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Reactor-produced radioisotopes from ORNL for bone pain palliation
Appl. Radiat. Isot. Vol.49, No. 4, pp. 309-315, 1998 Publishedby ElsevierScienceLtd. Printedin Great Britain 0969-8043/98 $19.00+ 0.00 PII: S0969-8043(97)00043-2
Pergamon
Reactor-produced Radioisotopes from ORNL for Bone Pain Palliation* F. F. ( R U S S ) K N A P P J R I t , S. M I R Z A D E H l, A. L. B E E T S I, M. O ' D O H E R T Y 2, P. J. B L O W E R 2, E. S. V E R D E R A 3, J. S. G A U D I A N O 3, J. K R O P P 4, J. G U H L K E 5, H. P A L M E D O 5 a n d H.-J. B I E R S A C K 5 ~Nuclear Medicine Group, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN, U.S.A., 2Kent and Canterbury Hospital, Canterbury, U.K., 3Department of Nuclear Medicine, Italia Hospital, Montevideo, Uruguay, 4Department of Nuclear Medicine, Carl Gustav University, Dresden, Germany and ~Clinicfor Nuclear Medicine, University of Bonn, Bonn, Germany
The treatment of painful skeletal metastases is a common clinical problem, and the use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical. There are currently several metastatic-targeted agents radiolabeled with various therapeutic radionuclides which are in various stages of clinical investigation. Since neutron-rich radionuclides are produced in research reactors and often decay by emission of 13- particles, most radionuclides used for bone pain palliation are reactor-produced. Key examples of radionuclides produced by single neutron capture of enriched targets include rhenium-186 and samarium-153. In addition, generator systems are also of interest which provide therapeutic daughter radionuclides from the decay of reactor-produced parent radionuclides. One important example is rhenium-188,available from generators via decay of reactor-produced tungsten-188. Tin-117m is an example of a reactor-produced radionuclide which decays with the emission of low-energy conversion electrons rather than by 13- decay. Each of these agents and/or radionuclides has specific advantages and disadvantages, however, the ideal agent for bone pain palliation has not yet been identified. The goal of this paper is to briefly review the production and use of several reactor-produced radionuclides for bone pain palliation, and to discuss the role of the ORNL High Flux Isotope Reactor (HFIR) for the production of many of these radionuclides. Published by Elsevier Science Ltd
Introduction The use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective new method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical (Silberstein, 1996; Freeman and Blaufoux, 1992). The palliative treatment of bone pain associated with metastases to the skeleton is an important application which has many advantages over the traditional use of analgesics and external radiation. Despite the very promising results which have been reported from numerous bone pain palliation studies using therapeutic radionuclides, state-of-the-art reviews describing therapy of bone pain still often omit this important technique and only discuss use of external irradiation and analgesics
*Presented at the Symposium on Measurements for Radionuclides Used for Bone Pain Palliation Therapy,
under the auspices of the CIRMS Medical Subcommittee, NIST, Gaithersburg, MD, 17 September 1996. tTo whom all correspondence should be addressed.
and other drugs for palliation (Thuerlmann and de Stoutz, 1996). Since rhenium-188 and t i n - l l 7 m are two of the most recent therapeutic radionuclides being evaluated for treatment of bone pain, in this paper we discuss the production of these two radionuclides as well as important examples of other radionuclides of current interest which are produced in the High Flux Isotope Reactor (HFIR) at ORNL. Since the development and use of rhenium-188-1abeled agents for bone pain palliation is one of our major research interests, recent improvements in the ORNL alumina-based tungsten-188/rhenium-188 generator are also discussed. In addition, issues associated with the status of the use of various rhenium-188-1abeled agents for bone pain palliation as well as an overview of current clinical protocols for use of rhenium-188 are described. Reactor-produced radionuclides are usually neutron-rich and are thus often stabilized by beta decay, and research reactors thus represent important facilities for production of a wide spectrum of radionuclides which are of interest for various therapeutic applications. Current upgrades of the HFIR, as described below, are also
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described which will permit increased production capabilities of tin-117m and tungsten-188. Results and Discussion
the targets from the PTP tubes in the H F I R pool area, with subsequent transportation to the hot cell processing area using the same carrier which is currently in use.
The ORNL High Flux Isotope Reactor (HFIR)
Strontium -89
The H F I R is located at the Oak Ridge National Laboratory (ORNL) in Oak Ridge, TN, and has the highest steady-state thermal neutron flux and the highest power density available in the world. The H F I R is a major resource for the ORNL Nuclear Medicine Program for production of many medical radionuclides which can often be produced with higher specific activity and higher production yields then elsewhere. The H F I R began operation in 1965 and was originally designed for the production of transuranium radionuclides, primarily californium252. Today the H F I R is a major resource for nuclear medicine research, and permits the production of very large amounts of high specific activity radionuclides which cannot be produced at other sites. The nine hydraulic tube (HT) positions in the high flux core position permit the insertion and removal of targets at any time during the operating cycle, allowing great flexibility in production schedules. The thermal neutron flux is about 2.5 x 10~5neutrons/ cmZ/s at the central HT #5 position, dropping off by about 20% at outer positions #1 and #9. Currently, samples which require high thermal neutron flux and long irradiation, such as tungsten-188 and tin-117m, are irradiated in the HT positions. Because of the importance of having the HT positions available for short-term irradiations and the practical importance of increasing the target size (mass), the outer Peripheral Target Positions (PTPs), which are located in the outer target region, are currently being modified to accept long target holders, each of which will house eight individual HT target tubes. Since there are six PTPs, the maximum number of HT targets housed in the PTPs will total 48, which represents nearly a seven-fold increase in the current number (nine) of HT targets which can currently be irradiated. Since the PTP targets can only be accessed during refueling when the top of the reactor vessel is removed, these positions are only suitable for long-term, multi-cycle irradiations. The use of HT targets in the PTP tubes is an important advantage of this design, since it permits removal of
Neutron irradiation of strontium-88-enriched targets produces strontium-89 which is commercially available in the U.S. and elsewhere as Metastron ~. The advantages of this radioisotope are its ready availability, long physical half-life (t~/: = 50.5 days) and well-established use. The disadvantages are the lack of gamma photons for imaging, the long biological half-life, and the high costs.
