WO2001070336A1

WO2001070336A1 - Methods and devices for radiation therapy

Info

Publication number: WO2001070336A1
Application number: PCT/CA2001/000397
Authority: WO
Inventors: Nabil Adnani
Original assignee: Neutron Therapy And Imaging Inc.
Priority date: 2000-03-23
Filing date: 2001-03-23
Publication date: 2001-09-27
Also published as: AU2001244001A1

Abstract

Device for and a method of irradiating a tissue in a subject by placing an implantable device of a material with a thermal neutron absorption capacity within or adjacent to the tissue and irradiating the tissue with fast neutrons to cause the material to emit radiation which irradiates the tissue. The irradiation of the tissue is ceased as soon as the thermal neutron is removed.

Description

METHODS AND DEVICES FOR RADIATION THERAPY

Field of the Invention

This invention relates to radiation therapy and more particularly to methods and devices for irradiating a tissue of a human or animal subject.

Background of the Invention

In the description which follows, references are made to certain literature citations which are listed at the end of the specification and all of which are incorporated herein by reference.

Soon after the discovery of x-rays by Roentgen in 1895, it became evident that ionizing radiation could kill tumor cells and that cancer patients could be treated by radiation therapy (1 ). It also quickly became evident that, above a certain dose level, x-rays cause damage to the normal tissues which are also irradiated during treatment. The probability of local control of a tumor increases with the radiation dose absorbed and a sufficiently high radiation dose should be delivered to the whole volume of tissues invaded by malignant cells. This goal must, however, be reached without causing severe and irreversible damage to the surrounding normal tissues. One approach to minimising normal tissue damage was the use of brachytherapy or "short range therapy" which relies on the placing of radiactive material directly into, or adjacent to, a tissue which one wishes to irradiate (2). Implantable radioactive seeds for use in brachytherapy are described, for example, in U.S. Patents Nos. 5,460,592 and 6,132,359. Conventional brachytherapy techniques, however, involve the handling and surgical insertion of radioactive materials, thus requiring special training and use of techniques to protect personnel involved. The implanted radioactive seeds may migrate from their original positions, reducing the accuracy of radiation dose calculations, and thus, dose delivery (3-5). Other approaches have aimed at minimising normal tissue damage during irradiation by external beam radiation therapy (EBRT). One is the use of multiple converging beams, where each beam contributes only a small radiation dose to the normal tissue it traverses, while the convergent beams together provide the required dose to the treated area . The use of multileaf collimators consisting of two sets of several leaves which can be moved independently, allowing the application of irregularly-shaped beams better adapted to the complex shape of the volume to be treated, is another approach (6). Intensity Modulated Radiation Therapy combines the use of both multileaf collimators and of converging beams of different intensities, using special mathematical algorithms to determine the number of fields required, their shapes and their intensities for a given prescribed radiation dose (7).

Another area in which radiation therapy has been employed is in vascular disease. Blocked arteries due to plaque deposits are the most common cause of morbidity and mortality in vascular diseases which afflict a wide spectrum of organs such as the heart, brain, kidney, liver and extremities (peripheral vascular system) . The most common pathology of vascular diseases is occlusion. Percutaneous Transluminal Angioplasty (PTA or coronary angioplasty) is currently the most common nonsurgical treatment for obstructed arteries. Unfortunately, the long term effectiveness of PTA is limited by a high re-occlusion or restenosis rate. Efforts to reduce post-PTA restenosis, including laser treatment, mechanical atherectomy, intravascular stenting and pharmacologic agents, have largely been unsuccessful. It has been demonstrated that the risk of restenosis can be reduced significantly by vascular radiotherapy subsequent to PTA; radiation techniques have been developed such as intravascular brachytherapy employing various sources of radiation, including radioactive stents (8-11). These techniques have the same drawbacks as described above for brachytherapy methods employing handling and implantation of radioactive materials into tumours.

Summary of the Invention

In accordance with one embodiment, the invention provides a method of irradiating a tissue in a subject, the method comprises the steps of: (a) providing a subject having a tissue in need of irradiation;

(b) placing at least one implantable device comprising a prompt radiation emitter within or adjacent to the tissue; and

(c) irradiating the tissue with a beam of fast neutrons, whereby the energy level of at least a portion of the fast neutrons is reduced within the subject to produce thermal neutrons which cause the prompt radiation emitter to emit radiation which irradiates the tissue.

In accordance with a further embodiment, the invention provides for the use of a prompt radiation emitter to fashion an implantable device for use in radiation therapy.

