Recent advances in radionuclide therapy

Recent Advances in Radionuclide Therapy Suresh Srivastava and Ekaterina Dadachova

A variety of radionuclides continue to be investigated and/or clinically used for different therapeutic applications in nuclear medicine. The choice of a particular radionuclide with regard to appropriate emissions, linear energy transfer, and physical half-life is dictated to a large extent by the character of the disease (eg, solid tumor or metastatic disease) and by the carrier used to selectively transport the radionuclide to the desired site. An impressive body of information has appeared in the recent literature that addresses many of these considerations. This article summarizes and discusses the many recent advances and the progress in the clinical applications of thera-

peutic radionuclides in relatively new and developing areas, such as radioimmunotherapy, peptide therapy, intravascular therapy to prevent restenosis, radiation synovectomy, and bone malignancy therapy. Projections are made as to the future directions and progress in these areas. The crucial issue of a reliable, year-round supply of new and emerging therapeutic radionuclides in quantities sufficient initially for research, and then for routine clinical use, is a very worthy goal which, in the United States, remains to be achieved.

URING THE LAST decade, several excellent publications have covered the many new and exciting developments in the rapidly advancing field of radionuclide therapy. These articles have outlined the principles for production and decay considerations for therapeutic radionuclides, 1 clarified the relationships between tumor size and curability for therapy with 13-emitting radionuclides,2'3 and set the criteria for the selection of radionuclides for cancer radioimmunotherapy.4'5 A description of the recent developments in the application of therapeutic radiopharmaceuticals in preclinical studies, as well as in the clinical setting, is also the subject of a recent review.6 The desirable therapeutic radionuclide should have particulate emission (13-, conversion electron, Auger electron, or a-emission) suited to the nature and stage of the disease, in sufficient abundance. A ",/-emission component, in reasonable abundance, can be of advantage for low-dose imaging, especially during staging, for dosimetry estimates and for monitoring response to therapy. A physical half-life of 1 to 14 d (preferably with stable daughter products) is optimal; it should be matched with the in vivo pharmacokinetics of the isotope-carrier vehicle combination. The radionuclide should have a chemistry amenable to its attachment with a broad class of compounds with high in vivo stability. Finally, a free or chelated radionuclide should be excreted rapidly after metabolic processes and should have little or no affinity for blood or normal body tissues. Although only few existing isotopes meet all these criteria, there are a number of emerging new radionuclides that appear promising and versatile and thus warrant continued investigation.7,s A list of current and future therapeutic radionuclides, chosen arbitrarily on the basis of particle emission and a few other parameters, is presented in Table 1. The nature of the delivery vehicle (carder) depends on the mechanisms that could be used to selectively target lethal doses of the radionuclide to the diseased tissue. A few representative examples for cancer therapy are shown schematically in Fig 1. In this article, we

summarize a number of important recent advances, which are classified and arranged according to the disease under treatment and/or the method of radionuclide delivery. A brief discussion of the issue of isotope availability is also included.

D

From the Brookhaven National Laboratory, Medical Department, Upton, NY; and the Albert Einstein College of Medicine, Bronx, NY. Supported by the United States Department of Energy, NE/Office of Isotopes for Medicine and Science, under Contract No. DE-ACO2-76CHO0016 at Brookhaven National Laboratory, and by Albert Einstein College of Medicine Grant #9-526-9593. Address reprint requests to Suresh C. Srivastava, PhD, Brookhaven National Laboratory, Medical Department, Building 801, P.O. Box 5000, Upton, NY 119735000. Copyright 9 2001 by W.B. Saunders Company 0001-2998/01/3104-0007535.00/0 doi:l O.lO53/snuc.2001.27043

330

Copyright 9 2001 by W.B. Saunders Company

RADIOIMMUNOTHERAPY

Radioimmunotherapy (RIT) is a technique that uses antigenspecific monoclonal antibodies (MAb) or MAb-derived reagents to deliver therapeutic radionuclides to tumors. The field of RIT is at least a couple of decades old. 9A~ After a brief hiatus, RIT has experienced renewed interest, as improved bioengineered delivery vehicles (such as humanized and chimeric whole antibodies, domain-deleted and single-chain antibodies, hypervariable domain region peptides, Fv fragments and their multimeric forms, minibodies and bispecific antibodies), and pretargeting protocols continue to become available. 11-14

Lymphoma and Leukemia RIT has been most successful for the treatment of radiosensitive malignancies, such as lymphoma and leukemia. Knox and Meredith ~5 summarized the results of 23 clinical trials for B-cell non-Hodgkin's lymphoma (NHL). Iodine-131 was the isotope of choice in 16 of these trials, followed by Y-90 (6 trials) and Cu-67 (1 trial). Apparently, the choice of 1-131 is because of its availability and well-established labeling protocols. The average percentage of complete responses (CR), defined as no evidence of disease for at least 1 month, for nonmyeloabtative doses was 22% (SD = 19). The use of pure [3-emitter Y-90 in 6 trials reflected the increased efficacy of more energetic [3-emission of this isotope (E . . . . . ge [Eav] = 935 keV, 100%) compared with that of 1-131 (Eav = 191 keV, 89%), with the higher energy possibly being responsible for delivering lethal doses to cells in large tumor masses through the "cross-fire" effect. In 5 trials in which nonmyeloablative doses of Y-90 were administered, the average percentage of CR was somewhat higher than for 1-131, with the results distributed much more uniformly (27%; SD = 5). One should bear in mind, however, that the trials discussed in this article differ in terms of eligibility criteria, antibody used, dose, number of treatments, doses of unlabeled antibody preinfused or coinfused, and the biodistribution or dosimetry estimations required for the administration of a therapeutic dose of radiolabeled Seminars in Nuclear Medicine, Vol XXXI, No 4 (October), 2001: pp 330-341

RADIONUCLIDE THERAPY

331

Table 1. Present and Future Therapeutic Radionuclides Nuclide

Half-life

P-32 t Sc-47 Cu-67 Ga-67 As-77 Sr-89 t Y-90 t Rh-105 Pd-109 Ag-111 In-111 Sn-117m 1-123 1-125 1-131 Sm-153 Gd-159 Ho-166 Lu-177 Re-186 Ra-188 Ir-194 Hg-195m

14.3 d 3.3 d 2.6 d 3.3 d 1.5 d 60.5 d 2.7 d 1.5 d 0.6 d 7.5 d 2.8 d 14.0 d 13.2 h 60,1 d 8.0 d 1.9 d 0.8 d 1.1 d 6.7 d 3.7 d 0.7 d 0.8 d 1.7 d

Pt-195m

4.0 d

Particle Emission

Au-199 TI-201 At-211 Bi-212

3.1 d 3.0 d 7.2 h 61 rain

Bi-213

46 min

13 13 13 Aug 13!3 13 1313 13 Aug CE Aug Aug 13 13" 13 13 13 13 13 1~ CE Aug CE Aug ff Aug a* ~ 1313

Ac-225 Fm-255

10.0 d 0.8 d

r ~

Eavg, keV* 695 162 141 0.04-9.54 (572) 228 583 935 190 360 350 0.5-25 (308) 127;152 = 0.7-30 (289) 0.7-30 (479) 181 225 311 666 140 329 795 808 13-259 (180) 2.5-9.6 (409) 17-130 (276) 2.4-63 (466) 143 2.7-77 (253) 5868 (41) 6051 (25) 2246 (max) 1390 (max) 5870 5915 ~ 7030 (93)

Principal Gamma Component E, keV(%) -159 (68) 185 (49) 93 (37) 239 (1.6) --319 (19) 88 (4) 342 (7) 171 (90); 245 (94) 159 (86) 159 (83) 36 (7) 364 (81) 103 (28) 363 (8) 80 (6) 208 (11) 137 (10) 155 (15) 328 (13) 262 (32) 99 (11) 158 (37) 167 (11) 79 (21.3) 727 (7) 440 (26) 99 (93) 109 (24.6)

Abbreviations: 13-, beta electrons; CE, conversion electrons; a, alpha particles; Aug, Auger electrons. * Weighted average; Total (%) per decay in parentheses. t No gamma emission. * Discrete energies. s Multiple decays to stable Bi-209; total energy ~28 MeV.