Rhenium-186- l-hydroxyethylidene diphosphonic acid (HEDP) Although rhenium-186-HEDP is unavailable in the U.S. on a routine basis, it is currently available for use in Europe on a physician-based prescription, but has not yet received approval for widespread use in the European Community. The advantages of rhenium-186 are its relatively high specific activity and production levels in even moderate flux nuclear reactors, and emission of a gamma photon suitable for imaging (Table 1). Disadvantages include the requirement of repeated, routine production and the high costs of the rhenium-186-HEDP agent. Rhenium- 186-HEDP is an example of a radiopharmaceutical where high specific activity is not an advantage, since some carrier (Guhlke et al., 1996a) seems to be required for the maintenance of metastatic targeting. Although high neutron flux is not absolutely required for production of rhenium-186, the availability of fluxes as high as in the H F I R provide high enough specific activity rhenium-186 for shipment to distant sites which may require one to two half-lives, thus decreasing the specific activity at delivery. High specific activity may also be useful, however, for receptor targeting of other therapeutic agents. Because of the high thermal neutron cross-section for the ~85Re(n,~,)~86Re nuclear reaction, H F I R irradiation of enriched rhenium-185 yields high specific activity rhenium-186. Typical production values for a cycle (24 days) of irradiation are 13-15 Ci/mg rhenium-185. Although the saturation yields and possible rhenium-186 "burn-up" have not yet been experimentally determined in the HFIR, a
Table 1. Key examplesof reactor-producedradioisotopesfor bone pain palliation Radioisotope Half-life(days) Beta energy (MeV) Gamma energy,keV (%) Chemicalform for clinicaluse Strontium-89 50.5 1.46 None Ionic-chloride Phosphorus-32 14.3 1.71 None Phosphate Tin-ll7m 13.6 None, CE 159 ( 8 6 % ) Sn(IV)-DTPA* Samarium-153 1.93 0.81 103 (28%) EDTMPt Rhenium-186 3.71 1.08 137 (9.2%) HEDP:~ Rhenium-188 0.70 2.1 155 (15%) HEDP, MDP, Re(V)-DMSA§ * DTPA = diethylenepentaaceticacid. t EDTMP = ethylenediaaminetrimethylenephosphonicacid. Hydroxyethylidenediphosphonieacid. § DMSA= dimeracptosuccinicacid.
Reactor-produced radioisotopes from ORNL for bone pain palliation
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Table 2. HFIR productionof tin-117mby radiative (n,'¢)and inelastic (n,n'7) routes Nuclear reaction Cadmiumfilteringof target Average saturation yield (mCi/mgtarget) "6Sn(nT)lt7mSn Without 7.03 With 5.32 "TSn(n,n"f)~*7=Sn Without 23.2 With 22.7
two-cycle irradiation would be expected to result in specific activity values of about 25 Ci/mg rhenium185. We currently use enriched rhenium-185 powder as the target material and processing involves simple oxidation to perrhenic acid using either nitric acid or hydrogen peroxide. Because specific activity values are so high in the HFIR and small powder targets are difficult to handle, we are now pursuing the use of enriched rhenium-185 metal foils, which permit greater ease of small target ( < 10 mg) handling. The foils also readily dissolve in 30% hydrogen peroxide solution at > 60°C.
evaluated both of these routes in detail using the ORNL HFIR (Table 2). Although specific activity values by either route are not high, the tin-117 target is now routinely used since the specific activity of tin-ll7m produced by this route is significantly higher (Table 2) than produced by irradiation of tin-116. In the ORNL H F I R the production specific activity values of 8-10 mCi/mg from enriched tin- 117 and long irradiation time (1 cycle = 24 days) are routinely obtained (Table 2). The metallic powder target is shipped directly to customers for processing and preparation of the tin-ll7m(IV)-DTPA complex.
Samarium- 153
This is another example of a I~--emitting therapeutic radionuclide for bone pain palliation which can be produced in large amounts with high specific activity in even moderate flux reactors. One agent which is currently under development is the samarium-153-labeled ethylenediaaminetrimethylene phosphonic acid (EDTMP) phosphonate analogue. Since high thermal neutron flux is not important for production of samarium-153, we have not evaluated its production in the HFIR. Tin-117m
In contrast to the other radioisotopes of current interest for palliation, tin-117m decays by conversion electron emission (Table 1). The low-energy conversion electrons travel only a very limited distance in tissue, and potential bone marrow depression, which can be a limiting factor with high-energy 13--emitting radionuclides, is precluded. Potential advantages of tin-ll7m are the absence of high-energy beta particles, the emission of a gamma photon of nearly optimal energy for imaging (Table 1), and high metastatic uptake. Phase III studies being organized by Diatech, Inc., are presently in progress. Disadvantages for widespread use of tin-117m for bone pain palliation may thus be the expected high costs associated with the relatively low specific activity values, and the availability of only limited reactor sites (HFIR) with sufficiently high neutron flux for production of this radioisotope. HFIR production by the inelastic (n,n'y) route from enriched tin-117
Production of tin-ll7m in a nuclear reactor involves radiative capture by the "6Sn(n,~,)"TmSn route by irradiation of enriched tin-ll6, or via the inelastic "TSn(n,n'v)'TmSn route by irradiation of enriched tin-ll7 (Mirzadeh et al., 1997). We have
Rhenium- 188
Rhenium-188 is available carrier-free from a tungsten-188/rhenium-188 generator. The generator which we have developed and optimized at ORNL is a chromatographic system which uses alumina as the adsorbent (Callahan et al., 1992; Knapp et al., 1992, 1993, 1994a, 1994b, 1995, 1996a, 1996b; Kamioki et al., 1994). Since one of the major issues facing the health care industry is the reduction of costs, an evaluation of the most cost-effective agents for treatment of bone pain is an important goal. A major important advantage for use of rhenium-188 is the inexpensive, ready availability from the generator which has a very long useful shelf-life (Knapp et al., 1992, 1995; Hashimoto and Yoshihara, 1996). The major advantage of in-house use for providing rhenium-188 on a daily basis is in a sense also a disadvantage, since the regulatory issues associated with in-house preparation of the rhenium-188-labeled agents add another dimension compared to the commercial availability, for instance, of rhenium186-HEDP (Verdera et al., 1996; Guhlke et al., 1996a). Another advantage is the emission of the 155 keV gamma for imaging. There are several rhenium- 188-labeled agents for bone palliation which are currently under investigation (Table 3). Although the I~- from decay of rhenium-188 has a high energy (2.1 MeV), similar to yttrium-90, the short 16.9 h half-life may compensate for this high energy. The short half-life of rhenium-188 may be a distinct advantage also, since the effectiveness in reducing bone pain may be possible by "titration" with a fractionated dose regimen. HFIR production o f tungsten- 188