In accordance with a further embodiment, the invention provides a system for irradiating a tissue in a subject, the system comprises:

(a) means for producing a beam of fast neutrons for irradiating a subject; and

(b) an implantable device comprising a prompt emitter for implantation in the tissue to be irradiated, whereby when the subject is irradiated with the beam of fast neutrons, the energy level of at least a portion of the fast neutrons is reduced within the subject to produce thermal neutrons which cause the prompt radiation emitter to emit radiation which irradiates the tissue.

In accordance with a further embodiment, the invention provides a method for optimising the irradiation of a tumor in a subject while minimising damage to normal tissues of the subject surrounding the tumor, the method comprises the steps of:

(a) providing a subject having a tumor in need of irradiation;

(b) placing at least one implantable device comprising a prompt radiation emitter within or adjacent to the tumor;

(c) subjecting the tumor to irradiation with a beam of fast neutrons of a first energy level produced by a high energy electron accelerator, whereby the energy level of at least a portion of the fast neutrons is reduced within the subject to produce a flux of thermal neutrons which cause the prompt radiation emitter to emit radiation which irradiates the tumor and shrinks the tumor;

(d) obtaining an image of the tumor to determine the reduced size of the tumor; (e) using a computer to calculate a further lower fast neutron beam energy level which will produce a reduced flux of thermal neutrons sufficient to cause the prompt radiation emitter to emit radiation which irradiates the tumor of reduced size while sparing the normal tissues surrounding the tumor;

(f) reducing the photon beam energy of the high energy linear accelerator to produce a fast neutron beam of the calculated further energy level; and

(g) subjecting the tumor to a further irradiation with the fast neutron beam of the calculated further energy level.

In accordance with a further embodiment, the invention provides a system for optimising the irradiation of a tumor in a subject while minimising damage to normal tissues of the subject surrounding the tumor, comprising:

(a) a high energy linear accelerator for producing a beam of fast neutrons for irradiating a subject;

(b) an implantable device comprising a prompt emitter for implantation in the tissue to be irradiated, whereby when the subject is irradiated with the beam of fast neutrons, the energy level of at least a portion of the fast neutrons is reduced within the subject to produce thermal neutrons which cause the prompt radiation emitter to emit radiation which irradiates the tissue; and (c) computer means for calculating the fast neutron beam energy level required to produce a flux of thermal neutrons sufficient to cause the prompt radiation emitter to emit radiation which irradiates a tumor of a specified size while sparing the normal tissues surrounding the tumor. In accordance with a further embodiment, the invention provides a method of irradiating a tumor in a subject, the method comprises the steps of: (a) providing a subject having a tumor in need of irradiation; (b) administering to the tumor an effective amount of a gadolinium 157-containing compound; and

(c) irradiating the tumor with a beam of fast neutrons, whereby the energy level of at least a portion of the fast neutrons is reduced within the subject to produce thermal neutrons which cause the gadolinium 157-containing compound to emit radiation which irradiates the tissue.

(a) providing a subject having a tumor in need of irradiation;

(b) placing at least one implantable device comprising a prompt radiation emitter within or adjacent to the tumor.

(c) subjecting the tumor to irradiation with a beam of fast neutrons of a first energy level produced by a high energy electron accelerator, whereby the energy level of at least a portion of the fast neutrons is reduced within the subject to produce a flux of thermal neutrons which cause the prompt radiation emitter to emit radiation which irradiates the tumor and shrinks the tumor; (d) obtaining an image of the tumor to determine the change in size of the tumor after one or several sessions of treatment;

(e) using a computer to calculate the new radiation dose distribution which will require an adjustment in the fast neutron beam intensity which will produce an adjusted flux of thermal neutrons which will ensure the prompt radiation emitter to emit radiation which irradiates the new tumor volume while sparing the normal tissues surrounding the tumor;

(f) adjusting the photon beam energy of the high energy linear accelerator to adjust the flux of the fast neutron; and

(g) subjecting the tumor to a further irradiation with the fast neutron beam thus adjusted.

Summary of the Drawings Certain embodiments of the invention are described herein and illustrated in the accompanying drawings, wherein:

Figure 1 shows thermal neutron flux measurements at depth in water, using an 18 MV photon beam generated by a Varian 2100C Clinac, with source to surface distance 100 cm.

Figure 2 shows the emitted photon dose rate profile resulting from ^• neutron activation of a Gd implant. The line is used as an aid to the eye and does not represent a functional fit.

Figure 3 shows the emitted beta dose rate profile resulting from neutron activation of a Gd implant. The line is used as an aid to the eye and does not represent a functional fit.

