PRODUCING THEM

Field of the Invention

The present invention relates generally to brachytherapy radioactive seeds designed for temporary implantation, and compositions and methods for fabricating, activating, and medical utilization of the same.

Background of the Invention

Cancerous tumors can be treated, among other procedures, via irradiation, by implanting radioactive seeds inside the tumor or adjacent to the malignant area. Such radiotherapy, called Brachytherapy, aims at killing a substantial part of the tumor cells, or - after surgical excision of the tumor - at killing residual cells therein, while causing a minimal damage to the neighboring normal body tissues and organs.

The cost of the currently available brachytherapy seeds is high and, hence, inaccessible to many patients worldwide. A low cost brachytherapy seeds will drastically increase the affordability of brachytherapy for oncological patients.

Conventional brachytherapy seeds comprise pure radio-isotopes that allow simple calculation of the dose-depth-time profile necessary for therapy control and regulatory approval. However, pure isotopes drastically increase the seeds' cost. Pre-fabricated seeds, comprised of pure or mixed material compositions can be skillfully selected for producing a mixture of radio-isotopes in the seeds, via bombardment with neutrons, high-energy protons, deuterons and other nuclei. Such innovative technique based on mixed material compositions can provide the desired therapeutic dose-depth-time profile, the necessary regulatory reassurances, as well as substantially reduced costs. The wide-range of compositions of the seeds calls for tethering and post-therapy removal from the body. The more complex calculations needed for such seeds are well taken care of by modern computers. Such seeds can be introduced and retrieved by already medically approved tethering methods, implantation devices, catheters and tethering methods .

It is an objective of the present invention to provide rather affordable high convenience brachytherapy seeds for use in medically approved brachytherapy devices, and to provide rather affordable high convenience compositions and methods of fabrication thereof.

Other objects and advantages of the invention will become apparent as the description proceeds.

Sinnπiary of the Invention

The present invention provides affordable radioactive seeds for brachytherapy, materials and methods for fabricating the same, and medical utilization thereof. In a preferred embodiment of the invention the radioactive seeds can be tethered and utilized in a medically-approved existing brachytherapy device and thereafter removed therefrom by means of a simple procedure. In one aspect the present invention is directed to radioactive brachytherapy seeds and devices for temporary implantation wherein the pristine seeds are comprised of one or more isotopes of a single element, or one or more elements, or one or more compounds comprising the elements or isotopes, wherein the seeds are configured to be introduced into elongated casing means adapted to obtain a tethered configuration, isolation of said seeds from body tissue, and to allow reuse of said seeds by allowing them to be removed from said casing for reactivation for subsequent use.

The brachytherapy seeds may be manufactured from compositions that can be activated by means of neutrons bombardment, high- energy protons, or deuterons. Preferably, the brachytherapy seeds are comprised of oxides and/or nitrides. The brachytherapy seeds may have spherical or cylindrical shape and a diameter or length of about 1-2 mm.

Advantageously, the seeds compositions undergoing nuclear activation are in the entire seed volume, or only in part of the seed, or provided as a layer mounted on top of another material comprising the seed. Optionally, the seeds may have ball, bead, ring, spring, or polyhedron shape. Additionally or alternatively, the seeds may be provided in a hollow, full, spongy, or porous configuration. Optionally, the form of the seeds is retained in the course of activation.

According to one specific embodiment the seeds are made of Aluminum coated by Rh-103 suitable for forming Pd-103 by means of the activation process. According to another specific embodiment the seeds are made of cubic zirconia beads, in which Y and Zr radioactive isotopes are being formed by means of the activation process. Advantageously, the seeds may comprise high-Z elements for imaging purposes.

Optionally, the removal of the seeds from the elongated casing means may be attained via dissolution, swelling or rupture.

Advantageously, the dose-rate at therapy start, location in the tumor and duration of stay are altered per physician orders. The seeds are preferably suitable for dose-depth measurements over time by means of one or more detectors, disposed at one or more locations on the patient's skin. In certain preferred embodiments the seeds are having beta and X- ray radiations. In some other certain preferred embodiments the seeds are designed to emit radiation comprising a mix of β and γ radiation.