We have had extensive experience over the last several years in evaluating the H F I R production of tungsten-188, from both enriched tungsten-186 metal
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Rhenium-188agent HEDP Re(V)-DMSA MDP
Table 3. Examplesof rhenium-188-1abeledagentsunderevaluationfor bone pain palliation Clinicals t a t u s Collaborating institution(s) Comment Phase I Universitiesof Bonnand Dresden, Germany; Analogueof Re-186 HEDP Italia Hospital, Montevideo.Uruguay Phase I Canterbury and Kent Hospital, U.K. Use of Tc(III)-DMSA"kit", no additivesrequired Pre-clinical CatholicUniversityHospital, Rome, Italy; Protocol in preparation in conjunctionwith Sorin BiomedicaS.P.
and tungsten oxide targets (Knapp et al., 1996a; Mirzadeh et al., 1992). The metallic powder targets are usually processed by oxidation with hydrogen peroxide and/or hypochlorite in the presence of base and oxide targets dissolved in base with concomitant oxidation (Table 4). The reactor production yields of tungsten-188 (Fig. 1) are about one order of magnitude lower than the calculated values using the published cross-section values (Mughabgab and Carter, 1973) for ~86W(n,y)~87W(tr = 37.9 + 0.6 barn) and 187W(n,y)tssW(6 = 64 + 10 barn) reactions. The neutron burn-up cross-section for the IsSW(n,y)lsgw nuclear reaction is one factor which has recently been shown to contribute to the reduced production yields observed for tungsten-188. By irradiation of tungsten-188, a value of 12.0+2.5 barn has been calculated for this neutron burn-up cross-section (Mirzadeh et al., 1996). Because of the relatively low density of powder targets and the limited space in the HT target holders, we are also evaluating the potential use of pressed, enriched tungsten-186 metal targets where the density is increased by a factor of 8 10 (Mirzadeh et al., unpublished result, 1997). Pressing and sintering ( > 1000°C) provides cylindrical targets that do not dissolve by the usual peroxide/hypochlorite oxidation methods but which are readily converted to tungsten oxide by heating under an air stream in a split-tube furnace. Subsequent dissolution in base then provides tungstate solutions. Performance generators
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We have demonstrated that large, clinical-scale generators loaded with high levels of tungsten-188 ( > 200 mCi) provide reproducible high rhenium-188 yields of 75-85%/bolus and low tungsten-188 parent breakthrough ( < 10- 6) for periods of several months (Knapp et al., 1993, 1994, 1996a). These studies have demonstrated that the costs of rhenium-188 will be very low on a bolus or unit dose basis. Very large generators loaded with greater than 1 Ci of
tungsten-188 also perform well for several months (Knapp et al., unpublished result, 1996c). Concentration o f rhenium-188 solutions The bolus volume from a typical 500mCi alumina-type tungsten-188/rhenium-188 generator is about 10-12 mL (Fig. 2). Although the void volume can be discarded and the principal bolus peak collected, the initially high specific volume (3040 mCi/mL) of eluant of course decreases with time as the tungsten-188 (69 day half-life) decays. Since the long useful shelf-life is an important aspect for use of this generator system, the availability of simple, efficient methods for concentration of the generator eluant is very important. The technical problem involves development of methods required for separation of very low microscopic levels of perrhenate anions in the generator eluant from large macroscopic levels of chloride anions. One approach "traps" the perrhenate anion on an anion exchange resin in nitrate form, but perrhenate is difficult to remove from this column, and nitric acid is the only eluate which we have found to be effective (Knapp et al., 1993, 1994a). A more recent approach developed by Blower and associates (Blower, 1993; Singh et al., 1993) is based on the unique use of initial cation columns containing silver ions. In this manner, the high levels of chloride ion in the generator eluant solution are selectively trapped as insoluble silver chloride. The solution eluted from the silver cation column contains only perrhenate as the anion, which is then trapped by passage through the quaternary ammonium anion column. This system represents a simple disposable concentration unit. Commercially available columns can be used and we are currently using "AG Plus" cartridges available from Alltech as the cation column, and Waters "AccellWTM Light QMA SepPak ~'' cartridges for the anion trapping column (Fig. 3). The concentration capacity is essentially unlimited, since the silver cation columns have a capacity for about 5 mL of 0.9% saline solution
Table 4. Typicaldata for HFIR productionof tungsten-188by irradiationof enrichedtungsten-186targets W-186 target material Processingtechnique Irradiationperiod (days) Yieldat EOI (mCi/mgtarget) Tungstenmetal 0.1 M NaOH and 30% hydrogenperoxide 37.1 8.57 43.5 10.39 Tungstenoxide 0.1 N NaOH and 5% NaOCI 21 7.17 43.4 10.39 24.I 6.75 67 9.42
Reactor-produced radioisotopes from ORNL for bone pain palliation
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Fig, 1. Production of tungsten-188 in the ORNL High Flux Isotope Reactor (HFIR) by irradiation of tungsten-186-enriched tungsten oxide or tungsten metal targets. Experimental production values (open and closed circles) are compared to theoretical production curves calculated for thermal neutron flux values of 1 × 10~5neutrons/cmZ/s (closed triangles) and 2 × 10~5neutrons/cm2/s (open triangles). (2 milliquivalents), and can be "stacked" based upon volume requirements. The QMA Light columns have a total void volume, including Luer connectors, of about 0.8 mL, so that the total bolus volume of perrhenate solutions can be readily concentrated to less than 1 mL by elution with saline.