Figure 4 shows the gamma dose rate profile of a 20 mg Gd-157 seed at 5 cm depth in water, derived from a combination of thermal neutron flux measurements of Figure 1 and the Monte-Carlo calculations shown in Figures 2 and 3.

Figure 5 shows in diagrammatic form a central slice of a 43 cm³ tissue volume implanted with 112 Gd-157 seeds of 20 mg each.

Detailed Description of the Invention The invention provides improved brachytherapy methods which avoid the problems and hazards of handling and implanting radioactive materials into tissues which one wishes to irradiate. The methods employ the placing, into or adjacent to the tissue to be treated, of an implantable device comprising a prompt radiation emitter, followed by activation of the emitter to cause it to emit radiation in sjtu and irradiate the tissue.

As used herein, "an implantable device" means a device which can be inserted surgically into a tissue of a subject in need of irradiation treatment.

A "prompt radiation emitter" means a material which can absorb thermal neutrons (energy range less than about 1eV) and, on absorption of thermal neutrons, is caused to emit electron and/or photon radiation and which ceases to emit such radiation substantially as soon as (micro to milliseconds after) the source of thermal neutrons is removed. Preferred prompt radiation emitters include boron-10, which emits photons and alpha and lithium particles, and gadolinium-157, which emits photons and electrons (gamma and beta particles respectively). Gadolinium- 157 may conveniently be employed in the form of natural gadolinium, which contains about 16% Gd-157 or in the form of enriched gadolinium, which contains greater than 16% up to 100% of Gd-157.

The implantable device may be fashioned entirely from a prompt radiation emitter or may include other components, as described herein.

Once the implantable device comprising a prompt radiation emitter is inserted into a target tissue in a subject, it is exposed to thermal neutrons by irradiating the target tissue with a beam of fast neutrons. As the fast neutrons pass through the subject to the target tissue, the energy level of at least a portion of the fast neutrons is reduced by the subject's tissues, producing thermal neutrons which are of an energy level suitable to cause the prompt radiation emitter to emit photon and/or electron radiation which irradiates the tissue.

"Tissues" to be treated by the method of the invention may be any tissue or organ of a human or animal subject in need of irradiation. These include, for example, a solid organ containing a tumor or a solid tumor, where the implantable device is inserted into the tissue or a tubular organ with a lumen, where the implantable device is placed within the tubular organ to irradiate the inner wall of the organ.

The fast neutron beam used to irradiate the tissue may be generated by a nuclear reactor or large scale accelerator as in conventional radiotherapy. Such machines are not, however, widely available and accessible. More commonly available are high energy electron linear accelerators (LINACs) which are used for electron-based and/or photon- based radiation therapies and are generally capable of producing beam energies of up to about 40 MeV. When LINACs are used to produce a photon beam, interactions of the accelerated electrons with the target produce fast neutrons as well as photons, giving a mixed photon and fast neutron beam; LINACs can therefore also be used as a source of fast neutrons, as described in International Patent Application No. PCT/CA01/00036, the contents of which are incorporated herein by reference. A LINAC - produced fast neutron beam may be used to irradiate a target tissue in accordance with the methods of the invention. The patient must be shielded from the photon component of the LINAC beam by completely closing the LINAC jaws or by partially closing the jaws and using lead or bismuth shielding in the path of the beam, if the radiation dose is to be delivered only by the radiation emitted from the implant. Alternatively, the radiation emissions from the implant can be used as dose enhancement to the dose delivered by the photon beam of the LINAC.

Irradiation of a target tissue by a method of the invention may be employed to kill cells, for example cells of a malignant tumor or cells causing restenosis of a blood vessel. Treatment may be curative or palliative. The method of the invention avoids the surgical handling and implantation of radioactive materials and permits one to wait until post- implantation swelling has subsided before commencing the radiation treatment. The method also provides excellent radiation dosage control, since the implantable device emits radiation only when acted on by the activating neutron beam. The method of the invention may be employed, in one embodiment, to irradiate a solid tissue, for example a tumor. Suitable implantable devices for this method include seeds similar in structure to the radioactive seeds previously described for use in conventional brachytherapy, but comprising a prompt radiation emitter. Implant positions within the tumor can be determined by traditional imaging methods and/or neutron imaging during the in situ activation process. Implant positions have to be known in order to perform a proper calculation of their activities when exposed to the beam. These activities are then entered into conventional treatment planning software in order to calculate the dose distribution in and around the tumor (12). Because existing treatment planning software may not be able to take into account the variation in implant activity as a function of position in the tumor, then by using several neutron fields to converge at the tumor (as in conventional radiation treatment), each seed will on average exposed to the same number of thermal neutrons. In other words, all implants will reach the same activity level and existing treatment planning software can be used. In accordance with one embodiment, a seed for use in radiation therapy of a tumor comprises a cylindrical rod made from a prompt emitter, preferably natural gadolinium and more preferably Gd-157-enriched gadolinium. The rod may be coated with or enclosed in a casing of a coating material. Suitable coating materials include titanium or a suitable plastic; preferred coating materials are those already approved for human use in medical devices by bodies such as the FDA, as known to those of skill in the art.