antibody. The highest overall response, CR rates, and the longest remission periods have been reported in patients treated with a single myeloablative dose in conjunction with autologous bone marrow transplantation or peripheral stem cell reinfusion. When myeloablative doses are administered, the range of 13-emission of the radionuclide is less important because the whole bone marrow is destroyed in order to eradicate micrometastases. This clearly shows that nonmyeloablative doses of 13-emitters, with their long optimal range in tissue3 (2.6 to 5.0 nm and 28.0 to 42.0 mm for 1-131 and Y-90, respectively) may not effectively stop the spread of micrometastases. In a recent article, DeNardo et al 16 provided a critical summary of their results in 70 patients with advanced stage B-cell NHL, who were studied by using Lym-1 antibody labeled with Cu-67, 1-131, and I n - I l l . Indium-Ill was used as a surrogate for the Y-90 distribution, and comparisons were made for the pharmacokinetics and dosimetry for Lym-1 labeled with 1-131, Cu-67, and Y-90 in matched patient populations. Radiometals in general, and

Cu-67 in particular, were shown to have greater tumor retention than 1-131 in all cases. The therapeutic indices for Cu-67-Lym-1, and less so for Y-90 Lym-1, were much more favorable than those for 1-131-Lym-1. These authors, through their careful studies, ~6-1s have made a very strong case for Cu-67 as a therapeutic radionuclide, at least for the radioimmunotherapy of NHL, and possibly for other cancers as well. Studies involving 134 patients with recurrent Hodgkin's disease were also recently summarized. ~9 The patients were treated with 1-131 or Y-90-radiolabeled antiferritin antibody. These trials are of interest because they allow a direct comparison of the results obtained with 2 different radioisotopes. Overall, more energetic Y-90 produced better results; there was an overall response rate of 60% after Y-90-antiferritin antibody therapy with a CR of 30%, compared with 40% overall and 2.5% CR for 1-131-radiolabeled antibody. Apparently, the longer range of Y-90 in tissue corrects for the uneven deposition of the radioconjugate and for the prevalence of "cold" spots in the tumor. :

332

SRIVASTAVAAND DADACHOVA

Fig 1. Schematic representation of the central role of radionuclides for certain promising approaches to cancer therapy.

The treatment of another type of "liquid" cancer, myeloid leukemia, provides an example of the first application of an c~-emitting radioisotope in clinical RIT. Patients with relapsed or refractory myeloid leukemia were treated with humanized HuM195 antibody labeled with Bi-213. 2~ Bismuth-213 (half-life, 45.6 minutes) emits a high linear energy transfer (LET) a-particle (E = 5.9 MeV), with a path length of 50 to 80 pin and can theoretically kill leukemia cells with 1 or 2 a-particle decays. Seventeen patients were treated with 0.28 to 1 mCi/kg of Bi-213Hu-M195 in 3 to 6 fractions over 2 to 4 days, with total Bi-213 doses ranging between 16 and 75 mCi. There was no acute toxicity, and delayed toxicity was limited to myelosuppression. Ten patients had decreased numbers of peripheral blood leukemia cells, and 12 of 17 patients had decreased bone marrow blasts. Although there have been no complete responses, these results showed for the first time that targeted a-particle therapy may be feasible under certain conditions.

Solid Tumors RIT of solid tumors remains the most challenging task for nuclear physicians because solid tumors present different complications, such as heterogeneity of antigen expression on tumor cell surface, slow penetration rate into tumor tissue, hypoxia, and low tumor-to-normal-tissue radioactivity ratio. Besides, solid tumors are often present in the body in different sizes or accompanied by metastatic spread, which makes it very difficult to match the emission range of a therapeutic radionuclide and tumor size. In results of 26 clinical trials 15 in ovarian, prostate, breast, and other cancers (I-131 was used in 13 of these; Y-90 in 8; Re-186 in 2; Lu-177 in 2; and 1-125 in 1), the response rates were generally poor and of relatively short duration. Intraperitoneal R1T in patients with recurrent or persistent ovarian cancer was generally more effective for small nodules (<1 cm). Interestingly, antibodies labeled with 2 newer radioisotopes (Re-18622 and Lu-17723"24

showed promise in intraperitoneal RIT, apparently because of the match between their mid-range energy emissions (Eav = 362 keV [73%] and 149 keV [79%] for Re-186 and Lu-177, respectively) and size of the lesions, present in the carcinomatous intraperitoneal cavity. RIT of brain tumors, which are usually very aggressive and characterized by extremely poor prognosis, deserves special discussion as it has been the most successful application of this technique so far. Intralesional RIT allows the delivery of a much higher radiation dose to the tumor than other routes of administration. By using an intratumoral route of administration, investigators have obtained encouraging results in the treatment of brain tumors by using predominantly antitenascin antibodies labeled with both low-energy I-13125 and high-energy Y-90.26 However, an intralesional approach makes it impossible to treat multifocal brain tumors. To solve this problem, Paganelli et al27 took advantage of intravenous administration combined with tumor pretargeting when biotinylated antitenascin MAb was administered to 48 patients intravenously (first step), followed 36 hours later by avidin and streptavidin (second step), and 18 to 24 hours later by Y-90-1abeled biotin (third step). Doses of 60 to 80 mCi/m2 were administered, and the maximum tolerated dose was determined to be 80 mCi/m2. Tumor mass reduction (25% to100%) occurred in 12/48 patients (25%), with 8/48 (16%) having a duration of response of at least 12 months: The authors concluded that this 3-step therapy interfered with the progression of highgrade glioma and may have produced tumor regression in patients no longer responsive to other therapies. PEPTIDE T H E R A P Y

Some of the first peptide-based tumor receptor imaging agents were radiolabeled analogues of the hormone somatostatin. Somatostatin-type receptors (STTR), found on cell surface, occur in a number of different places, including the central nervous system, the gastrointestinal tract, and the pancreas. A large number of human tumors are also STTR-positive. Octreotide, an 8-amino acid somatostatin analogue with a longer biologic half-life than somatostatin, has been labeled with In-111 by using diethylenetriaminepentaacetic acid (DTPA) as the bifunctional chelating agent and is approved in the United States and Europe as a diagnostic imaging agent for neuroendocrine tumors. This receptor-binding radiopharmaceutical shows low nanomolar atfinities for somatostatin receptors in neuroendocrine tumors, and more than 80% of intact (In-111-DTPA) octreotide (In-111-octreotide) clears rapidly through the kidneys.28 It has recently been shown that tumor-bound In-lll-octreotide undergoes receptor-mediated internalization,29'3~which results in some degradation to the radiolabeled metabolite and translocation of radioactivity through the cytoplasmic compartment and into the nucleus. This internalization is essential for successful radionuclide therapy of tumors if very short-range (few micrometers) Auger and conversion electron emitters such as I n - l l l are used for therapy. Kwekkeboom et al31 summarized the results of a study of 30 patients with primarily neuroendocrine tumors, which first clinically showed the usefulness of high specific-activity I n - l l l for therapy. The typical dose per administration was 160 to 190 mCi I n - l l l incorporated into 40 to 50 lag In-lll-octreotide, reaching a cumulative dose of more than 146 mCi. Of the 21

RADIONUCLIDETHERAPY patients who received this cumulative dose, a reduction in tumor size was found in 6 patients and stable disease in 8 others; the only side effects were a transient decline in platelet counts and lymphocyte subsets. Thus, treatment with In- 111-octreotide seems to be a viable option in an adjuvant setting after surgery for STTR-positive tumors to eradicate occult metastases without damaging the surrounding healthy tissue. The ability of octreotide to deliver Y-90 to tumors was also used by several groups of investigators,32'33 who relied on the crossfire effect in eradicating tumor cells. In these studies, octreotide was conjugated with the polyazamacrocycle DOTA (1, 4, 7, 10tetraazacyclododecane-N,N',N",N'"-tetraacetic acid, which forms very stable complexes with Y-90) through the tyrosine residue: DOTA-D-Phel-Tyr3-octreotide (also known as DOTATOC). In the trial conducted by Paganelli et al,32 20 patients received 3 equal intravenous injections of Y-90-DOTATOC, for a total of 180 mCi. Complete and partial tumor mass reduction was measured in 25% of patients, along with 55% showing stable disease and 20% progressive disease. In the study by Otte et al,33 29 patients with advanced STTR-positive tumors of different histology received 4 or more single doses of Y-90-DOTATOC with ascending activity at intervals of approximately 6 weeks, and a cumulative dose of -<200 mCi. Twenty of the 29 patients showed disease stabilization, 2 had a partial remission, 4 had a reduction of tumor mass of less than 50%, and 3 had a progression of tumor growth. The observation of side effects in both trials showed that high activities of Y-90-DOTATOC can be administered with a low risk of myelotoxicity, although the radiation dose to the kidneys required careful consideration. Because of its small molecular weight, Y-90-DOTATOC is filtered through glomerular capillaries in the kidneys and is subsequently absorbed and retained in the proximal tubular cells, thereby delivering a high radiation dose to the kidneys. Infusions of positively charged amino acids (eg, Hartmann-Hepa 8% solution) during Y-90-DOTATOC treatments with the aim of reducing renal toxicity has shown some promise. 33