The seeds in some preferred embodiments of the invention are suitable for delivering therapeutic dose at about 2-5 mm depth.

According to another aspect the present invention is directed to a brachytherapy treatment comprising: providing a tethered radioactive seeds device comprising a sealed elongated casing means in which a plurality of brachytherapy seeds are dispensed, and an elongate retrieval element; introducing the distal end of the device via a surgical incision, wound or other body opening into a treatment site; anchoring the proximal end of the retrieval element to the surface of the skin or body wall adjacent to the body opening; closing the body opening and leaving the device at the treatment site for the desired period of time, during which the patient may be released from hospital; and removing the device by retracting the proximal end of the retrieval element in a proximal direction. _ C _

Preferably, the treatment period is of several days or about a week. The brachytherapy treatment may further comprise removing the radioactive seeds from the elongated casing means and reactivating them for further brachytherapy treatments.

Brief Description of the Drawing

Fig. 1 schematically illustrates a possible implementation of the tethered seeds of the invention.

Detailed Description of Preferred Embodiments

It is noted that the preferred embodiment of the invention described hereinbelow with reference to the drawing illustrates by way of example, and " not by way of limitation, the principles of the invention. The drawing, which is not necessarily in scale, exemplifies a preferred embodiment of the invention, and by no means limits the invention to the particular elements described.

The present invention provides a rather highly affordable radioactive seeds for brachytherapy, and methods and compositions for their fabrication.

In accordance with an embodiment of the invention, the radioactive seeds for brachitherapy are made of prefabricated seeds having a composition which can be activated via bombardment with neutrons, high-energy protons, deuterons and other nuclei (hereafter "nuclear activation") . Nuclear activation is carried out preferably after, or shortly prior to tethering and use of these seeds in a medically approved brachytherapy device. By way of a non-limiting example, the composition of the seeds subjected to nuclear activation may be comprised of one or more isotopes of a single element, or one or more elements, or one or more compounds of the desired elements or isotopes, such as oxides, nitrides and the like. By way of a specific non-limiting example, the seeds can be made of natural or of cubic-zirconia which comprises ca 67% zirconia, 32% silica and many more elements of minor quantities.

By way of a non-limiting example, the geometrical dimensions of the radioactive seeds may be substantially similar to those of conventional seeds as used in brachytherapy procedures. For example, the seeds may have a spherical or cylindrical shape having a diameter/length of about 1-2 mm.

By way of a non-limiting example, the seeds can comprise the compositions undergoing nuclear activation in the entire seed volume, or only in part of the seed, or as a layer mounted, via any method, on top of another material comprising the seed.

By way of a non-limiting example, the form of the seeds subjected to nuclear activation may be ball, bead, ring, spring, polyhedron of any type, and the like, while the seeds can be hollow, full, spongy, or porous, for example. By way of a further non-limiting example, the form of the seeds is retained in the course of activation, and seeds can be utilized as such since no dissolution and/or separation processes are involved in their production.

By way of a non-limiting example, fabrication and shaping of the seeds may be carried out via any technique suitable for the selected material and shape of the seed, such as but not limited to, molding, casting, pressing, milling, metalworking, cutting, and the like.

By way of a non-limiting example, tethering of the seeds may be attained by any connecting element utilized in a medically approved brachytherapy device. By way of a further specific non-limiting example, the seeds are tethered via tubing (catheter) into which they are packed, as specified hereinbelow. By way of a further non-limiting example, the tubing (catheter) used for tethering the activated seeds is made from a material approved for medical or surgical applications, such as polyimide, Teflon, Silicone, or any other such medically approved material satisfying the medical needs and capable of sustaining the radiation level during the treatment .

By way of a non-limiting specific example, the tubing comprising the tethered seeds is plugged with a resin approved for medical or surgical applications, such as Silicone, epoxy and the like. By way of a further non-limiting specific example, discreet seeds are packed in the said tubing for a double purpose of tethering and isolation from the body, and the seed-filled tubing is sealed.

By way of a non-limiting specific example, the seeds are made of Aluminum that is coated with Rh-103. From the latter, Pd- 103 is being formed via the activation process. By way of a further non-limiting specific example, the seeds are made of cubic zirconia beads, in which Y and Zr radioactive isotopes are being formed via the activation process.