In accordance with a further embodiment, a seed for use in radiation therapy of a tumor comprises a casing containing a linear array of particles of a prompt emitter, preferably gadolinium and more preferably Gd-157-enriched gadolinium.

The particles preferably have no dimension greater than about 0.5 mm, to reduce self-attenuation of the thermal neutron beam. The particles may be, for example, spheres of a diameter up to about 0.5 mm. The length of the array of particles may vary according to the site in which it is intended to be implanted. For example, the typical dimensions of conventional brachytherapy seeds may be used (5 mm length and 0.8 mm diameter). The casing may be made of a coating material as described above. In accordance with a further embodiment, a seed for use in radiation therapy of a tumor comprises a casing containing a prompt radiation emitter in powder form, preferably gadolinium in powder form and, more preferably powdered Gd-157-enriched gadolinium. For example, a seed of 5 mm length and 0.8 mm diameter might contain about 20 mg gadolinium powder. Seeds are implanted in the tissue to be irradiated by conventional methods as described for brachytherapy with radioactive seeds (12). For example, seeds may be implanted into the target tissue by injection through a hypodermic needle of suitable bore.

The method of the invention may be employed, in a further embodiment, to irradiate a tubular tissue having a lumen. In this embodiment, the implantable device preferably takes the form of a stent comprising a prompt radiation emitter. Suitable stents may be similar in structure to radioactive stents previously described for use in restenosis (13-14). The stent is placed within the lumen of the tissue and is held, by its shape, in close proximity to the wall of the lumen so that when the stent is activated to emit radiation, the tissue of the lumen wall is irradiated. Those of skill in the art are familiar with the shape and construction of stents, which have been described principally for use in treating coronary artery restenosis (14).

The stent preferably comprises a prompt radiation emitter selected from boron-10, natural gadolinium or Gd-157-enriched gadolinium.

This method of the invention may be employed to irradiate cancerous portions of the gastro-intestinal tract, to treat, for example, colorectal cancer or oesophageal cancer.

In accordance with a further embodiment, this method of the invention may be employed to irradiate a blood vessel which is susceptible to or is undergoing restenosis. Assessing the need for such treatment and the proper method of placing the stent in the blood vessel is within the skill of the physician or surgeon treating the subject (14).

During exposure to thermal neutrons, gadolinium-157 is transformed into stable gadolinium-158 and gamma and beta energy spectra are emitted with an average energy around 1.42 MeV and 0.047 Mev respectively. The boron neutron capture reaction of boron-10 releases about 2.3 MeV of energy in the form of alpha and Li-7 particles and a 0.48 MeV photon.

As shown by the results summarized in Table 1 , a stent of 1g gadolinium-157 will yield a photon dose rate of 18.2 Gy/min at 0.5 mm distance. 0.5 mm is the recommended reference distance by the American Association of Physicists in Medicine (AAPM) TG-60 Protocol (15). The electron dose rate is much higher but does not extend beyond 0.4 mm distance from the source, due to the low energy of the emitted electrons. It may be desired to expose a blood vessel to both the photon and electron emissions; in this case an uncoated Gd stent may be used. If it is desired to shield the tissue from the short range electron emission, the Gd stent is coated with a coating material. Suitable coating materials include titanium or a suitable plastic as described above.

When a stent of 100 mg of ¹⁵⁷Gd is exposed to the neutron beam generated by an 18 MV LINAC photon beam at 50 cm SSD, closed jaws and 600 MU/min, prompt gammas are emitted and the resulting activity is 22.5 mCi for as long as the beam is on.