INTRAVASCULAR RADIATION THERAPY TO PREVENT RESTENOSlS Although nuclear medicine has been making important contributions to the diagnosis and management of cardiovascular disease for many years, only recently has radioactivity found its first specific therapeutic application in cardiology, for the treatment of restenosis. Coronary angioplasty is effective for the treatment of stenosed coronary arteries. Although the initial success rate of this procedure is greater than 90%, in approximately 30% to 50% of patients, restenosis occurs within 6 months (the lumen narrows more than 50% as seen angiographically).34 A substantial body of experimental evidence suggests that local application of radiation at sites of angioplasty or stent implantation prevents neointima formation. Recent preliminary clinical studies have reported a significant reduction in clinical restenosis rates when ~/-emitting radiation sources were used to treat the site of coronary intervention. Because of the energy of therapeutic ~/-sources and the shielding requirements, it would be far more preferable to deliver ionizing radiation by using a 13-emitter.35 Hoher et a136 and Kotzerke et al37 evaluated the feasibility and safety of intracoronary irradiation with a balloon catheter filled with Re-188, a

333 high-energy 13-emitter (Eav = 795 keV [71%]) conveniently available in saline solution from the W-188/Re-188 generator.38 They performed irradiation of lesions with 1,500 rad at 0.5-mm tissue depth for 515 --- 199 seconds in 1 to 4 fractions. There were no procedural complications. At 6-month follow-up, target lesion restenosis rate (>50% in diameter) was low (3 of 26 patients, 12%). These investigators concluded that coronary irradiation with a Re-188-filled balloon is technically feasible and safe, requiring only standard percutaneous transluminal coronary angioplasty techniques. For this application, Re-188 has a clear advantage over other high-energy 13-emitters, such as Y-90 or radiolanthanides. If an unlikely balloon rupture should occur, the short physical half-life of Re-188 (16.9 hours) and its lack of concentration in bone should reduce the systemic radiation dose.

RADIATION SYNOVECTOMY Radiation synovectomy is an attractive alternative to chemical or surgical synovectomy for the treatment of inflammatory synovial disease, including rheumatoid arthritis. The procedure entails a single injection of a 13-emitting radiopharmaceutical directly into the synovium to control and ablate inflammation. The injected agents, typically colloids or larger aggregates, are assumed to be rapidly phagocytized by synoviocytes and then distributed within the synovium, primarily at the surface. The most common agents have been radiocolloids or macroaggregates with high-energy 13-emitters (Y-90, Au-198, Dy-165, and Re-186). 39 Although these agents have shown good results, they are not widely used, especially in the United States. All display some degree of leakage of the radionuclide from the joints, leading to an increased radiation dose to normal organs. The size of these radiolabeled particles cannot be adequately controlled during formation, and it is assumed that small (<10 0rn) particles leak from the synovium over time. However, a new type of particle, made from hydroxyapatite (HA), a natural constituent of bone, has become commercially available in various controlled sizes ranging from 1 to 80 prn. Research interest has thus focused recently on incorporating HA particles into new agents for radiation synovectomy. Initial studies in rabbits with antigeninduced arthritis with Sm-153-1abeled HA showed minimal leakage of activity (0.09% over 4 days) from the treated joint, compared with leakage rates obtained with other radiocolloid agents (5% to 45%). Results with Re-186-HA, however, showed 3.05% leakage over 4 days. 4~ The presumed heterogeneous distribution of radionuclide within the synovium has limited existing agents to only those labeled with high-energy 13-emitters. It is presumed that the longer range of these particles is necessary to treat medium to large joints. However, low-energy 13-emitters may be equally or more effective in reducing inflammation for small to medium joints because a much larger radiation dose could be delivered to the synovium without excessive irradiation of surrounding tissue. This could be analogous to the effectiveness of the short range conversion electrons from Sn-ll7m for bone pain palliation, compared with the high-energy 13-emitter 81"-89.7 The only clinical example to date for treating synovial inflammation with a low-energy 13-emitter is the use of Er-169 (13" avg 111 keV) colloids to treat inflammation in the small finger joints. 39 Based on various

SRIVASTAVA AND DADACHOVA

334

considerations, appropriate size particles labeled with Sc-47, Sn-ll7m, Sm-153, and Er-169 seem to be the agents of choice for radiation synovectomy. BONE MALIGNANCY

THERAPY

There has been a revival of interest in applying radionuclides to the therapy of bone malignancies, including palliative relief of bone pain. Both Sr-89 and P-32 were investigated as early as the 1940s and 1950s for the treatment of metastatic cancer to bone.41-43 Robinson and others further explored the use of Sr89,44-47 resulting in the Food and Drug Administration (FDA) approving its routine application in 1993. This work also stimulated further clinical research to find other radionuclides that may have improved physical properties that permit treatment with fewer side effects on the myeloproliferative cells in the bone marrow. Such agents may be useful in the treatment of bone malignancy and thus may provide increased benefits to patients. The half-life of these agents is important because it determines the initial dose rate and therefore the total amount of radioactivity to be administered. What is an appropriate physical half-life is not well understood. A higher initial dose rate may result in more effective cell killing, but the therapeutic ratio of malignant cell destruction to normal cell recovery may be less. Too long a half-life creates obvious problems in environmental safety in case of spill or early death of the patient. A very short half-life is problematic as far as shipping and shelf life are concerned. It also requires a larger total of administered activity, which increases the radiation dose to personnel and family members and may require some hospitalization, thus increasing cost. However, repetitive doses may be given at shorter intervals, making it possible to titrate dose to response. Accompanying photon emission of appropriate energy can be useful in monitoring the distribution of the radiopharmaceutical in the patient for assessing dosimetry, but this is not essential for bone pain palliation therapy. Both Sr-89 and P-32, the earliest radionuclides used for this purpose, have highly energetic [3-emissions, and no "y-emission. The energetic [3 particles penetrate deep into the marrow cavity and cause increased myelotoxicity. More recent research has focused on radionuclides that have much lower-energy electron emissions and, therefore, potentially reduced toxicity. The relevant physical characteristics of the various radionuclides are given in Table 2. Thus far, only Sr-89 chloride (Metastron, Nycomed/Amersham, Arlington Heights, IL) and Sm-153 EDTMP (Quadramet, Berlex Laboratories, Montville,