By way of a non-limiting example, a dose-depth profile of the radiation emitted from the activated seeds device is measured in a biological-like medium, as a function of time, and these data are utilized by the physicians to plan the location and duration of implanting the device.

By way of a non-limiting example, the tubing containing the tethered activated seeds is introduced into a tumor, along a selected axis, or above a tumor, or near the edge of an apparently healthy tissue from which a tumor has been removed.

By way of a non-limiting example, the tubing containing the tethered activated seeds is introduced into its therapy site in the body directly as such, or via a leading catheter, or via any other method preferred by the physician in charge of the radiotherapy. By way of a non-limiting specific example, the non-active end of the device may be secured outside the body or under the skin, in a way facilitating its removal in due time.

By way of a non-limiting example, imaging of the tethered activated seeds radiotherapy-device inside the body may be carried out via ultrasound, MRI, CT, and the like. By way of a further non-limiting example, if so prescribed by the physician, the device may comprise special "imaging seeds" made of high-Z elements (e.g. tungsten), to allow a more accurate positioning of the device in the body.

By way of a non-limiting example, the activated tethered seeds radiotherapy-device is left in or adjacent the tumor, for a period, determined according to the dose suitable for effective treatment of the specific patient and the half life of the primary active isotopes in the device, as well as according to the all medical and social considerations applicable for the specific patient, the organ treated, and type of tumor. By way of a non-limiting specific example, the said device is removed from the patient after a few days, or weeks, preferably after about one week. By way of a further non-limiting specific example, the patient may be released from hospital after implanting the device.

By way of a non-limiting example, after removal from the body, any tubing enveloping the activated seeds is chemically dissolved or ruptured to allow retrieval of the tethered seeds, which can undergo repetitive activation, tethering, sealing and reuse for radiotherapy.

Some non-limiting features of the invention include:

• The radiotherapy parameters such as length of the activated part of the tethered seeds, dose-rate at therapy start, location in the tumor and duration of stay, can be altered per the orders of the physician in charge of the radiotherapy.

• The surgical parameters such as introduction and retrieval methods can be altered per the orders of the physician in charge of the radiotherapy.

• The dose-depth measurements vs. time can be made by employing a single detector, or an array of detectors, at one or more locations and in desired distances from the tethered seeds, and the calculations can be made by employing existing software packages for calculating dose- depth-time from the measurements data.

• The radiotherapy process can be monitored by measuring the rather low radiation dose-rate on the patient's skin at selected control points.

Accordingly, the tethered brachytherapy seeds of the present invention are designed for temporary implantation in the body- site to be treated using a medically approved brachytherapy devices and methods. In such procedure the brachytherapy treatment is completed by retrieval of the seeds, which may be simply carried out by pulling the device in a proximal direction. This new attitude broadly expands the seeds' composition to mixed radio-isotopes, which provide primarily but not exclusively beta and X-ray radiations characterized by small penetration depth and short half-life. These mixed radio-isotopes will inevitably emit a minor dose of radiations characterized by large penetration depth or/and long half- life, which have a negligible effect in view of the relatively short implantation time (days) periods.

In the present invention, seeds composed of "parent" isotopes for the desired activation are produced prior to the activation step. For example: Beads made of Cubic Zirconia (currently used for ornamentation) which are activated by fast or slow neutrons and produce a mix of radioactive isotopes of Zr, Nb, Hf and many more, that together provide the desired dose-depth-time profile. Linking the said seeds into a chain is made preferably prior to the activation, or shortly afterwards. The tethered activated seeds may be utilized without costly separation steps. They may be hermetically sealed in a leak-free shell or tubing, if so desired, and utilized for radiotherapy via currently used methods as well as new methods developed from time to time hand-in-hand with the newly developed products.