The dose delivered to an artery by such a ¹⁵⁷Gd stent will be a combination of the beta and gamma dose. Table I below shows the dose rate from the two components at different distances from a 1 g point source of ¹⁵⁷Gd. The short range of the emitted betas means that the dose from the electrons is confined to the first few fractions of a mm. The AAPM TG-60 recommends that when a radioactive stent is used in vascular brachytherapy, the dose should be prescribed to 0.5 mm from the stent. 0.5 mm is chosen because it represents the center of the inner artery wall of 1 mm thickness. Because of their very short range, beta emissions from the ¹⁵⁷Gd stent cannot make a contribution to the dose to the inner wall of the artery unless the stent is bare (i.e., the ¹⁵⁷Gd is not covered by any other material with a capacity to absorb electrons). If the stent is coated to shield the electron emissions, dose rates of 18.2 Gy/min can be deposited at 0.5 mm distance by a 1 g ¹⁵⁷Gd stent. (Table I). If natural Gd is used instead of ¹⁵⁷Gd, the dose rate will drop by a factor of 5 to 3.64 Gy/min due to the reduction in the thermal neutron capture cross section in natural Gd. The dose rate can be increased dramatically if bare Gd is used as a stent material to take advantage of the contribution to the dose from the beta emission. In this case, however, the reference distance should be 0.3 mm instead of 0.5 mm as recommended in AAPM TG-60. In a further embodiment, the stent is made of Boron-10 which emits alpha and lithium particles and a photon of 0.48 MeV energy.

If it is desired to shield the tissue from the alpha and lithium particles, the stent may be coated as described above. Many cancer patients presenting for radiation therapy have, in addition to a primary tumor of a size suitable for insertion of an implantable device as described herein, one or more metastatic tumors of a size too small for implantation with sucr device.

In accordance with a further embodiment, the invention provides a method for irradiating these metastatic tumors by delivering a compound comprising Gd 157-enriched gadolinium in a liquid formulation via the circulation to the tumor. Once the emitter has been taken up by the tumor, the subject is irradiated with a fast neutron beam in the same manner as described above for irradiation after implantation of an implantable device of a prompt radiation emitter. Thermal neutrons are produced in the subject and cause the Gd-157 in the tumor to emit and irradiate the tumor.

A number of gadolinium-containing compounds are suitable for use in this method. For example, a number of gadolinium-containing compounds have been described for use in medical imaging; these are readily taken up by tumor tissue. One such group of compounds are the gadopentetic acids (Gd- DTPA). Commercially available examples of such compounds are ProHance and Multihance from Bracco Diagnostics (Mississauga, Ontario, Canada). The synthesis of these compounds is described in (16) and the same method may be used to produce Gd-157 analogs, by replacing the natural gadolinium of the method with Gd157-enriched gadolinium. Enrichment to 50% Gd-157 is preferred and 100% is especially preferred.

The Gd-enriched compound may be prepared in the same type of formulation as is used for MRI for use in the method of the invention. The formulated compound is administered intravenously either as a bolus or by slow injection. The waiting time between the end of the injection and the commencement of the irradiation treatment will depend on the pharmacokinetics of the particular compound used and the tissue to be treated. Determination of the appropriate time is within the skill of ordinary practitioners in the art. For previously described MRl agents, the waiting time will be as described for MRl.

When a ¹⁵⁷Gd-containing compound is injected intravenously, the concentration of Gd may be either homogenously distributed around the tumor volume or exhibit a particular distribution. In all cases, an MRl image of the region of the tumor should be taken before commencement of irradiation, to allow calculation of an optimal radiation dose. Example 3 shows a typical calculation. IMRT or Intensity Modulated Radiation Therapy is a technique which attempts to achieve as much tissue sparing as possible by changing the intensity of the radiation beams used during dose delivery. It permits optimising the irradiation of a tissue such as a tumor in a subject while minimising damage to normal tissues of the subject surrounding the tissue to be irradiated.

This technique has not been possible previously in radiation therapy employing a neutron beam generated by a nuclear reactor, since the neutron flux cannot be adjusted. The technique has therefore previously been applicable only in the context of radiation therapy using photon beams, but even here, little improvement in selectivity is available in delivery of radiation dose.