NJ) have been approved by the FDA. Phosphorus-32 as sodium phosphate was "grand_fathered" as an approved drug when the FDA took over jurisdiction of radiopharmaceuticals from the Atomic Energy Commission. Re-186 (and Re-188) 1-hydroxyethylidene diphosphonate, although used clinically outside of the United States, and Sn-ll7m stannic DTPA are still under investigation. Strontium-89 is a pure B-emitter with a high [3" max and average penetration of --2.4 mm in soft tissue. The long physical half-life results in a rather low initial dose rate and also limits the possibility of repeat doses until long after the initial dosing. The energetic [3 particles also result in a low bone-to-marrow dose ratio, but myelotoxicity for the low palliation doses ( - 4 mCi/70 kg) has not been a major factor. Although individual studies vary in results, the overall efficacy in terms of patients experiencing pain relief (complete + marked + moderate) appears to be in the range of 54%48 to 80%. 47 Results with P-32 have been similar to Sr-89, but toxicity to the bone marrow has been severe at times, a951 Therefore, its use in the United States is not favored at the present time. However, because of the low cost of P-32, some investigations have continued to further evaluate its clinical value, particularly in the developing countries. 52 Samarium-153 has a short physical half-life of 1.9 days. This can be advantageous for administering repeated doses but makes manufacturing and delivery a ditficult problem. The range of its [3-particles is short (average 0.55 mm), resulting in good bone-tomarrow ratios ranging between 2 to 5.5. Myelotoxicity has been manageable a t the approved dose schedule (1 mCi/kg), and efficacy is in a similar range as 5r-89. 53-56 At high levels of administered Sm-153, an increase in survival of patients with metastatic prostate cancer was shown, but at the cost of severe myelotoxicity. 55 The physical half-life of Re-t86 (3.7 days) makes shipment and shelf life a lesser problem than with Sm-153. However, because of its higher [3- energy and consequently a longer range, the dose ratio of bone to marrow is not particularly favorable. It has been safe at - 1 - to 2-mCi/kg levels. 57,58 In a recent study,59 its effectiveness for pain palliation by using an administered dose of 35 mCi was found to be --67% in patients with prostate cancer but only 36% in patients with breast cancer. Any benefits over Sr-89 were not apparent. At present, only limited clinical experience has been obtained with Sn-ll7m stannic DTPA.6~ Its physical characteristics are very favorable. The range of the electron emission (monoenergetic conversion electrons) is less than that of any of the other radionuclides, so that the radiation absorbed dose to the marrow is

Table 2. Radionuclides for Bone Pain Therapy

Half-life (days) Strontium-89 Phosphorus-32 l]n-117m

Maximum 13 Energy (MeV)

50.5 14.3 14.0

Average [3 Energy (MeV)

Average Range (mm)

1.46

0.58

1.71

0.70

3.0 0.22 0.29

0.13"

0.15"

2.4

84

3' Photon (MeV) none none 0.159 (86%)

Rhenium-186

3.7

1.08

0.33

1.05

0.137 (9%)

Samarium-153

1.9

0.81

0.22

0.55

0.103 (29%)

*Conversion electrons with discrete energies (and range).

RADIONUCLIDE THERAPY

335

Table 3. Dosimetry of Bone Agents Radiation Dose (rad/mCi)

Strontium-89CI 2 Rhenium-186 HEDP Samarium-153 EDTMP "13n-117m stannic DTPA

Bone Surfaces 63.0 7.0

Red Marrow 40.7 3.0

Bone/Marrow Dose Ratio 1.6 2.3

15.4

2.8

5.5

65.1

9.8

6.8

Data from Srivastava et al. 83

considerably less, giving the best bone-to-marrow ratio (Table 3). The initial dose rate is higher than that obtained with Sr-89, and the half-life is ideal for shipment and shelf life. Its in vitro and in vivo stability is very high. 64 An accompanying ",/-photon is useful for monitoring. Results so far indicate a very low myelotoxicity (Table 4), and the efficacy is similar to the other compounds.63 All agents discussed previously have been considered primarily to provide pain palliation in advanced metastases involving bone. The requirements for achieving this purpose are rather modest. It is not necessary to obtain much tumor regression, and it is desirable to avoid significant toxicity. Therefore, for achieving pain palliation, it is not necessary to administer the highest tolerated doses. However, there are hints that more than just pain palliation can be achieved in the appropriate clinical situation. Recent data indicate that an earlier onset of response occurs with higher levels of administered Sn-117m activity. 6s The transCanada study, performed with high doses of Sr-89 in patients with relatively early metastatic disease of the prostate, showed that, as an adjuvant to external beam treatment, the interval to new painful metastases could be significantly lengthened.6s In addition, others have shown reversal of changes on the radionuclide bone imaging study with 81"-89. 69 Radiographs after radionuclide therapy have shown healing of lytic metastases, 42'7~ thus showing that tumor regression can actually occur. It has also been shown that treatment

of earlier disease is more successful than the treatment of more advanced disease. Prolongation of survival has been reported by using very high doses (2.5 mCi/kg) of Sm-153 EDTMPY This has been attained at the expense of increased morbidity, as evidenced by a greater increase in myelotoxicity. Based on these and other recent findings, it is reasonable to assume that these agents may be useful in other situations, such as adjuvant to external-beam radiation therapy and chemotherapy. In primary bone malignancy, the use of radionuclide therapy as an adjuvant to surgery may prevent the appearance of metastatic disease. Earlier application of these agents in a prophylactic mode is warranted. Their ease of administration and relative lack of toxicity present a strong argument for this approach, as well as for treatment of asymptomatic cancer patients. If higher doses do prove advantageous, then the agent with the lowest toxicity should be considered the most appropriate candidate. Sn-ll7m stannic DTPA appears to be the agent of choice if future studies (an extended phase [I clinical trial is under way) continue to show reduced toxicity compared with the other agents, particularly Sr-89 and Sm-153. In a recent study, 71 Sn-ll7m had a substantial therapeutic advantage over high-energy I3-emitters, and its myelotoxicity was considerably lower, pointing to the possibility of administering much higher therapeutic doses for the treatment of primary/metastatic bone cancer.

DOMESTI C AVAI LABI LI TY OF THERAPEUTI C RADIONUCLIDES

Silberstein72 made a list of all reactor- and cyclotron-produced radionuclides, most of them provided in the United States in a limited manner only by the major industrial, government, or academic sources. Approximately 32 of these radionuclides have physical characteristics suitable for therapeutic applications, and 16 of them (Bi-213, Cu-67, Au-198, Ho-166, l n - l l l , Ir-192, Lu-177, P-32, Re-186, Re-188, Sm-153, Sr-89, Sn-117m, Y-90, 1-125, and 1-131) have been through at least 1 clinical therapeutic trial. Nine of the listed radionuclides (Au-198, I n - I l l , Ir-192, P-32, Sm-153, Sr-89, Y-90, 1-125, and 1-131) are routinely available from commercial vendors at modest prices, and their

Table 4. Myelotoxicity Levels*

No. of Patients With Grade ->2 Toxicity Radiopharmaceutical Sr-89 CI2

Dose Group (mCi/k~l)

n

WBC

Platelets

Reference

0.154 0.040

67 161

25 (37%) 48 (31%) t

41 (61%) -

65 66

0.500-1.143

12

2 (17%)

3 (25%)

67

Sm-153-EDTMP

1.00 1.50 3.00

20 4 4

3 (15%) 3 (75%) 4 (100%)

5 (25%) 1 (25%) 2 (50%)

55

Sn-117m DTPA

0.143 0.179 0.286

9 5 12

1 (11%) 0 (0%) 1 (8%)

0 (0%) 0 (0%) 0 (0%)

63

Re-186-HEDP

*Using National Cancer Institute criteria. tOnly "hematologic toxicity grade" ---2 mentioned.

SRIVASTAVA AND DADACHOVA

336

future availability for radionuclide therapy studies appears assured. The only problem may arise with the use of In- 111 for therapy; the projected cost for a 150- to 200-mCi treatment batch of highspecific activity I n - l l l could run into several thousand dollars.

