2~ 038 LOW ENERGY RADIATION SOURCE AND DEYICES
This invention relates to "low" energy photon radiation sources for use in brachytherapy, a form of therapeutic radiology. In particular it is directed to the use of the isotope Yb-169, whose primary photon radiations fall within the energy band from 50 - 300 keV.
Brachytherapy refers to the treatment of diseases especially the treatment of tumors, including malignant tumors such as cancer, with radiation. The objective is to destroy malignant tissue whilst minimising the radiation damage to nearby healthy tissues which are likely to receive considerable ~
;~ radiation. Techniques of placing radiation sources based on radioisotopes into or adjacent to the 20 treatment volume are well established. Radioactive -~
materials which have been useful for such sources have included radium-226, Radon-222, caesium-137, gold-198, irid~ium-192 and cobalt-60. Soùrces based on these prior materials have been made by methods developed 25 over many decades and have been used benefically in -therapy.
The~ penetrating power of the high energy radiations characteristic of these materials of prior ~ :~
use makes it very difficult to adequatel~ shield the nursing staff, clinicians etc and also impose constraints on the treatment rooms during the period of insertion or contact. Whilst under treatment patients must be segregated and shielded from others which causes additional expense and inconvenience.
Another disadvantage results from the irradiation of the patient's healthy tissues outside - 2 - 20~038 the diseased area due to the high penetrating power of the radiation produced by these prior sources.
Attempts have been made to overcome the above named disadvantages by use of the very low energy 5 radiation of Iodine-125. However recent reports of 10 ~-year retropsective studies indicate that this isotope is not suitable clinically in some cases, due to the low energy and low dose rates achievable.
USP 4,702,228 decribes the use of Palladium-103 in such seeds. But Pd-103 suffers from the same problems as I-125, namely low radiation energy and low achievable dose rates and is therefore likely to be of limited clinical use.
Therefore it is the object of this invention to provide optimised therapeutic radioactive sources ~ ~ ~
which will overcome the unwanted exposure problems but ~-offer efficaceous clinical treatment. Such sources will give output radiations nearer to the "optimum"
In considerating the "ideal" brachytherapy source we have to consider all the various techniques and procedures currently in use. The way in which -sources are used sets limits on their physical size ;~
which is determined for any particular nuclide by the activity concentration available and the air kerma or exposure rate constant. These properties are important because they determine the radiation output from a given volume. See N.G. Trott, "Radionuclides in Brachytherapy~ Radium and After", Britilsh Journal of ;
Radiology, Supplement No. 21, pages 4-8, published in 1987 by The British Institute of Radiology.
The optimum energy for photons from brachytherapy sources can be deduced from the following considerations~
"Low" energy: minimizes protective shielding requirements;
"High" energy: (i) avoids increased energy deposition - 2~Qo38 in bone (ii) minimizes attenuation of photons in the volume of tissue which is to be irradiated (dimension; typically only a few centimetres).
(iii~ minimizes radiation scatter and facilitates dose calculations.
Consideration of all factors points to an -"optimum" energy of about 200 kev.
The use of 169Yb as a source of radiation to treat tumours was suggested by Chary in 1968 (Am. J.
Roentgenology Radium Ther. Nuc. Med. 102, 193-198).
This was however in the field of therapeutic pharmaceuticals. Chary used naked microspheres of ;
9Yb and 131I, suspended in a dextran solution, injected into tumour sites. Thus the spheres carried by the solution were able to disperse into the patient's tissues and were not necessarily maintalned at the desired site but also were not removable.'' ~,.''~:;i,'':'~''i!',~,''.'' 20; ~ ; The present invention provides in one aspect a device for implantation in a living body for radiation therapy, comprising a container of blocompatible material having an elongate cavity-;q~ therein, a therapeutic concentration of a radionuclide that emits gamma-radiation being present in the cavity, ; the container being penetrateable by the emitted gamma-radiation,-~
characterized in that the radionuclide is Ytterbium-169.~
~ 30 The device of the present invention provides 0 ~for a contained source of 169Yb to be placed positively and preferably permanently at the desired site of , treatment. The radioactive material is placed inside a titanium, or other suitable metal container. Should ;~
the patient undergo some trauma, free 169Yb will not be ~- dispersed into the patient's tissues. Thus the ~-' ' '' ~.~:. .:
~ .~'. . ..
structure of the capsules ensures their integrity.