bone pain treatment. Although the 16.9 h half-life is shorter than the 90 h half-life of rhenium-186, the shorter half-life may offer several important advantages which include the opportunity to "titrate" the dose required for maximal palliative action by fractional administration with monitoring of marrow suppression. In this manner, the dose can be optimized. In addition, the short half-life of rhenium-188 may provide an important opportunity for marrow ablation using agents such as rhenium188-HEDP, prior to stern cell rescue, which is not possible with the longer-lived radioisotopes of
Clinical use of rhenium-188 for bone pain palliation Since rhenium-188 is readily available from the tungsten-188/rhenium-188 generator, broad interest has recently developed for use of these therapeutic radioisotopes as an alternative to rhenium-186 for
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~ GENERATOR SALINE ELUENT
SILVER CATION EXCHANGE COLUMN
THREE-WAY VALVE ~
j
~ I SALINE
ANION EXCHANGE COLUMN I ~ SODIUM PERRHENATE OR PERTECHNETATE SOLUTION Fig. 3. Detailed schematic diagram of the tandem cation (Alltech IC-Ag Plus)/anion (Millipore AccellTM QMA "Light" SepPak ) ex~ffange column components used for concentration of the generator 0.9 eYo NaC1 rhenium-188 perrhenate eluant.
current interest for bone pain palliation. Phase I/II clinical studies with rhenium-188-HEDP have recently been initiated at the Clinic for Nuclear Medicine at the University of Bonn, Germany (Palmedo et al., unpublished result, 1996), and initial studies in patients presenting skeletal metastases from prostatic cancer exhibit the expected high skeletal metastatic localization with successful pain palliation, suggesting that broader multi-center evaluation of this agent should be pursued. Another example of a new potential bone pain palliation agent is the rhenium-188(V)-DMSA complex (Blower et al., 1996; Guhlke et al., 1996b). Preliminary tracer-targeting studies with the rhenium-188(V)-DMSA agent in patients with prostate cancer metastatic to the skeleton have demonstrated high lesion uptake. One advantage for use of this agent is that commercially available "kits" used for preparation of technetium-99m(III)-DMSA for renal studies can be used by direct addition of the rhenium-188 solution and heating. Although many technetium-99m kits require the addition of additional tin(II) for reduction of perrhenate, the commercially available technetium(III)-99m-DMSA kits contain sufficient stannous ion.
Summary and Conclusions Research reactors represent important facilities for production of therapeutic radioisotopes for bone
pain palliation. The very high flux of the O R N L H F I R is a unique capability, and this reactor represents an important resource for the production of a variety of medical radioisotopes which require a very thermal neutron flux, including several of current interest for bone pain palliation, such as tungsten-188 and tin-117m. Since a major issue is the reduction of health care costs, the potential use of a generator with a long shelf-life which would provide sufficient doses of a therapeutic radioisotope on a daily basis for bone pain palliation raises some unique regulatory issues, since all commercially available therapeutic agents are currently prepared by the manufacturer where careful quality control is possible prior to distribution. The most cost effective approach for using the tungsten-188/rhenium-188 generator, however, would be its use in a hospital or centralized radiopharmacy, and it remains to be seen if this will be possible.
Acknowledgements--Research at ORNL supported by the Office of Health and Environmental Research (OHER), U.S. Department of Energy (DOE), under contract DE-AC0596OR22464 with Lockheed Martin Energy Research Corporation. The submitted manuscript has been authored by a contractor of the U.S. Government under contract No. DE-AC0596OR2464. Accordingly, the U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Government purposes.
Reactor-produced radioisotopes from ORNL for bone pain palliation
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Knapp, F. F. Jr., Lisic, E. C., Mirzadeh, S. and Callahan, A. P. (1994b) Tungsten-188/carrier-free rhenium-188 perrhenic acid generator system. U.S. Patent No. 5,275,802, January 4, 1994. Knapp, F. F. Jr., Mirzadeh, S., Beets, A. L., Sharkey, R., Grittiths, G. and Goidenberg, D. M. (1995) Curie-scale tungsten-188/rbenium-188 generators can cost-effectively provide carrier-free rhenium-188 for routine clinical applications. In Technetium and Rhenium in Nuclear Medicine, pp. 367-372. SGEditoriali, Padova, Italy. Knapp, F. F. Jr., Mirzadeh, S. and Beets, A. L. (1996a) Reactor-production and processing of therapeutic radioisotopes for applications in nuclear medicine. J. Radioanal. Nucl. Chem. Lett. 10, 19-32. Knapp, F. F. Jr., Mirzadeh, S., Zamora, P., Guhlke, S., Biersack, H.-J., O'Doherty, M. J. and Blower, P. J. (1996b) Rbenium-188 - cost effective therapeutic applications of a readily available generator-derived radioisotope. Nucl. Med. Commun. 17, 268. Knapp, F. F. et al. (1996c) Unpublished results. Mirzadeh, S., Knapp, F. F. Jr. and Callahan, A. P. (1992) Production of tungsten-188 and osmium-194 in a nuclear reactor for new clinical generators. In Proceedings of the International Conference on Nuclear Data for Science and Technology, ed. S. M. Qaim, pp. 595-597. SpringerVerlag, New York. Mirzadeh, S., Knapp, F. F. Jr., Alexander, C. W. and Mausner, L. F. (1997) Evaluation of neutron inelastic scattering for radioisotope production. Appl. Radiat. Isot., 48, 441-446. Mirzadeh, S., Knapp, F. F. Jr. and Lambrecht, R. M. (1996) Burn-up cross section of tungsten-188. Submitted to Radiochim. Acta. Mirzadeh, S. et al. (1997) Unpublished results. Mughabgab, S. F. and Carter, D. J. (1973) Report BNL-325, 3rd edn., Vol. 1. U.S. Government Printing Office, Washington, DC. Palmedo, H. et al. (1996) Unpublished results. Silberstein, E. B. (1996) Dosage and response in radiopharmaceutical therapy of painful osseous metastases. J. Nucl. Med. 37, 249-252. Singh J., Reghebi K., Lazarus C. R., Clarke S. E. M., Callahan A. P., Knapp F. F. Jr. and Blowe P. J. (1993) Studies on the preparation and isomeric composition of ~rRe and ~SSRe pentavalent rhenium dimercaptosuccinic acid complex. Nucl. Med. Commun. 14, 197203. Thuerlmann, B. and de Stoutz, N. D. (1996) Causes and treatment of bone pain of malignant origin. Drugs 51, 383-398. Verdera, E. S., Gaudiano, J., Leon, A., Martinez, G., Robles, A., Savio, E., Leon, E., McPherson, D. W. and Knapp, F. F. Jr. (1996) Rhenium-188 HEDP-kit formulation and quality control. In Proceedings of Symposium on Radiochemistry and Radioimmunotherapy, American Chemical Society, Washington, DC, August 25-29, 1996. Submitted to Radiochim. Acta.