Reactor Production The situation is quite complicated with a number of nonroutine reactor-produced therapeutic radionuclides, which are required in high specific activities for various clinical applications. The US Department of Energy (DOE) laboratories, mostly Oak Ridge National Laboratory (ORNL), TN, and also the University of Missouri Research Reactor (MURR), are the main sources at the present time. The isotopes, which are produced in carrier-added form by direct irradiation of enriched or natural (high abundance) targets in the reactor (such as Re-186, Ho-166, or Lu-177), cost several thousand dollars per batch. This high cost may be because of attempts to recover production costs from a single customer (Re-186 is sold by ORNL in batch sizes of I Ci at over $7,000), to impose a minimal charge (MURR has a minimum charge of $1,000 per order, which does not include shipping and handling), or a combination of the above. Clearly, such high costs place these B-emitters out of reach of most clinical and laboratory investigators, which, combined with the very limited usable time frame of the radionuclides (1 to 3 days after end of bombardment because of decreasing specific activity and increasing radiolysis), may remain as major obstacles for future clinical research with high specific-activity carrier-added 13-emitters. The isotopes, which are produced by the decay of their parent and subsequently obtained in carrier-free form in a generator system, 7"8 offer a cost-effective alternative to carrier-added radionuclides. Currently, 2 isotopes, very different in their decay and chemical properties (the high-energy 13-emitter, Re-188, and the a-emitter, Bi-213) are available from the W-188/Re-188 and Ac-225/Bi-213 generators, respectively. Tungsten-188 parent can be obtained from MURR, ready for use. One hundred millicurie to 1 Ci W-188/Re-188 generators are also routinely produced by ORNL. The 69-day half-life of the W-188, at least 80% elution yields in 24-hour intervals,38 and techniques to prolong the life of a generator73 by possibly obtaining Re-188 in a small volume, make W-188/Re-188 generators an attractive source of carrier-free Re-188 for clinical research. Ac-225, which is a parent of Bi-213, can be purchased from ORNL for approximately $500/mCi. Two different generator designs are now in use, both using ion exchange for separation of Bi-213 as Bi-213 iodide solution from Ac-225. 74"75 Although the price ofAc-225 is substantial, it should be pointed out that because of the short time needed for Ac-225 parent and Bi-213 daughter to reach equilibrium, Ac-225/Bi-213 generators can be eluted 4 times during a 9-hour period. When this is combined with the relatively long half-life of Ac-225 (10 days) and the considerably lower activities in comparison with 13-emittersneeded to deliver tumoricidal doses, the routine use of Bi-213 in a clinical setting looks plausible. It would also be gratifying to see the introduction of another supply source of Ac-225 in the United States, such as Ac-225 produced in a cyclotron via a Ra-226(p,2n)Ac-225 reaction.76 This production route is used in Europe and seems to be cheaper and easier than the Th-228 cow, as is currently done at ORNL.

Accelerator Production

For many therapeutic radionuclides, accelerator production constitutes a viable and more cost-effective alternative to reactor production. However, a reliable year-round supply of acceleratorproduced research isotopes in the United States has not yet been achieved. 77-79 Radionuclides produced by using a charged-particle accelerator (linac or cyclotron) and their properties depend on a number of factors that include targetry, irradiation conditions, and processing chel~iStl"y. 1"4'77 The low-energy (--<30MeV) cyclotron production and the supply of a few therapeutic radionuclides that have a commercial market have continued at a satisfactory level.8~ Examples include the high-LET, low-energy conversion and Auger electron emitters 1-123, 1-125, Ga-67, In-111, and T1-201; a emitters such as At-211; and a few 13 emitters. Many other therapeutic isotopes are either not produced because of the low-volume market(s) or cannot be produced in sufficient quantities on a regular basis by using these low-energy cyclotrons. Many therapeutic radionuclides can be produced either only or just more efficiently by using higher-energy accelerators. Two DOE-owned facilities, the BLIP (Brookhaven Linac Isotope Producer) at Brookhaven National Laboratory (BNL), and the IPF (Isotope Production Facility) at LANSCE (Los Alamos Neutron Science Center), have been used for this purpose. These machines are very expensive to operate, and isotope production cannot support the full independent operating costs or is in conflict with their primary mission, which is usually physics research. 8"81-83 Isotope production in these machines has been undertaken only as a parasitic or a secondary activity. Parasitic isotope production is very cost-effective because only incremental accelerator operating costs are charged, and the high intensity and high energy of these machines allow simultaneous production of several isotopes. In recent years, these isotopes have become more costly, scarce, or unavailable.8'79 The reason is that declining budgets in physics programs have severely restricted the operating periods of these accelerators, which in turn has curtailed the supply of radioisotopes needed for patient health care. This situation is not new; the shortage of radioisotopes for medical use has been discussed and debated for the last 15 years by various user groups, professional and scientific organizations, and i n d u s t r y . 78'81-83 However, the concern has been rapidly mounting now that a number of both high-specific activity reactor- and accelerator-produced isotopes are emerging as potentially useful and, in some cases, even unique for therapeutic applications in nuclear medicine and will be required in large quantities with an uninterrupted supply. 83 In the past, DOE had assumed the responsibility of providing some of the radioisotopes that are difficult to obtain to the research and industrial community. However, as mentioned previously, facility and budgetary limitations have prohibited the DOE from reaching their objectives. To address and resolve these problems, in particular with accelerator-produced isotopes, the Office of Isotopes for Medicine and Science (OIMS) within DOE/Office of Nuclear Energy, Science and Technology (NE) has recently instituted a network of large accelerators around the world, the Virtual Isotope Center (VIC), to supply the most needed radioisotopes on a year-round basis (J. Carty, personal communication, 2000). This currently includes the following facilities: BLIP at

RADIONUCLIDE THERAPY

BNL; LANSCE at the Los Alamos National Laboratory (LANL); National Accelerator Center (NAC), Faure, South Africa; the Institute of Nuclear Research (INR), Troitsk, Russia; and possibly in the future, Paul Scherrer Institute (PSI), Villigen, Switzerland. Specialized target design and fabrication is done at BNL, and the cold targets are shipped to South Africa and Russia. The NAC and INR accelerators irradiate targets, which are then shipped to LANL o r BNL for processing. The US facilities also handle necessary approvals from the FDA. However, the success to date of the VIC has been limited and continues to be a struggle to maintain. It will be difficult to significantly expand the list of radioisotopes provided through this mechanism, and it will be too costly to be practical to distribute small quantities of short-lived isotopes with this multinational consortium. Also, for many isotopes, decay loss in transit may lead to.unacceptable low specific activity. In response to the recent shutdown of the beam stop target station at LANSCE, the DOE/NE/OIMS is also funding the construction at LANL of a new 100-MeV, 250-I.tA IPF at LANSCE similar to the BLIP at BNL. 79 This facility may be complete in 2003 and could eventually operate for a period of up to 8 months per year in a parasitic mode. It will still be tied to the operation of another facility and will run in a fashion similar to the old IPF, with all the attendant problems of the parasitic mode of operation. In short, there are currently not enough reliable sites for an uninterrupted radioisotope supply. There is no dedicated accelerator facility owned by DOE to develop and produce new or existing radioisotopes in sufficient quantity, with year-long availability, and at reasonable cost, for biomedical research. Also, no existing facility is suitable to carry out high-current targetry research, which is required for new radioisotope development. The option of a dedicated higher-energy (~70 MeV), higher-beam current ( - 2 mA) cyclotron for continuous and reliable production of various radionuclides is currently under serious consideration by DOE/NE/ OIMS. Were such a dedicated facility available, it would also successfully fulfill the urgent national need7s's4"86 to rebuild opportunities for hands-on and broad-based education and training in nuclear and radiochemical techniques. A new dedicated cyclotron would certainly go a long way toward facilitating the large-volume, cost-effective production of many therapeutic radionuclides. For example, the current specific activity ( - 1 0 mCi/mg) of the very promising reactor-produced therapeutic radionuclide Sn-ll7m is adequate for bone pain therapy, but it is not high enough for radiobioconjugate development. Its use to target nuclear antigens or to label antibodies, peptides, or receptor-binding tracers will have to await the development of methods (p,n reactions in a cyclotron) that could provide a no-carrier-added product. 87"8sAnother example is Cu-67 (which as discussed earlier, has shown very promising results in the therapy of patients with B-cell NHL with Cu-67-2IT-BATLym-1 antibody-chelator conjugate), ~6-~s which after many interruptions in supply is now available with a somewhat higher frequency and on a more regular basis from BNL (produced via the Zn(p, 2pxn)Cu-67 reaction in the BLIP). aa A dedicated cyclotron7s'79 would certainly assure close to a year-long supply of Cu-67 and Sn-ll7m, and indeed of many other important therapeutic radionuclides, for existing as well as many new and promising therapeutic applications.