As described above, it as now been shown that, using a neutron beam generated by a LINAC, it is possible to provide effective neutron radiation therapy. A further advantage of a LINAC-based method of treatment is that IMRT is now possible in neutron therapy. In accordance with a further embodiment of the invention, LINAC neutron IMRT utilises the ability to modulate the fast neutron flux generated by the machine by modulating the energy and intensity of the electron beam obtained from the accelerator and hence the intensity of the mixed photon/neutron beam produced. In addition to modulating the energy and intensity, one can vary the distance between the patient and the source. The shorter the distance, the higher is the neutron beam intensity. By modulating the fast neutron flux used to irradiate the subject, one can modulate the intensity of the radiation emitted either by an implanted device comprising a prompt radiation emitter or by a prompt radiation emitter- containing compound located in a tissue of the subject. A method is thereby provided for optimising the irradiation of a tumor in a subject while minimising damage to normal tissues of the subject surrounding the tumor. At least one implantable device comprising a prompt radiation emitter is placed within or adjacent to the tumor and the subject is irradiated with a beam of fast neutrons produced by a LINAC, as described above. As the tumor is destroyed, its volume shrinks. Its reduced size is determined by obtaining an image of the tumor, for example by MRl. A computer calculation is then carried out, first to determine by how much the thermal neutron flux produced by irradiation of the subject should be lowered in a further treatment, to limit emitted radiation to the reduced volume of the tumor and spare surrounding normal tissue, and then to determine the new lower fast neutron beam energy level required to produce the desired thermal neutron flux. The photon beam energy, its intensity (usually referred to as machine output) and the source to patient surface are then adjusted accordingly and the subject is subjected to a further radiation treatment. A system is also provided to carry out this method.

Based on the results of thermal neutron flux measurements, Table I shows the different levels of activity obtained for 1 g Gd using different neutron generation techniques or neutron flux modulation as well as the corresponding beta and gamma dose rates at different distances from the seed (or source).

From Table I it can be seen that a tumor with a 40 cm³ volume is equivalent to a sphere of about 2 cm radius. To keep the healthy tissue dose around the tumor at a very low dose, one can use the irradiation technique given in Table I, row 2. As the tumor starts to shrink, for example if its radius halved to 1 cm, then using the irradiation technique of row 3 or row 4, will keep the healthy tissues beyond 1 cm at a very low dose. As the tumor continues to shrink, one can use a technique equivalent to rows 5 and 6. When bare Gd seeds are employed, the beta component of the dose needs to be considered in the estimation of the total dose.

Another important aspect of the dosimetry to consider is the contribution from the remaining photons in the beam (leakage photons) and fast neutrons. Table II shows the contribution to a tumor dose from these components as well as the thermal neutron capture dose contributions from Nitrogen and Hydrogen capture reactions which are predominant in a human body.

The form and dimensions of the gadolinium seed may have an effect on the shape of the beta and gamma dose profiles shown in Figures 2 and 3. Consequently, the numbers in Table I are expected to change when the seed dimensions are changed. One of skill in the art can readily perform similar calculations for selected seed dimensions. Because gadolinium has a very high cross section for thermal neutron capture, the seeds should be as thin as possible in the direction facing the beam. For example, small spheres of 0.5 mm diameter or powder of -40 mesh or less may be used to manufacture a seed of the desired dimensions. Recommendations for protocols for dosimetry studies are described in AAPM TG-43 (17) and AAPM TG-64 (18).

Examples

The examples are described for the purposes of illustration and are not intended to limit the scope of the invention.

Methods of physics and nuclear medicine referred to but not explicitly described in this disclosure and examples are reported in the scientific literature and are well known to those skilled in the art.

Example 1 : Activation of Gd-157

The cross section for thermal neutron capture for Gd-157 is 2.55 x 10⁵ barns. Thermal neutron capture causes Gd-157 to emit a photon spectrum with an average energy around 1.42 MeV. A 1 g ¹⁵⁷Gd seed exposed to the thermal neutron beam generated by an 18 MV photon beam will result in a prompt activity (emission) of: A = 225 mCi.

Figures 2 and 3 show the gamma and beta dose rate profiles obtained during neutron activation of a Gd seed. These results were obtained by Monte-Carlo calculations, using the EGS4 code, of a 0.1 mm diameter and 1 mm length gadolinium seed. Expressing the dose rate per emission of a photon or electron allows one to modulate the dose rate in Gy/min by changing the level of seed activity during the neutron irradiation. The low energy betas emitted have a short range of penetration in tissue, not in excess of 0.4 mm. The dose rate at distances shorter than 0.4 mm is high.

Combining the results of the measurements shown in Figure 1 and the dose profiles of Figures 2 and 3, it is possible to derive the dose at any point from a Gd seed in a patient exposed to a neutron beam of a specified energy, as shown in Table 1 and Figure 4.