Pergamon
Reactor-produced Radioisotopes from ORNL for Bone Pain Palliation* F. F. ( R U S S ) K N A P P J R I t , S. M I R Z A D E H l, A. L. B E E T S I, M. O ' D O H E R T Y 2, P. J. B L O W E R 2, E. S. V E R D E R A 3, J. S. G A U D I A N O 3, J. K R O P P 4, J. G U H L K E 5, H. P A L M E D O 5 a n d H.-J. B I E R S A C K 5 ~Nuclear Medicine Group, Oak Ridge National Laboratory (ORNL), Oak Ridge, TN, U.S.A., 2Kent and Canterbury Hospital, Canterbury, U.K., 3Department of Nuclear Medicine, Italia Hospital, Montevideo, Uruguay, 4Department of Nuclear Medicine, Carl Gustav University, Dresden, Germany and ~Clinicfor Nuclear Medicine, University of Bonn, Bonn, Germany
The treatment of painful skeletal metastases is a common clinical problem, and the use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical. There are currently several metastatic-targeted agents radiolabeled with various therapeutic radionuclides which are in various stages of clinical investigation. Since neutron-rich radionuclides are produced in research reactors and often decay by emission of 13- particles, most radionuclides used for bone pain palliation are reactor-produced. Key examples of radionuclides produced by single neutron capture of enriched targets include rhenium-186 and samarium-153. In addition, generator systems are also of interest which provide therapeutic daughter radionuclides from the decay of reactor-produced parent radionuclides. One important example is rhenium-188,available from generators via decay of reactor-produced tungsten-188. Tin-117m is an example of a reactor-produced radionuclide which decays with the emission of low-energy conversion electrons rather than by 13- decay. Each of these agents and/or radionuclides has specific advantages and disadvantages, however, the ideal agent for bone pain palliation has not yet been identified. The goal of this paper is to briefly review the production and use of several reactor-produced radionuclides for bone pain palliation, and to discuss the role of the ORNL High Flux Isotope Reactor (HFIR) for the production of many of these radionuclides. Published by Elsevier Science Ltd
Introduction The use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective new method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical (Silberstein, 1996; Freeman and Blaufoux, 1992). The palliative treatment of bone pain associated with metastases to the skeleton is an important application which has many advantages over the traditional use of analgesics and external radiation. Despite the very promising results which have been reported from numerous bone pain palliation studies using therapeutic radionuclides, state-of-the-art reviews describing therapy of bone pain still often omit this important technique and only discuss use of external irradiation and analgesics
*Presented at the Symposium on Measurements for Radionuclides Used for Bone Pain Palliation Therapy,
under the auspices of the CIRMS Medical Subcommittee, NIST, Gaithersburg, MD, 17 September 1996. tTo whom all correspondence should be addressed.
and other drugs for palliation (Thuerlmann and de Stoutz, 1996). Since rhenium-188 and t i n - l l 7 m are two of the most recent therapeutic radionuclides being evaluated for treatment of bone pain, in this paper we discuss the production of these two radionuclides as well as important examples of other radionuclides of current interest which are produced in the High Flux Isotope Reactor (HFIR) at ORNL. Since the development and use of rhenium-188-1abeled agents for bone pain palliation is one of our major research interests, recent improvements in the ORNL alumina-based tungsten-188/rhenium-188 generator are also discussed. In addition, issues associated with the status of the use of various rhenium-188-1abeled agents for bone pain palliation as well as an overview of current clinical protocols for use of rhenium-188 are described. Reactor-produced radionuclides are usually neutron-rich and are thus often stabilized by beta decay, and research reactors thus represent important facilities for production of a wide spectrum of radionuclides which are of interest for various therapeutic applications. Current upgrades of the HFIR, as described below, are also
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described which will permit increased production capabilities of tin-117m and tungsten-188. Results and Discussion
the targets from the PTP tubes in the H F I R pool area, with subsequent transportation to the hot cell processing area using the same carrier which is currently in use.