337 FUTURE DIRECTIONS

The field of RIT of solid tumors and lymphomas will in the near term probably be dominated by 2 not quite ideal but readily available radionuclides, 1-131 and Y-90. If Cu-67 continues to be made more regularly available by DOE at BNL or from other accelerators, 7s'88 and in the future from a dedicated cyclotron on a routine basis, this radionuclide certainly will make an impact on the treatment of B-cell NHL and other cancers. Scandium-47, a no-carrier-added reactor-produced (Ti-47(n,p)Sc-47 reaction) radionuclide, has been proposed as a replacement of Cu-67 because of its very similar properties and potentially wider availability.89'9~ It can also be produced in a cyclotron with adequate radionuclidic purity for most applications.9~ Commitment of the DOE to supply both clinical and laboratory researchers, for example with these and other isotopes, such as Bi-213, will ensure the continuity of research investigations and clinical trials for the treatment of blood and other cancers, and of micrometastatic disease from these malignancies. Peptide therapy, which has attracted much attention in recent years, will no doubt continue to grow by including other than STTR-binding peptides. These include antiangiogenic peptides, 91'92 such as anti-vascular endothelial growth factor peptides, 93 anti-otv133 integrin peptides, matrix metalloproteinase inhibitors, and other classes of peptides. 94'95 Yttrium-90 and In-111 will initially be the isotopes of choice, but I-125 and other newer isotopes that have low-energy electron (conversion electron, Auger) yields per decay comparable with or higher than I n - I l l are expected to emerge as useful alternatives. 5"96 Tinl17m appears to have very attractive therapeutic properties, and again, if in the future it becomes available in the no-carrieradded form, its use for antibody and peptide-based therapy and other forms of treatment may turn out to be very advantageous. 7s With a large number of coronary angioplasty operations performed each year by departments of cardiothoracic surgery in various hospitals, the use of Re-188--filled balloons for intravascular radiation to prevent restenosis could result in substantial savings. Also, the use of Re-188 compounds, such as Re-188DTPA or Re-188-MAG3 in place of Re-188 perrhenate, may greatly reduce the dose to the thyroid and stomach in an unlikely case of balloon rupture. 97 As far as bone pain palliation is concerned, Sr-89 chloride will most likely dominate the field, along with Sm-153 EDTMP and perhaps Sn-117m-DTPA63 eventually gaining wider acceptance. Also, there may be a new interesting therapeutic application for 1-131, as it has recently been discovered that more than 80% of mammary cancers in humans express a sodium iodide symporter (NIS). 9s'99 NIS is known to mediate iodide accumulation in the thyroid gland. ~~176 The capability to concentrate and organify iodide allows the use of 1-131 for the treatment of differentiated thyroid cancers and hyperthyroidism. The presence of the endogenous NIS in mammary tumors may open a new avenue for the treatment of cancer with this mechanism. This strategy could potentially be further enhanced for the targeted radiotherapy of many tumors through the adenovirus-mediated transfer of NIS into tumor cells, 1~ or through other transfer mechanisms.

338

SRIVASTAVA AND DADACHOVA Table 5. Choice Radionuclides for Principal Therapeutic Applications

Application

Route of

Best-suited

Administration

Radionuclide(s)

Tumor therapy Solid tumors Large lesions Micrometastases

Leukemias, lymphomas Pain palliation Soft tissue Metastatic bone pain Non-oncology Synovectomy Marrow ablation Microspheres Receptor-binding tracers and cellular (nuclear) antigens

iv

Sc-47, Y-90, 1-131, Lu-177, Re-188 Sc-47, Sm-153, Re-188 Sc-47, Sn-117m, Sm-153, other Auger, conversion electron, (x, and short-range 13emitters Sc-47, Cu-67, Sn-117m, 1-131

iv iv

Y-9O, 1-131, Ho-166, Re-188 Sr-89, Sn-117m, Sm-153, Re-186, Re-188

regional iv iv iv

Sc-47, Sn-117m, Sm-153, Er-69 Sn-117m, Ho-166 Y-90, other radiolenthanides Auger, conversion electron, c~, and short-range [3" emitters

iv

intratumoral iv

Note. The isotopes in various categories are listed in order of increasing atomic mass and not necessarily based on their degree of therapeutic effectiveness. Data from Srivastave. 8

In summary, there are a number of potential present and future radionuclides for tumor therapy and for other therapeutic applications. This article has provided a brief description of the various radionuclides and some recent advances in specific applications involving radionuclide therapy. The choice of the radionuclide best suited for a particular application ultimately depends on a number of factors, including: (1) half-life, (2) type of emission (c~, [3, % Auger, or conversion electrons), (3) specific activity, (4) chemistry, (5) route of administration, (6) internal dosimetry, (7) radiation safety and environmental concerns, (8) vehicle used as the carrier, (9) in vivo pharmacokinetics of the labeled carrier and the free radionuclide, and (10) cost of production and availability. Selected important therapeutic applications, applications where radionuclide therapy may have an important role to play, and the radionuclides that are considered best suited for the application are summarized in Table 5. It should be noted that this list is not meant to be exhaustive, and additional radionuclides can be added based on present and future work as well as various other considerations.

At times, the nuclear and radiochemical challenges to the development of a radionuclide, compounded by issues of cost and availability, especially if the radionuclide is new and/or difficult to produce, become issues of paramount importance, and these factors ultimately determine the future therapeutic value of many otherwise very promising radionuclides. Despite the various unresolved issues and concerns, the substantial recent progress of investigations in areas such as tumor radioimmunotherapy, bone pain palliation, and others discussed in this article offer renewed hope and promise for the widespread use of internally administered radionuclides for various novel and effective therapeutic approaches.

ACKNOWLEDGMENT

Special thanks are due to Ms. Susan Cataldo for help with the preparation of this manuscript.

REFERENCES

1. Volkert WA, Goeckler WF, Ehrhardt GJ, et al: Therapeutic radionuclides: Production and decay property considerations. J Nucl Med 32:174185, 1991 2. Wheldon TE: Targeting radiation to tumors. Int J Radiat Biol 65:109-116, 1994 3. O'Donoghue JA, Bardibs M, Wheldon TE: Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nucl Med 36:1902-1909, 1995 4. Mausner LF, Srivastava SC: Selection of radionuclides for radioimmunotherapy. Med Phys 20:503-509, 1993 5. Srivastava SC: Criteria for the selection of radionuclides for targeting nuclear antigens for cancer radioimmunotherapy. Cancer Biother Radiopharm 11:43-50, 1996

6. Ercan MT, Caglar M: Therapeutic radiopharmaceudcals. Cur Pharm Design 6:1085-1121, 2000 7. Srivastava SC: Therapeutic radionuclides: Making the right choice, in Mather SJ (ed): Current Directions in Radiopharmaceutical Research and Development, Dordrecht, The Netherlands, Kluwer Academic Publishers, 1996, pp 63-79 8. Srivastava SC: Traditional and new isotopes for radioimmunotherapy, in Riva P (ed): Therapy of Malignancies With Radioconjugated Monoclonal Antibodies: Present Possibilities and Future Perspectives, Chur, Switzerland, Harwood Academic Publishers, 1999, pp 11-26 9. Srivastava SC (ed): Radiolabeled Monoclonal Antibodies for Imaging and Therapy. New York, Plenum Press, 1988 10, Larson S, Digvi C, Scott A, et al: Current status of radioimmunotherapy. Nucl Med Biol 21:785-792, 1994