This form is also convenient to manufacture.
The invention provides in another aspect metal wire for preferably temporary implantation in a 5 living body for radiation therapy, the wire comprising a therapeut i c concentrat i on of a rad i onuc l i de that emits gamma-radiation and a carrier metal preferably having an atomic number in the range 4 to 28, characterized in that the radionuclide is Ytterbium-169.
TABLE 1 be l ow 9 i ves deta i l s of the nuc l i desused commonly in prior sources.
Chief properties of radionuclides used io prior sources for brachtherapy.
Radionuclide Half-life Principal ~ P'bximum Air kenna Transmission energy concentration rate through ~ -available constant lead .~., o (MeV) (GBq mn ~ Gy nf H~L T~L
GBq 1h 1) (mm) (mm) 2519BA,1 2.965 days 0.41 7.4 55.5 3 11 125I 60.14 days 0.035 3.7 33 0.03 0.1 Ir 74.02 days 0.3-0.61 330 113 4.5 15 182Ta 115.0 days 0.07-1.23 85 156 12 40 60Co ~5.27years ~1.17,1.33130 309 12 ! 40 13710.74 years 0.053 0.390.4 71 N4(.7<2) NA(.?d) ; ~ Cs30.0 years 0.66 1.2 78 6.5 21 252cf2.64 years Mixed n~ 0.37 tl~g lh n 1.99 1.0B
; '' ~
, 2~1~038 TABLE 2: the properties of the ytterbium isotope are as follows:-- j .. ,i.
Radionuclide Half-life Principal ~ ~XinLm Air kerma Transmission eneryy concentration rate through avai lable constant lead ,, ,~ , ~
(McV) (OE3q mn J)(,uGy rf HVL TVL
(m~ m) Yb 169 32 days 0.05 0.30 - 42.5 0.75 1.~2.8 ~ ~,. ...
which overall has properties closer to the optimum than ;~ 15 those of the nucl ides used in prior sources.
In the above Tables, the air kerma rate constant values indicate the attainable dose rate in air for a given size of source; comparable figures for dose rates in tissue are currently not avai lable. The 20 abbreviations HVL and TVL refer to the half value layer and tenth value layer respectively, i.e. the thickness of lead required to reduce radiation to one half or one tenth of its initial value. Disadvantages of the prior radionuclides listed may be summarized in ~ ;~b~
25 qualitative terms as follows:
98Au. The radiation energy is rather high and the half life inconveniently short, limiting the use to certain permanent implant therapies.
5I. Both radiation energy and dose rate are too 1 3 3 B a i s n o t re a d i l y a v a i l a b l e .
- Cf emits neutrons, not gamma radiation. .-.--191Ir, 182Ta, 60Co and 137Cs all have rather high radiation energy. As a result, the requirements for shielding the medical staff who implant the -de v i c e , a nd f or s h i e l d i ng t h e pa t i en t i n wh om t h e .
Z1~0038 device is implanted, are inconveniently severe.
This is brought out particularly with reference to the last two columns of the tables.
With the low energy radionuclides [125I3 iodine in particular, various problems have been reported. Some clinicians are questioning the the adequacy of iodine-125 in permanent implant therapy at prostate tumours (Giles and Brady ...., Kuban et al ..).
Also problems due to the low energy of I-125 have been highlighted by Dale 1983 Am. Assoc. Phys. Med., 10, 176-183. The low radiation energy of 125I results in the following problems. ~-(i) dose uncertainties due to the dependence of the specific dose constant on the effective atomic number of the implanted tissue (and this varies for different sites in the body);
(ii) anisotropy of the emitted radiation around I-125 seeds, leading to some tissues only receiving 30-50% of the intended dose.
(Dale (1983) Am. Assoc. Phys. Med. 10, 176-183).