The ORNL High Flux Isotope Reactor (HFIR)
Strontium -89
The H F I R is located at the Oak Ridge National Laboratory (ORNL) in Oak Ridge, TN, and has the highest steady-state thermal neutron flux and the highest power density available in the world. The H F I R is a major resource for the ORNL Nuclear Medicine Program for production of many medical radionuclides which can often be produced with higher specific activity and higher production yields then elsewhere. The H F I R began operation in 1965 and was originally designed for the production of transuranium radionuclides, primarily californium252. Today the H F I R is a major resource for nuclear medicine research, and permits the production of very large amounts of high specific activity radionuclides which cannot be produced at other sites. The nine hydraulic tube (HT) positions in the high flux core position permit the insertion and removal of targets at any time during the operating cycle, allowing great flexibility in production schedules. The thermal neutron flux is about 2.5 x 10~5neutrons/ cmZ/s at the central HT #5 position, dropping off by about 20% at outer positions #1 and #9. Currently, samples which require high thermal neutron flux and long irradiation, such as tungsten-188 and tin-117m, are irradiated in the HT positions. Because of the importance of having the HT positions available for short-term irradiations and the practical importance of increasing the target size (mass), the outer Peripheral Target Positions (PTPs), which are located in the outer target region, are currently being modified to accept long target holders, each of which will house eight individual HT target tubes. Since there are six PTPs, the maximum number of HT targets housed in the PTPs will total 48, which represents nearly a seven-fold increase in the current number (nine) of HT targets which can currently be irradiated. Since the PTP targets can only be accessed during refueling when the top of the reactor vessel is removed, these positions are only suitable for long-term, multi-cycle irradiations. The use of HT targets in the PTP tubes is an important advantage of this design, since it permits removal of
Neutron irradiation of strontium-88-enriched targets produces strontium-89 which is commercially available in the U.S. and elsewhere as Metastron ~. The advantages of this radioisotope are its ready availability, long physical half-life (t~/: = 50.5 days) and well-established use. The disadvantages are the lack of gamma photons for imaging, the long biological half-life, and the high costs.
Rhenium-186- l-hydroxyethylidene diphosphonic acid (HEDP) Although rhenium-186-HEDP is unavailable in the U.S. on a routine basis, it is currently available for use in Europe on a physician-based prescription, but has not yet received approval for widespread use in the European Community. The advantages of rhenium-186 are its relatively high specific activity and production levels in even moderate flux nuclear reactors, and emission of a gamma photon suitable for imaging (Table 1). Disadvantages include the requirement of repeated, routine production and the high costs of the rhenium-186-HEDP agent. Rhenium- 186-HEDP is an example of a radiopharmaceutical where high specific activity is not an advantage, since some carrier (Guhlke et al., 1996a) seems to be required for the maintenance of metastatic targeting. Although high neutron flux is not absolutely required for production of rhenium-186, the availability of fluxes as high as in the H F I R provide high enough specific activity rhenium-186 for shipment to distant sites which may require one to two half-lives, thus decreasing the specific activity at delivery. High specific activity may also be useful, however, for receptor targeting of other therapeutic agents. Because of the high thermal neutron cross-section for the ~85Re(n,~,)~86Re nuclear reaction, H F I R irradiation of enriched rhenium-185 yields high specific activity rhenium-186. Typical production values for a cycle (24 days) of irradiation are 13-15 Ci/mg rhenium-185. Although the saturation yields and possible rhenium-186 "burn-up" have not yet been experimentally determined in the HFIR, a
Table 1. Key examplesof reactor-producedradioisotopesfor bone pain palliation Radioisotope Half-life(days) Beta energy (MeV) Gamma energy,keV (%) Chemicalform for clinicaluse Strontium-89 50.5 1.46 None Ionic-chloride Phosphorus-32 14.3 1.71 None Phosphate Tin-ll7m 13.6 None, CE 159 ( 8 6 % ) Sn(IV)-DTPA* Samarium-153 1.93 0.81 103 (28%) EDTMPt Rhenium-186 3.71 1.08 137 (9.2%) HEDP:~ Rhenium-188 0.70 2.1 155 (15%) HEDP, MDP, Re(V)-DMSA§ * DTPA = diethylenepentaaceticacid. t EDTMP = ethylenediaaminetrimethylenephosphonicacid. Hydroxyethylidenediphosphonieacid. § DMSA= dimeracptosuccinicacid.
Reactor-produced radioisotopes from ORNL for bone pain palliation
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Table 2. HFIR productionof tin-117mby radiative (n,'¢)and inelastic (n,n'7) routes Nuclear reaction Cadmiumfilteringof target Average saturation yield (mCi/mgtarget) "6Sn(nT)lt7mSn Without 7.03 With 5.32 "TSn(n,n"f)~*7=Sn Without 23.2 With 22.7
two-cycle irradiation would be expected to result in specific activity values of about 25 Ci/mg rhenium185. We currently use enriched rhenium-185 powder as the target material and processing involves simple oxidation to perrhenic acid using either nitric acid or hydrogen peroxide. Because specific activity values are so high in the HFIR and small powder targets are difficult to handle, we are now pursuing the use of enriched rhenium-185 metal foils, which permit greater ease of small target ( < 10 mg) handling. The foils also readily dissolve in 30% hydrogen peroxide solution at > 60°C.
evaluated both of these routes in detail using the ORNL HFIR (Table 2). Although specific activity values by either route are not high, the tin-117 target is now routinely used since the specific activity of tin-ll7m produced by this route is significantly higher (Table 2) than produced by irradiation of tin-116. In the ORNL H F I R the production specific activity values of 8-10 mCi/mg from enriched tin- 117 and long irradiation time (1 cycle = 24 days) are routinely obtained (Table 2). The metallic powder target is shipped directly to customers for processing and preparation of the tin-ll7m(IV)-DTPA complex.