RADIONUCLIDE THERAPY

11. Milenic DE: Radioimmunotherapy: Designer molecules to potentiate effective therapy. Semin Radiat Oncol 10:139-155, 2000 12. Saga T, Weinstein J, Jeong J, et al: Two-step targeting of experimental lung metastases with biotinylated antibody and radiolabeled streptavidin. Cancer Res 54:2160-2165, 1994 13. Hu S-Z, Shively L, Raubitschek A, et al: Minibody: A novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res 56:3055-3061, 1996 14. Wu A, Yazaki P: Designer genes: Recombinant antibody fragments for biological imaging. Quart J Nucl Med 43:268-283, 1999 15. Knox SJ, Meredith RF: Clinical radioimmunotherapy. Semin Radiat Oncol 10:73-93, 2000 16. DeNardo GL, DeNardo SJ, O'Donnell RT, et al: Are radiometallabeled antibodies better than iodine-13 I-labeled antibodies: Comparative pharmacokinetics and dosimetry of copper-67-, iodine-131-, and yttrium90-labeled Lym-I antibody in patients with non-Hodgkin's lymphoma. Clin Lymphoma 1: 118-126, 2000 17. DeNardo GL, DeNardo SJ, Kukis DL, et al: Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin's lymphoma: A pilot study. Anticancer Res 18:2779-2788, 1998 18. DeNardo SJ, DeNardo GL, Kukis DL, et al: Cu-67-21T-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma. J Nucl Med 40:302-310, 1999 19. Vriesendorp HM, Morton JD, Quadri SM, et al: Review of five consecutive studies of radiolabeled immunoglobulin therapy in Hodgkin's disease. Cancer Res 55:5888-5892, 1995 (suppl) 20. Scheinberg DA: Antibody-mediated therapy of minimal residual leukemia: Use of humanized monoclonal antibodies and targeted alpha particles, in Proceedings of the European Biological Society 4th International Symposium on the Biological Therapy of Cancer, Munich, Germany, 1997 21. Sgouros G, Ballangrud AM, Jurcic JG, et al: Pharmacokinetics and dosimetry of an alpha-particle emitter labeled antibody: 213-Bi-HuM 195 (anti-CD33) in patients with leukemia. J Nucl Med 40:1935-1946, 1999 22. Jacobs AJ, Fer M, Su FM, et al: A phase I clinical trial of 186-rhenium-labeled monoclonal antibody administered intraperitoneally in ovarian carcinoma: Toxicity and clinical response. Obstet Gynecol 82:586-593, 1993 23. Alvarez RD, Partridge EE, Khazaeli MB, et al: Intraperitoneal radioimmunotherapy of ovarian cancer with 177-Lu-CC49: A phase I/II study. Gynecol Oncol 65:94-101, 1997 24. Meredith RF, Partridge EE, Alvarez RD, et al: Intraperitoneal radioimmunotherapy of ovarian cancer with lutetium-177-CC49. J Nucl Med 37:1491-1496, 1996 25. Riva P, Arisata A, Sturiale C, et al: Treatment of intracranial human glioblastoma by direct intratumoral administration of 131-I-labeled antitenascin monoclonal antibody BC-2. lnt J Cancer 51:7-13, 1992 26. Westlin JE, Snook D, Nilsson S, et al: Intravenous and intratumoral therapy of patients with malignant gliomas with 90-yttrium-labeled monoclonal antibody MUC 2-63, in Epenetos A (ed): Monoclonal Antibodies 2: Applications in Clinical Oncology, London, Chapman & Hall, 1993, pp 17-25 27. Paganelli G, Grana C, Chinol M, et al: Antibody-guided three-step therapy for high-grade glioma with yttrium-90 biotin. Eur J Nucl Med 26:348-357, 1999 28. Cutler CS, Lewis JS, Anderson CJ: Utilization of metabolic, transport and receptor-mediated processes to deliver agents for cancer diagnosis. Ad Drug Deliv Rev 37:189-211, 1999 29. de Jong M, Bernard HF, de Bruin E, et al: Internalization of radiolabeled [DTPA]-octreotide and [DOTA, Tyr3] octreotide: Peptides for somatostatin receptor-targeted scintigraphy and radionuclide therapy. Nucl Med Commun 19:283-288, 1998

339

30. Janson ET, Westlin JE, Ohrvall U, et al: Nuclear localization of In-111 after intravenous injection of [In-11 l-D-Phe~]-Octreotide in patients with neuroendocrine tumors. J Nucl Med 41:1514-1518, 2000 31. Kwekkeboom D, Krenning EP, de Jong M: Peptide receptor imaging and therapy. J Nucl Med 41:1704-1713, 2000 32. Paganelli G, Zoboli S, Cremonesi M, et al: Receptor-mediated radionuclide therapy with 90Y-DOTA-D-Phel-Tyr3-Octreotide: Preliminary report in cancer patients. Cancer Biother Radiopharm 14:477-483, 1999 33. Otte A, Herrmann R, Heppeler A, et al: Yttrium-90 DOTATOC: First clinical results. Eur J Nucl Med 26:1439-1447, 1999 34. Popma JJ, Califf RM, Topoi EJ: Clinical trials of restenosis after coronary angioplasty. Circulation 84:1426-1436, 1991 35. Weinberger J: Intracoronary radiation using radioisotope solutionfilled balloons. Herz 23:366-372, 1998 36. Hoher M, Wohrle J, Wohlfrom M, et al: Intracoronary betairradiation with a liquid Re-188-filled balloon: Six-month results from a clinical safety and feasibility study. Circulation 101:2355-2360, 2000 37. Kotzerke J, Hanke H, Hoher M: Endovascular brachytherapy for the prevention of restenosis after angioplasty. Eur J Nucl Med 27:223-236, 2000 38. Knapp FF, Jr: Rhenium-188: A generator-derived radioisotope for cancer therapy. Cancer Biother Radiopharm 13:337-349, 1998 39. Deutsch E, Broadack J, Deutsch K: Radiation synovectomy revisited. Eur J Nucl Med 20:1113, 1993 40. Chinol M, Vallabhajousula S, Goldsmith S, et al: Chemistry and biological behavior of samarium-153 and rhenium- 186-labeled hydroxyapatite particles: Potential radiopharmaceutical for radiation synovectomy. J Nucl Med 34:1536, 1993 41. Pecher C: Biological investigations with radioactive calcium and strontium: Preliminary report on the use of radioactive strontium in the treatment of bone cancer. University of California Publications in Pharmacology 1 t:117-149, 1942 42. Friedell HL, Storaasli JP: The use of radioactive phosphorus in the treatment of carcinoma of the breast with widespread metastases to bone. AJR Am J Roentgenol 64:559-575, 1950 43. Firusian N, Mellin P, Schmidt CG: Results of Sr-89 therapy in patients with carcinoma of the prostate and incurable pain from bone metastases: A preliminary report. J Urol 116:764-768, 1976 44. Robinson RG: Radionuclides for the alleviation of bone pain in advanced malignancy. Clin Oncol 5:39-49, 1986 45. Quilty PM, Kirk D, Bolger JJ, et al: A comparison of the palliative effects of strontium-89 and external beam therapy radiotherapy in metastatic prostate cancer. Radiother Oncol 31:33-40, 1994 46. Lewington VJ, McEwan AJ, Ackery DM, et al: A prospective, randomized double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 27:954-958, 1991 47. Robinson RG, Spicer JA, Preston DF, et al: Treatment of metastatic bone pain with strontium-89. Nucl Med Biol 14:219-222, 1987 48. Katin MJ, Salenius SA, Blitzer PH, et al: Hematologic effects of Sr-89 treatment for metastases to bone. Proc Amer Soc Clin Oncol 3:12, 1993 49. Kaplan E, Fels IG, Kotlowski BR: Therapy of carcinoma of the prostate metastatic to bone with P-32-1abeled condensed phosphate. J Nucl Med 1:1-13, 1960 50. Edland RW: Testosterone potentiated radiophosphorus therapy of osseous metastases in prostate cancer. AIR Am J Roentgenol 120:678-683, 1974 51. Maxfield JR, Jr, Maxfield JGS, Maxfield WS: The use of radioactive phosphorus and testosterone in metastatic bone lesions from breast and prostate. South Med J 51:320-328, 1958 52. Nair N: Relative efficacy of P-32 and Sr-82 in palliation in skeletal metastases. J Nucl Med 40:256-261, 1999

