54 mm slope occurred The other modified seed (C) was placed on a thin rubber sheet during the deformation and resulted in several thinner helical grooves with approximately 0.03 mm depth and 0.2 mm in space of slots Figures 7A, 7B and 7C show magnified views of the seeds A, B and C respectively The images were transferred to an image analysis program (Optimal) for the measurements of the deformations. was calibrated using the undistorted length of the seed as a reference and various measurements of slot thickness, width and slope were averaged for a representative characterization of the seed surface distortion.A series of measurements that map the ultrasound backscatter of AC Give one of the seeds through the full range of incident angles (-64 to 65 degrees) were carried out. After exact positioning at the desired angle, 10 ultrasound pulses were transmitted at a PRF of 10 Hz and the received echoes were digitized and stored. The 10 pulses were averaged coherently before further processing. Three different methods were tested for the estimation of the backscattered echo intensities; a) the square of the peak amplitude; b) the integral of the signal in a gate of 0.5 microseconds around the peak amplitude; and c) the integral of a filtered pass-band version (5-9 MHz) of the signal in a microsecond time gate centered as in b). The method a)
better represents the "brightness" ^ the seed in an ultrasound image, ri while methods b) and c) more closely represents the total backscattering energy.The three methods produced very similar results for all seeds and angles and the results of the method a) are used in the present.In addition, the envelope images that detected individual scan lines at different angles were made for viewing.These images directly represent what a small section of the image containing the seed would look like in a Normal B-mode image The numerical results of the backscattered intensity are presented in graphical form in Figure 7D The intensity at normal incidence (ie, with the seed axis orthogonal to the ultrasound beam) was very similar between the different For the unmodified seed A, the backscattered intensity fell very rapidly with the angle increasing away from the Normally, at an angle of 10 degrees in either direction, the intensity has reached a minimum of approximately 23 dB below the normal incidence level (0 degrees). When judging these measurements, the seed would be dramatically less visible, if visible at all, at angles that exceed +2.5 degrees of normal incidence. The backscattered intensity increased again as the angle of incidence approached 60 degrees as the tip of the seed entered the ultrasound beam and the sound was reflected off the round seed tip. Modified seeds B and C had a much less pronounced reduction in backscattered intensity with incidence angle
growing. The intensity did not fall more than about 10 db for either of the two modified seeds within + 60 degrees of the angle of incidence, and the seeds were therefore expected to be visible in a much longer angular range than the unmodified seed. For the lower angles, the variations in intensities caused by the constructive and destructive interference of the sound reflected in the slots could be observed. This was more pronounced for seed B since the helical pattern here was deeper and more defined than for seed C. Dispersion of dispersed energy across longer angles for the modified seeds compared to the unmodified seed did not significantly effect the backscattered intensity at normal incidence. Example 4 The ultrasound visibility of three types of seed in a prostate ghost was investigated. The prostate ghost was a commercially available ghost and the seeds were inserted into the phantom using the clinical setting for seed implantation: ie, B & ultrasound machine; Panther using a 7.5 MHz transrectal ultrasound transducer; MMS treatment planning software, B & k hardware for seed implantation; standard 18-gauge seed implantation needles. Three different types of seed were investigated. The reference seeds (ref) were fictitious (ie non-radioactive) seeds corresponding to the seeds commercially available from Medi-Physics, Inc., under model number 671 1. The A seeds correspond to the
reference seed modified by the addition of five longitudinally spaced slots around the central portion of each seed and the AC seeds were prepared in a manner analogous to seed B of Example 3. Seeds were implanted in a range of beam angles ultrasound (with 0o corresponding to the long axis of the seed being orthogonal to the ultrasound beam) and the ultrasound visibility of the implanted seeds was measured. Figure 8 shows the results of the three different types of seeds. When the ultrasound beam strikes a seed inside the phantom with a deviation of 0o + 2o (ie: exactly 90 ° to the long axis of the seed) there was little difference between the reference and the modified seeds of the invention. However, when the seeds were implanted at an angle to the ultrasound beam, the modified seeds retained their echogenicity to a much greater degree than the reference seeds.