The dose rate drops from close to 23.9 Gy/h at 0.45 mm from the seed to 0.29 Gy/h at 1 cm away. The rapid drop in radiation dose at short distance from the source has great potential for reducing normal tissue complication probability (NTCP) while increasing tumor control (TC). In practice, and due to the high cross section of Gd for thermal neutron capture, only the Gd atoms close to the surface layers of the Gd seed will be exposed to thermal neutrons and thus activated. It will then be necessary to use several smaller seeds instead of one single large seed at the center of the tumor. The number of seeds needed to achieve the desired dose fraction is determined by proper treatment planning software calculations which take into account seed activity, tumor volume and the distribution of the seeds (18). Based on the results shown in Figure 3, the dose distribution of a set of 20 mg 157Gd seeds in a 43 cm³ volume has been calculated (representing the average volume of a prostate). The inner part of the volume, about 3 cm³, which represents the urethra in the case of a prostate is not implanted. The results of the dose distribution calculations are shown in Figure 5. It can be seen that while the rest of the prostate volume receives a dose rate higher than 61 Gy/h, the urethra remains relatively cold at less than 4 Gy/h while the tissues outside the prostate volume receive less than 1 Gy/h.

Example 2: Activation of Boron-10

On activation by thermal neutron captive, boron-10 emits gamma radiation of 0.48 MeV and two high LET particles, α and Li-7. The two particles release their total energy of 2.32 MeV within 12 to 15 μm. The prompt activity achieved by a 1 mg of ¹⁰B at 5 cm depth in a subject is:

A=0.521 mCi

Based on the gamma emission alone, the dose rate emitted by 1g of ¹⁰B seed will be 5 cGy cm²/s. 8.56 minutes of exposure to neutron beam of a LINAC will be sufficient to deposit a dose of 2Gy at 1 cm from the ¹⁰B seed. To avoid excessive dose from the alpha and Li-7 particles, it may be useful to coat the boron-10 with a suitable coating as described herein.

Example 3

An example of the calculation of the radiation dose to be used when irradiating a tumor containing a Gd157-enriched compound is as follows:

The volume of the tumor is notionally divided into several smaller volumes (the smaller these unit volumes, the better is the resolution in isodose distribution). The equivalent mass of ¹⁵⁷Gd in each of these smaller volumes will be approximated as a single seed of ¹⁵⁷Gd of the same mass positioned in the center as shown in Figure 5. The coordinates of the center of each of these unit volumes being given by the MRl imaging information, it is possible to calculate the isodose distribution as a result of exposure to the neutron beam of a high energy linac.

For example, in the case where 1 g of ¹⁵⁷Gd is evenly distributed in a tumor of 50 cm³, isodose distribution in and around the tumor can be approximated by that of 50 point sources of ¹⁵⁷Gd, weighing 20 mg each, positioned at the center of each 1 mm³ of the tumor. The resulting activity from each point source will depend on its depth relative to the surface of the patient even though a more homogeneous activity can be achieved by using several fields converging at the tumor.

The present invention is not limited to the features of the embodiments described herein, but includes all variations and modifications within the scope of the claims.

Table I. Gamma and beta (or photon and electron) dose rates in Gy/min obtained by activating a 1 g Gd seed at 5 cm depth in patient using an 18 MV photon beam with jaws completely closed. NGD stands for Natural Gadolinium. Otherwise, it is assumed that ¹⁵⁷Gd is used. These numbers are derived assuming a 1 g seed of Gd will generate the profiles shown in Figures 1 and 2 and all self-attenuations are neglected.

Table 11. Contribution from the other components of the neutron beam compared to the neutron conversion to photons inside the tumor by Gadolinium neutron capture. The numbers in the third row (10 mm distance from the Gd seed) may change depending on whether one is going towards the beam or away from the beam. This applies to both the photon, fast neutrons and thermal neutron captures by hydrogen and nitrogen. However, since these contributions are small anyway, they are given here at 10 mm on the same horizontal plane.

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Claims

23Claims:

1. A method of irradiating a tissue in a subject, the method comprising the steps of: (a) providing a subject having a tissue in need of irradiation;

2. The method of claim 1 wherein the tissue is a solid tissue.

3. The method of claim 2 wherein the prompt radiation emitter is selected from the group consisting of boron-10, natural gadolinium and gadolinium- 157.

4. The method of claim 2 wherein the implantable device comprises a rod of a prompt radiation emitter.

5. The method of claim 4 wherein the implantable device further comprises a coating or a casing covering the rod.

6. The method of claim 2 wherein the implantable device comprises a linear array of particles of a prompt radiation emitter or a prompt radiation emitter in powder form contained in a casing.

7. The method of any one of claims 4 to 6 wherein the prompt radiation emitter is selected from the group consisting of boron-10, natural gadolinium and Gd-157. 24

8. The method of any one of claims 1 to 7 wherein the tissue is a tumor.

9. The method of claim 8 wherein the tumor is selected from the group consisting of a prostate tumor, a mammary tumor, a brain tumor and a lung tumor.