Other radionuclides have been proposed from time to time, including 103Pd, 145Sm, 13~CS and 51Cr, but have proved less satisfactory than those listed -~ above and have not achieved significant commercial success.
It has been determined for the purposes of the present invention that 169Yb has a totally unsuspected and hitherto unknown property. The effect of this property is that the highest value of the parameter (radiation dose times distance squared) occurs at some distance from the source. This is illustrated in Fig. 1. The graph of Fig. 1 shows a computer simulation of energies emitted over the same eV range as 169Yb through an aqueous medium. The inverse square law which states that the intensity of radiation is inversely proportional to the square of :
the distance travelled from the point source has not been taken into account. This "throwing power" of 169Yb is expected to be valuable in the design and location of seeds and other sources.
169Yb is made by irradiating 168Yb with neutrons. Natural Yb contains 0.2% of the 168-isotope, but enriched mixtures containing up to 40X of the 168-isotope have been commercially available for many ~;
years. Neutron irradiation of these enriched isotope mixtures gives Yb containing acceptable concentrations of the 169-isotope. The minimum concentration of 168Yb in the starting material, required to give an acceptable concentration of 169Yb, depends on the required specific volume activity of the 169Yb. This -is likely to be between 0 5 to 40X.
In the past, Yb has been used mainly for industrial purposes and to a small extent for medical imaging by means of a gamma-camera. 168Yb is available as Yb203 in the form of sintered spheres typically 0.3mm to lmm diameter. These spheres can be made by methods generally described in British Patent Specifications 1313750; 1363532; and 1575300, or by similar methods to produce mixed oxide matrices.- These ~
spheres can be incorporated in seeds or other sources. -25 Alternatively these spheres may be readily combined ~ `
with carrier metals chosen to minimize the absorption of the emitted gamma-radiation, and drawn or swaged into metal wire of the required diameter, which may typically be in the range 0.3mm to 1mm.
Finally, the seed or wire or other source is subjected to neutron iradiation to convert a desired proportion of the 168Yb to 169Yb. Neutron irradiation also tends to make other metals radioactive. Ti is rather resistant to this, and is preferred for this reason for the preparation of seeds and capsules.
With Al, the radioactivity generated by neutron ~ ; .
- 8 - 2(~11QO38 irradiation is short-lived, and sources based on Al can be used when this has mostly decayed. Preparation of sources by neutron irradiation of 168Yb has two practical advantages:-i) The bulk of the preparation is carried out using non-radioactive materials which reduces cost and user hazard. Radioactivity is introduced by neutron irradiation only at the last stage of manufacture.
ii) Because the half-life of 169Yb is only 32 days, supplies need to be held for despatch immediately on receipt of an order. If stocks are not sold for so long that the 169Yb decays, they can be "reactivated" by neutron irradiation at any time to convert more of the reserve of 158Yb to 169Yb.
In addition the use of 169Yb has a further ~ ~.
advantage with regard to removable implants. The device may be reactivated via neutron irradiation after removal from the patient. Hence the device may be re- ;20 used several times. Devices containing 1 to 15~ ;
~` ~reactivated 169Yb can be used 10 to 20 times.
Measurements of the relative biological effect (RBE) have shown that 169Yb possesses a RBE of 1.3 relative to 60Co. Survival curves have shown that little cell repair occurred thus indicating desirable tumour destruction effects will be obtained.
Three preferred forms of the device are envisaged:-a) The ~irst is of the type known as a radioactive seed. These are well described in the literature, see for example British Patent Specification 1133219 and US Patents 4323055 and 4702228. The seed comprises a container or capsule of biocompatible material which is penetrateable by the emitted gamma-radiation. Preferably, the capsule is made of titanium; alternatives are aluminium, PTFE-~.~
20~0()38 : ~
coated aluminium, and PTFE or other plastics capsules. ~ -The capsule should be hermetically sealed, e.g. by welding in the case of metals, effectively to contain the radionuclide. The radionuclide may be present in the form of one or more metal oxide spheres. A heavy metal or other metal X-ray marker may also be present and may also serve to determine the location of the implanted seeds in the tissue. However it has been ~-found that Yb itself is sufficiently visible under X- ~ -ray, so a separate X-ray marker is generally not needed.