Fig. 1 schematically illustrates one possible embodiment of the invention of a tethered radioactive seeds device 10, and also exemplifies a possible method of use thereof. In this non-limiting example device 10 comprises a plurality of radioactive therapeutic seeds 12 placed inside an elongated casing 11 made from a suitable biocompatible material. For example, elongated casing 11 may be implemented by means of a flexible sleeve or tube, such as a medical catheter. The distal and proximal openings of elongated casing 11 may be sealed by corresponding plugs 14b and 14a, for example, made from a biocompatible medical adhesive material. However, elongated casing 11 may be sealed at one of its extremities and include only one opening through which radioactive therapeutic seeds 12 may be introduced or discharged.

Elongated casing 11 may be manufactured from any material medically approved for temporary use in the body. The diameter of elongated casing 11 may generally be in the range of 2 to 10 mm, preferably about 4 mm. Radioactive therapeutic seeds 12 placed inside elongated casing 11 may be implemented by spherical seeds having a diameter of about 1 to 9 mm, preferably about 2 mm.

Preferably, the position of the radioactive therapeutic seeds 12 inside elongated casing 11 is defined by means of internal stoppers 13a and 13b, which prevents migration of the seeds 12 towards the extremities of elongated casing 11, at 14a and 14b, while defining a zone 12s along which the seeds are distributed. In this example elongated casing 11 of device 10 is placed inside the body 20 of a treated subject, adjacent, or inside, a region comprising a tumor 15. Optionally, only a desired section of the elongated 11 casing between stoppers 13a and 13b may be activated in order to restrict the area to which radiation is to be applied.

Elongated casing 11 may be introduced into tumor region 15 via an incision 16c, e.g., embodied inside a regular sterilized medical catheter, while its proximal end at 14b protrudes from, and anchored to, the external surface of the treated subject skin 16. A preferred treatment session employing device 10 may endure for about a week. However, the treatment session may be prolonged or shortened according to characteristics of the tumor 15 and of the radioactive therapeutic seeds 12.

In one preferred embodiment of the invention the radioactive therapeutic seeds are designed to emit radiation comprising a mix of β and γ radiation suitable for delivering therapeutic dose at about 2-5 mm depth and acceptable dose at 20-50 mm. This most beneficial balance is attainable by the β radiation which penetrates only a few millimeters while delivering all its radiation energy in that range, whereas the γ radiation is delivered throughout a more extended range. The mixed radiation device is, hence, superior to a single radiation device currently utilized.

EXAMPLE

50 Zirconia beads, of 1.5 mm diameter (cost = 0.2 USD), are activated via 20 MeV protons, at a current of 1 mA, in an adequate cooling device (for eliminating damage to the beads), till a total activation level of 100 mCi is reached. The irradiated beads are then threaded on a polyimide wire, enveloped in a polyimide tubing of 0.1 mm wall, which is loaded at a length of 5 cm per the physician planning and orders. The loaded edge is sealed with a silicone resin. A tubing empty tail of ca Im is left attached to the tethered seeds for retrieval. The tethered beads are then calibrated to their dose-rate vs. distance, and shipped to the hospital in an adequate shielding (eliminating stuff exposure) within 2-10 h after the irradiation.

In the hospital, immediately after removal of a malignant tumor, the tethered beads are placed in the remaining cavity and the tumor-neighboring tissues are tightened around the tethered beads. Upon closing the wound, the tubing tail is guided all the way to the skin, and anchored just under it before putting in the external stitches, leaving the Brachytherapy device inside. The patient can be released home once the medical condition so permits, without worrying about the device inside. Once the time-span planned for the Brachytherapy has elapsed, the patient will be invited to the hospital for a checkup and removal of the device, which can be reprocessed and reactivated, for reuse.

All of the abovementioned parameters are given by way of example only, and may be changed in accordance with the differing requirements of the various embodiments of the present invention. Thus, the abovementioned parameters should not be construed as limiting the scope of the present invention in any way. In addition, it is to be appreciated that the different tubes/sleeves, seeds, and other members, described hereinabove may be constructed in different shapes (e.g. having oval, square etc. form in plan view) and sizes differing from those exemplified in the preceding description.

The above examples and description have of course been provided only for the purpose of illustration, and are not intended to limit the invention in any way. As will be appreciated by the skilled person, the invention can be carried out in a great variety of ways, employing more than one technique from those described above, all without exceeding the scope of the invention.