Samarium- 153
This is another example of a I~--emitting therapeutic radionuclide for bone pain palliation which can be produced in large amounts with high specific activity in even moderate flux reactors. One agent which is currently under development is the samarium-153-labeled ethylenediaaminetrimethylene phosphonic acid (EDTMP) phosphonate analogue. Since high thermal neutron flux is not important for production of samarium-153, we have not evaluated its production in the HFIR. Tin-117m
In contrast to the other radioisotopes of current interest for palliation, tin-117m decays by conversion electron emission (Table 1). The low-energy conversion electrons travel only a very limited distance in tissue, and potential bone marrow depression, which can be a limiting factor with high-energy 13--emitting radionuclides, is precluded. Potential advantages of tin-ll7m are the absence of high-energy beta particles, the emission of a gamma photon of nearly optimal energy for imaging (Table 1), and high metastatic uptake. Phase III studies being organized by Diatech, Inc., are presently in progress. Disadvantages for widespread use of tin-117m for bone pain palliation may thus be the expected high costs associated with the relatively low specific activity values, and the availability of only limited reactor sites (HFIR) with sufficiently high neutron flux for production of this radioisotope. HFIR production by the inelastic (n,n'y) route from enriched tin-117
Production of tin-ll7m in a nuclear reactor involves radiative capture by the "6Sn(n,~,)"TmSn route by irradiation of enriched tin-ll6, or via the inelastic "TSn(n,n'v)'TmSn route by irradiation of enriched tin-ll7 (Mirzadeh et al., 1997). We have
Rhenium- 188
Rhenium-188 is available carrier-free from a tungsten-188/rhenium-188 generator. The generator which we have developed and optimized at ORNL is a chromatographic system which uses alumina as the adsorbent (Callahan et al., 1992; Knapp et al., 1992, 1993, 1994a, 1994b, 1995, 1996a, 1996b; Kamioki et al., 1994). Since one of the major issues facing the health care industry is the reduction of costs, an evaluation of the most cost-effective agents for treatment of bone pain is an important goal. A major important advantage for use of rhenium-188 is the inexpensive, ready availability from the generator which has a very long useful shelf-life (Knapp et al., 1992, 1995; Hashimoto and Yoshihara, 1996). The major advantage of in-house use for providing rhenium-188 on a daily basis is in a sense also a disadvantage, since the regulatory issues associated with in-house preparation of the rhenium-188-labeled agents add another dimension compared to the commercial availability, for instance, of rhenium186-HEDP (Verdera et al., 1996; Guhlke et al., 1996a). Another advantage is the emission of the 155 keV gamma for imaging. There are several rhenium- 188-labeled agents for bone palliation which are currently under investigation (Table 3). Although the I~- from decay of rhenium-188 has a high energy (2.1 MeV), similar to yttrium-90, the short 16.9 h half-life may compensate for this high energy. The short half-life of rhenium-188 may be a distinct advantage also, since the effectiveness in reducing bone pain may be possible by "titration" with a fractionated dose regimen. HFIR production o f tungsten- 188
We have had extensive experience over the last several years in evaluating the H F I R production of tungsten-188, from both enriched tungsten-186 metal
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Rhenium-188agent HEDP Re(V)-DMSA MDP
Table 3. Examplesof rhenium-188-1abeledagentsunderevaluationfor bone pain palliation Clinicals t a t u s Collaborating institution(s) Comment Phase I Universitiesof Bonnand Dresden, Germany; Analogueof Re-186 HEDP Italia Hospital, Montevideo.Uruguay Phase I Canterbury and Kent Hospital, U.K. Use of Tc(III)-DMSA"kit", no additivesrequired Pre-clinical CatholicUniversityHospital, Rome, Italy; Protocol in preparation in conjunctionwith Sorin BiomedicaS.P.
and tungsten oxide targets (Knapp et al., 1996a; Mirzadeh et al., 1992). The metallic powder targets are usually processed by oxidation with hydrogen peroxide and/or hypochlorite in the presence of base and oxide targets dissolved in base with concomitant oxidation (Table 4). The reactor production yields of tungsten-188 (Fig. 1) are about one order of magnitude lower than the calculated values using the published cross-section values (Mughabgab and Carter, 1973) for ~86W(n,y)~87W(tr = 37.9 + 0.6 barn) and 187W(n,y)tssW(6 = 64 + 10 barn) reactions. The neutron burn-up cross-section for the IsSW(n,y)lsgw nuclear reaction is one factor which has recently been shown to contribute to the reduced production yields observed for tungsten-188. By irradiation of tungsten-188, a value of 12.0+2.5 barn has been calculated for this neutron burn-up cross-section (Mirzadeh et al., 1996). Because of the relatively low density of powder targets and the limited space in the HT target holders, we are also evaluating the potential use of pressed, enriched tungsten-186 metal targets where the density is increased by a factor of 8 10 (Mirzadeh et al., unpublished result, 1997). Pressing and sintering ( > 1000°C) provides cylindrical targets that do not dissolve by the usual peroxide/hypochlorite oxidation methods but which are readily converted to tungsten oxide by heating under an air stream in a split-tube furnace. Subsequent dissolution in base then provides tungstate solutions. Performance generators
of
large,
clinical-scale
multi-Curie
We have demonstrated that large, clinical-scale generators loaded with high levels of tungsten-188 ( > 200 mCi) provide reproducible high rhenium-188 yields of 75-85%/bolus and low tungsten-188 parent breakthrough ( < 10- 6) for periods of several months (Knapp et al., 1993, 1994, 1996a). These studies have demonstrated that the costs of rhenium-188 will be very low on a bolus or unit dose basis. Very large generators loaded with greater than 1 Ci of