These seeds are intended to be injected, e.g. ,~
by means of d hypodermic needle or catheter, into living tissue, where they are implanted and remain at a -desired site. They are typically 0.3 to 1.0 mm diameter and 1 to 10 mm long. Typical activities for ~--radiation treatment using seeds are in the range 0.2 mCi (7.4 MBq) to 35 mCi (1.3 GBq).
b) The radionuclide is provided in the form of wire, which may be used in various ways. A length of plastic tubing may be implanted in living tissue, and a ;~
length of the wire inserted into the tubing by means of a hypodermic needle. In certain cases, e.g. for treatment of tumours in the tongue, the wire may be positioned by means of a sheath which is afterwards removed, leaving the bare wire in position.
c) For intracavitary treatment, e.g. for cervical cancer, larger cylinders or tubes are appropriate, which may be a few cm long and a few mm in diameter.
Re-usable cylinders or tubes are preferably made of metal, such as titanium, and contain 169Yb in the form of oxide spheres, pellets or rods. Pellets may take the form of a Yb metal matrix whereas rods may be solid Yb metal.
Table 3 shows the principal radiation emissions of 169Yb from an infinitely thin source (i.e.
2oloo~8 - l o where there is no internal or external absorption). It will be understood in practical sources the relative intensitites will be somewhat modified by absorption both within the source and the outer capsule, particularly at low energies.
TABLE 3: Yb-169 radiation emissions .
Energy Intensity 7.176 keY(Tm L X-rays) 20.5X
108.224 keV(Tm L~ X-rays) 19.8X
49.772 keV(Tm K~2 X-rays) 53.5X
50.742 keV(Tm K~1 X-rays) 94.3X
57.444 keV(Tm KB1 X-rays) 29.6X
59.296 keV(Tm K32 X-rays) 8.21g 1563.121 keVy-rays 43.7% ~ ~
109.780 keV y-rays 17.4X ; -130.524 keV y-rays 11.1X
177.214 keV y-rays 21.15X
197.958 keV y-rays 34.9X
20307-738 keVy-rays 10.8X
[Taken from "Table of Isotopes" by E Browne and R B Firestone, John Wiley and Sons, 1986.]
Radiotherapy treatment is often given in one of two regimes:
- A high dose rate regime, in which the required dose is given to the patient in a matter of minutes. In thisl regime, the specific activity of the radionuclide chosen is of critical importance. The isotope 169Yb is available at high specific volume activities. -- A low dose rate regime, in which the required dose is given more slowly, e.g. in a matter of days. The devices of this invention are particularly suitable for use in a low dose rate regime.
- 11 - 2010(~38 Reference is directed to Figure 2 of the accompanying drawings, which consists of longitudinal sections through five implantation devices according to the invention.
Referring to Fig. 2A, a radioactive seed for implantation in living tissue for radiation therapy comprises a capsule lO of titanium metal 0.1 mm thick, sealed by laser or other welding at both ends 12.
Within the capsule are two sintered spheres 14 of high purity Yb203, and positioned between them a cylindrical block 16 of high purity lead to act as an X-ray marker.
The spheres 14 are 0.5 - 0.6 mm diameter and together contain 4 - 6 mCi of 169Yb. The seed has a length of -5.0 mm and a diameter of 0.8mm.
Fig. 2B shows a radioactive seed similar to that shown in Fig. 2A except it contains an aluminium marker 20.
Fig. 2C illustrates a different seed with one sintered sphere 14 and two titanium spacers 22.
The radioactive seed in Fig. 2D is filled - , ~- with sintered spheres only.
~ , Fig. 2E represents a wire insert which has a radioactive core 24 composed of 15% Yb203 and 85g Al.
Reference is directed to Figure 3, which is a graph of relative dose distribution for the Fig. 2D
seed placed at the centre with its longitudinal axis parallel to the Y-axis. The values are normalised to unity at l cm along the transverse axis. This dose matrix was generatediby computer simulation. The ~-radiation dose is uniform in all directions. The other Fig. 2 seeds were shown to generate similarly uniform radiation doses in all directions.
; . -, .