10. The method of claim 1 wherein the tissue is a tubular organ.

11. The method of claim 10 wherein the tissue is a portion of the gastrointestinal tract affected by a tumor.

12. The method of claim 10 wherein the tissue is a portion of a blood vessel.

13. The method of claim 12 wherein the prompt radiation emitter is selected from the group consisting of boron, natural gadolinium and Gd-157.

14. The method of any one of claims 10 to 13 wherein the implantable device comprises a stent of a prompt radiation emitter.

15. The method of claim 14 wherein the implantable device further comprises a coating covering the stent.

16. The method of claims 14 or 15 wherein the prompt radiation emitter is selected from the group consisting of boron-10, natural gadolinium and Gd- 157.

17. The method of any one of claims 1 to 16 wherein the subject is a human subject. 25

18. The method of any one of claims 1 to 17 wherein the fast neutron beam is generated by a high energy electron accelerator.

19. The method of claim 18 wherein the intensity of the radiation emitted within the tissue by the prompt radiation emitter is modulated by modulating the photon beam energy of the high energy electron accelerator, thereby modulating the energy of the fast neutron beam.

20. Use of a prompt radiation emitter to fashion an implantable device for use in radiation therapy.

21. Use of a prompt radiation emitter as in claim 20 wherein the implantable device comprises a rod of the prompt radiation emitter.

22. Use of a prompt radiation emitter as in claim 21 wherein the implantable device further comprises a coating or a casing covering the rod.

23. Use of a prompt radiation emitter as in claim 20 wherein the implantable device comprises a linear array of particles of a prompt radiation emitter or a prompt radiation emitter in powder form contained in a casing.

24. Use of a prompt radiation emitter as in claim 20 wherein the implantable device comprises a stent of the prompt radiation emitter.

25. Use of a prompt radiation emitter as in claim 24 wherein the implantable device further comprises a coating covering the stent.

26. Use of a prompt radiation emitter as in any one of claims 20 to 25 wherein the prompt radiation emitter is selected from the group consisting of boron-10, natural gadolinium and Gd-157.

27. A system for irradiating a tissue in a subject comprising: 26

(a) means for producing a beam of fast neutrons for irradiating a subject; and

28. The system of claim 27 wherein the means for producing a beam of fast neutrons is a LINAC.

29. The system of claim 28 wherein the prompt radiation emitter is selected from the group consisting of boron-10, natural gadolinium and Gd-157.

30. The system of claim 29 wherein the implantable device comprises a rod of the prompt radiation emitter.

31. The system of claim 30 wherein the implantable device further comprises a coating or a casing covering the rod.

32. The system of claim 29 wherein the implantable device comprises a linear array of particles of a prompt emitter or a prompt emitter in powder form contained in a casing.

33. The system of claim 29 wherein the implantable device comprises a stent.

34. A method for optimising the irradiation of a tumor in a subject while minimising damage to normal tissues of the subject surrounding the tumor, the method comprising the steps of:

(a) providing a subject having a tumor in need of irradiation; 27

(d) obtaining an image of the tumor to determine the reduced size of the tumor;

(e) using a computer to calculate a further lower fast neutron beam energy level which will produce a reduced flux of thermal neutrons sufficient to cause the prompt radiation emitter to emit radiation which irradiates the tumor of reduced size while sparing the normal tissues surrounding the tumor; (f) reducing the photon beam energy of the high energy linear accelerator to produce a fast neutron beam of the calculated further energy level; and

35. A system for optimising the irradiation of a tumor in a subject while minimising damage to normal tissues of the subject surrounding the tumor, comprising:

(b) an implantable device comprising a prompt emitter for implantation in the tissue to be irradiated, whereby when the subject is irradiated with the beam of fast neutrons, the energy level of at least a portion of the fast neutrons is reduced within the subject to produce thermal neutrons which cause the prompt radiation emitter to emit radiation which irradiates the tissue; and 28

(c) computer means for calculating the fast neutron beam energy level required to produce a flux of thermal neutrons sufficient to cause the prompt radiation emitter to emit radiation which irradiates a tumor of a specified size while sparing the normal tissues surrounding the tumor.

36. A method of irradiating a tumor in a subject, the method comprising the steps of:

(a) providing a subject having a tumor in need of irradiation;

(b) administering to the tumor an effective amount of a gadolinium 157-containing compound;

37. The method of claim 36 wherein the gadolinium 157-containing compound is administered to the tumor by intravenous administration of the compound to the subject.

38. The method of claim 37 wherein the compound is a gadopentetic acid.

39. The method of any one of claims 37 to 39 wherein the beam of fast neutrons is produced by a high energy linear accelerator.