tungsten-188 also perform well for several months (Knapp et al., unpublished result, 1996c). Concentration o f rhenium-188 solutions The bolus volume from a typical 500mCi alumina-type tungsten-188/rhenium-188 generator is about 10-12 mL (Fig. 2). Although the void volume can be discarded and the principal bolus peak collected, the initially high specific volume (3040 mCi/mL) of eluant of course decreases with time as the tungsten-188 (69 day half-life) decays. Since the long useful shelf-life is an important aspect for use of this generator system, the availability of simple, efficient methods for concentration of the generator eluant is very important. The technical problem involves development of methods required for separation of very low microscopic levels of perrhenate anions in the generator eluant from large macroscopic levels of chloride anions. One approach "traps" the perrhenate anion on an anion exchange resin in nitrate form, but perrhenate is difficult to remove from this column, and nitric acid is the only eluate which we have found to be effective (Knapp et al., 1993, 1994a). A more recent approach developed by Blower and associates (Blower, 1993; Singh et al., 1993) is based on the unique use of initial cation columns containing silver ions. In this manner, the high levels of chloride ion in the generator eluant solution are selectively trapped as insoluble silver chloride. The solution eluted from the silver cation column contains only perrhenate as the anion, which is then trapped by passage through the quaternary ammonium anion column. This system represents a simple disposable concentration unit. Commercially available columns can be used and we are currently using "AG Plus" cartridges available from Alltech as the cation column, and Waters "AccellWTM Light QMA SepPak ~'' cartridges for the anion trapping column (Fig. 3). The concentration capacity is essentially unlimited, since the silver cation columns have a capacity for about 5 mL of 0.9% saline solution
Table 4. Typicaldata for HFIR productionof tungsten-188by irradiationof enrichedtungsten-186targets W-186 target material Processingtechnique Irradiationperiod (days) Yieldat EOI (mCi/mgtarget) Tungstenmetal 0.1 M NaOH and 30% hydrogenperoxide 37.1 8.57 43.5 10.39 Tungstenoxide 0.1 N NaOH and 5% NaOCI 21 7.17 43.4 10.39 24.I 6.75 67 9.42
Reactor-produced radioisotopes from ORNL for bone pain palliation
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Fig, 1. Production of tungsten-188 in the ORNL High Flux Isotope Reactor (HFIR) by irradiation of tungsten-186-enriched tungsten oxide or tungsten metal targets. Experimental production values (open and closed circles) are compared to theoretical production curves calculated for thermal neutron flux values of 1 × 10~5neutrons/cmZ/s (closed triangles) and 2 × 10~5neutrons/cm2/s (open triangles). (2 milliquivalents), and can be "stacked" based upon volume requirements. The QMA Light columns have a total void volume, including Luer connectors, of about 0.8 mL, so that the total bolus volume of perrhenate solutions can be readily concentrated to less than 1 mL by elution with saline.
bone pain treatment. Although the 16.9 h half-life is shorter than the 90 h half-life of rhenium-186, the shorter half-life may offer several important advantages which include the opportunity to "titrate" the dose required for maximal palliative action by fractional administration with monitoring of marrow suppression. In this manner, the dose can be optimized. In addition, the short half-life of rhenium-188 may provide an important opportunity for marrow ablation using agents such as rhenium188-HEDP, prior to stern cell rescue, which is not possible with the longer-lived radioisotopes of
Clinical use of rhenium-188 for bone pain palliation Since rhenium-188 is readily available from the tungsten-188/rhenium-188 generator, broad interest has recently developed for use of these therapeutic radioisotopes as an alternative to rhenium-186 for
ELUTE WITH SALINE SOLUTION
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Fig. 2. Schematic for set-up of alumina-based tungsten-188/rhenium-188generator system with tandem silver cation cartridge/QMA anion cartridge system for generator 0.9% saline eluant concentration.
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~ GENERATOR SALINE ELUENT
SILVER CATION EXCHANGE COLUMN
THREE-WAY VALVE ~
j
~ I SALINE
ANION EXCHANGE COLUMN I ~ SODIUM PERRHENATE OR PERTECHNETATE SOLUTION Fig. 3. Detailed schematic diagram of the tandem cation (Alltech IC-Ag Plus)/anion (Millipore AccellTM QMA "Light" SepPak ) ex~ffange column components used for concentration of the generator 0.9 eYo NaC1 rhenium-188 perrhenate eluant.
current interest for bone pain palliation. Phase I/II clinical studies with rhenium-188-HEDP have recently been initiated at the Clinic for Nuclear Medicine at the University of Bonn, Germany (Palmedo et al., unpublished result, 1996), and initial studies in patients presenting skeletal metastases from prostatic cancer exhibit the expected high skeletal metastatic localization with successful pain palliation, suggesting that broader multi-center evaluation of this agent should be pursued. Another example of a new potential bone pain palliation agent is the rhenium-188(V)-DMSA complex (Blower et al., 1996; Guhlke et al., 1996b). Preliminary tracer-targeting studies with the rhenium-188(V)-DMSA agent in patients with prostate cancer metastatic to the skeleton have demonstrated high lesion uptake. One advantage for use of this agent is that commercially available "kits" used for preparation of technetium-99m(III)-DMSA for renal studies can be used by direct addition of the rhenium-188 solution and heating. Although many technetium-99m kits require the addition of additional tin(II) for reduction of perrhenate, the commercially available technetium(III)-99m-DMSA kits contain sufficient stannous ion.
Summary and Conclusions Research reactors represent important facilities for production of therapeutic radioisotopes for bone
pain palliation. The very high flux of the O R N L H F I R is a unique capability, and this reactor represents an important resource for the production of a variety of medical radioisotopes which require a very thermal neutron flux, including several of current interest for bone pain palliation, such as tungsten-188 and tin-117m. Since a major issue is the reduction of health care costs, the potential use of a generator with a long shelf-life which would provide sufficient doses of a therapeutic radioisotope on a daily basis for bone pain palliation raises some unique regulatory issues, since all commercially available therapeutic agents are currently prepared by the manufacturer where careful quality control is possible prior to distribution. The most cost effective approach for using the tungsten-188/rhenium-188 generator, however, would be its use in a hospital or centralized radiopharmacy, and it remains to be seen if this will be possible.
Acknowledgements--Research at ORNL supported by the Office of Health and Environmental Research (OHER), U.S. Department of Energy (DOE), under contract DE-AC0596OR22464 with Lockheed Martin Energy Research Corporation. The submitted manuscript has been authored by a contractor of the U.S. Government under contract No. DE-AC0596OR2464. Accordingly, the U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Government purposes.
Reactor-produced radioisotopes from ORNL for bone pain palliation
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