340

53. Turner JH, Claringbold PG: A phase II study of painful multifocal skeletal metastases with single- and repeated-dose samarium-153 ethylenediaminetetra methylene phosphonate. Eur J Cancer 27:1084-1086, 1991 54. Farhangi M, Holmes RA, Volkert WA, et al: Samarium-153 EDTMP: Pharmacokinetics, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer. J Nucl Med 33:1451-1458, 1992 55. Collins C, Eary JF, Donaldson G, et al: Samarium-153-EDTMA in bone metastases of hormone refractory prostate cancer: A phase IBI trial. J Nucl Med 34:1839-1844, 1993 56. Resche I, Chatal J-F, Pecking A, et al: A dose-controlled study of Sm-153-ethylenediaminetetra methylene phosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 33:15831591, 1997 57. Maxon HR, Ill, Schroder LE, Thomas SR: Re-186(Sn)HEDP for treatment of painful osseous metastases: Initial clinical experience in 20 patients with hormone-resistant prostate cancer. Radiology 176:155-159, 1990 58. de Klerk JMH, Dijk AV, Schip BH, et al: Pharmacokinetics of rhenium-186 after administration of rhenium-186-HEDP to patients with bone metastases. J Nucl Med 33:646-651, 1992 59. Kolesnikov-Gauthier H, Carpentier P, Depreux P, et al: Evaluation of toxicity and efficacy of Re-186-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer. J Nucl Med 41:1689-1694, 2000 60. Atkins HL, Mansner LF, Srivastava SC, et al: Human biodistribution of Sn- 117m(4 +)DTPA: A new agent for palliative treatment of painful osseous metastases. Radiology 186:279-283, 1993 61. Atldns HL, Mausner LF, Srivastava SC, et al: Tin-ll7m(4+)-DTPA for palliation of pain from osseous metastases: A pilot study. J Nucl Med 36:725-729, 1995 62. Kfishnamurthy GT, Swailem FM, Srivastava SC, et al: Tin117m(4 +)DTPA pharmacokinetics and imaging characteristics in patients with metastatic bone pain. J Nucl Med 38:230-237, 1997 63. Srivastava SC, Atkins HL, Krishnamurthy GT, et al: Treatment of metastatic bone pain with tin-ll7m stannic DTPA: A phase I/II clinical study. Clin Cancer Res 4:61-68, 1998 64. Srivastava SC, Meinken GE, Mausner LF, et al: Nuclear, chemical, mad mechanistic consideration in the use of Sn-117m(4+)-DTPA relative to Re-186-HEDP and other agents for bone pain therapy, in Nicolini M, Bandoli G, Mazzi U (eds): Technetium and Rhenium in Chemistry and Nuclear Medicine, Padova, SG Editoriali, 1995, pp 287-292 65. Porter AT, McEwan AJB, Powe JE, et al: Results of a randomized phase-II trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine-resistant metastatic prostate cancer. Int J Radiat Oncol Biol Physics 25:805-813, 1993 66. Carretta RF, Weiland FL, Vande Streek PR, et al: Five years of clinical experience with Sr-89. Eur J Nucl Med 21:$44, 1994 67. de Klerk JMH, van het Schip AD, Zonnenberg BA, et al: Phase 1 study of rhenium-186-HEDP in patients with bone metastases originating from breast cancer. J Nucl Med 37:244-249, 1996 68. Srivastava SC, Atkins HL, Krishnamurthy GT, et al: Long-term analysis of clinical data from patients treated with Sn-ll7m DTPA for metastatic bone pain. J Nucl Med 40:65P, 1999 (abstr) 69. Robinson RG, Blake GM, Preston DF, et al: Strontium-89: Treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. Radiographics 9:271-281, 1989 70. Fossa SD, Paus E, Lochoff M, et al: Strontium-89 in bone metastases from hormone resistant-prostate cancer: Palliation effect and biochemical changes. Br J Cancer 66:177-180, 1992 71. Bishayee A, Rat DV, Srivastava SC, et al: Marrow-sparing effects of Sn- 117m(4 +)diethylenetriaminepentaacetic acid for radionuclide therapy of bone cancer. J Nucl Med 41:2043-2050, 2000

SRIVASTAVAAND DADACHOVA

72. Silberstein EB: Availability of radioisotopes produced in North America. J Nucl Med 41:10N-13N, 2000 73. Blower PJ: Extending the life of a 99Tcm generator: A simple and convenient method for concentrating generator eluate for clinical use. Nucl Med Commun 14:995-997, 1993 74. Wu C, Brechbiel MW, Gansow OA: An improved generator for the production of Bi-213 from Ac-225. Radiochem Acta 79:141-144, 1997 75. McDevitt MR, Finn RD, Sgouros G, et al: An 22SAc/213Bigenerator system for therapeutic clinical applications: Construction and operation. Appl Radiat Isot 50:895-904, 1999 76. Koch L, Apostolidis C, Molinet R, et al: Bi-213 conjugated to MAb for alpha-immunotherapy. Abstr Soc Meeting 1:$215, 1998 77. Srivastava SC, Mausner LF: Production and supply of radionuclides with high-energy particle accelerators: Current status and future directions, in Proceedings of the 21st Japan Conference on Radiation and Radioisotopes, Japan Atomic Industrial Forum, B-550, February 2-4, 1994, pp 1-11 78. Srivastava SC: Is there life after technetium: What is the potential for developing new broad-based radionuclides? Semin Nucl Med 26:119131, 1996 79. Mausner LF, Srivastava SC: Current status and future directions of production of radioisotopes with high-energy accelerators, in Proceedings of the Third International Topical Meeting on Nuclear Applications of Accelerator Technology, American Nuclear Society, Long Beach, CA, November 14-18, 1999, pp 13-19 80. Vera-Ruiz H: Cyclotron Facilities With Radionuclide Production Programs in Member States. International Atomic Energy Agency, Vienna, Austria, 1983 81. US Department of Energy, Health and Environmental Research Advisory Committee, Subcommittee on Nuclear Medicine, 1989 82. Holmes RA: National Biomedical Tracer Facilities: Planning and Feasibility Study. US Department of Energy, Society of Nuclear Medicine, New York, New York, 1991 83. Adelstein SJ: Isotopes for Medicine and the Life Sciences. Washington, DC, National Academy Press, 1995 84. Choppin GR, Welch MJ: Training requirements for chemists in nuclear medicine, nuclear industry, and related areas: Report of a workshop. Washington, DC, National Academy Press, 1988 85. Yates W: Future challenges in nuclear science education. J Radioanalytical Nucl Chem 171:15-21, 1993 86. Isaacs T: Nuclear education and training: Cause for concern? ISBN 92-64-18521-6, Nuclear Energy Agency, Organization for Economic Cooperation and Development, 2000 87. Mausner LF, Mirzadeh S, Maher R, et al: Production of high specific-activity ll7msn with the Szilard-Chalmers process. J Labelled Compds Radiopharm 16:177-178, 1989 88. Mausner LF, Kolsky KL, Joshi V, et al: Radionuclide development at BNL for nuclear medicine therapy. Appl Radiat Isot 49:285-294, 1998 89. Kolsky KL, Joshi V, Mausner LF, et al: Radiochemical purification of no-carrier-added scandium-47 for radioimmunotherapy. Appl Radiat Isot 49:1541-1549, 1998 90. Mausner LF, Kolsky KL, Joshi V, et al: Scandium-47, a replacement for Cu-67 in nuclear medicine therapy with I31~emitters, in Stevenson NR (ed): Proceedings of the 3rd International Conference on Isotopes: Isotope Production and Applications in the 21 st Century, 1999, Vancouver, Canada, World Scientific, 1999, pp 43-45 91. Griffioen AW, Molema G: Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237-266, 2000 92. Mousa SA: Angiogenesis Inhibitors and Stimulators: Potential Therapeutic Implications. Georgetown, TX, Landes Bioscience, 2000 93. Klement G, Barnchel S, Rak J, et al: Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24, 2000

RADIONUCLIDE THERAPY

94. Arap W, Pasqualini R, Ruoslahti E: Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279:377380, 1998 95. Blok D, Feitsma RI, Vermeij P, et al: Peptide radiopharmaceuticals in nuclear medicine. Eur J Nucl Med 26:1511-1519, 1999 96. Mariani G, Bodeli L, Adelstein SJ, et al: Emerging roles for radiometabolic therapy of tumors based on Auger electron emission. J Nucl Med 41:1519-1521, 2000 97. Lin WY, Tsai SC, Hsieh BT, et al: Evaluation of three rhenium-188 candidates for intravascular radiation therapy with liquid-filled balloons to prevent restenosis. J Nucl Cardiol 7:37-42, 2000

341

98. Kilbane MT, Ajjan RA, Weetman AP, et al: Tissue iodine content and serum-mediated I-125 uptake-blocking activity in breast cancer. J Clin Endocrinol Metab 85:1245-1250, 2000 99. Tazebay UH, Wapnir IL, Levy O, et al: The mammary gland iodide transporter is expressed during location and in breast cancer. Nature Med 6:871-878, 2000 100. Carrasco N: Iodide transport in the thyroid gland. Biochim Biophys Acta 1154:65-82, 1993 101. Boland A, Ricard M, Opolon P, et al: Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. Cancer Res 60:3484-3492, 2000