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Treatment of Bone and Joint Pain with Electron Emitting Radiopharmaceuticals
Abstract
IJNM, 19(3): 89-97, 2004 as the 1940's for the treatment of metastatic cancer to bone (1, 2). The work of Firusian et al. (3) suggested again that strontium-89 would be useful for relief of pain secondary to osseous metastases. Robinson and others further explored the utility of strontium-89 (4–7) resulting in the FDA approval for its routine application in 1993. This work has also stimulated clinical research in order to find other radionuclides, which may have improved physical properties that permit treatment with fewer side effects on the myeloproliferative cells in the bone marrow. This paper will compare the several agents that may be useful in the treatment of bone malignancy and bone metastases in addition to just palliation of metastatic bone pain, and discuss possible ways in which they may thus be applied to provide increased benefits to patients, and thus fulfill their full potential. A short discussion of joint treatment (radiosynovectomy) is also included. The basis for the action of these therapeutic agents is their incorporation into bone mineral and their beta emission, which limits their range of action to the near neighborhood of B one-seeking therapeutic radiopharmaceuticals are utilized on the basis of the radionuclide's particulate emissions (primarily low to intermediate energy electron emission). The requirements therefore are different from those of bone imaging agents that consist mainly of short-lived single photon emitters. Lately, the therapeutic bone-seeking radiopharmaceuticals have attained increasing importance due to their potential role in alleviating pain from osseous metastases in cancer patients, for the treatment of joint pain resulting from inflamed synovium (radiosynoviorthesis, or radiosynovectomy), or from various other forms of arthritic disease, and their possible application for the treatment of metastatic bone disease. There is, however, a paucity of published data on the bio-pharmacokinetics of most of these agents when used following intravenous administration for the above applications. This paper will briefly review and summarize the presently available chemical and biopharmacokinetic information on the various clinically approved as well as experimental bone-localizing therapeutic radiopharmaceuticals, currently utilized primarily for bone pain palliation, and make projections on their potential clinical application for the treatment joint diseases and of primary/metastatic cancer in bone.
... 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. On the other hand, repetitive doses may be given at shorter intervals making it possible to titrate dose to response (Srivastava, 2004). [3] Strontium-89 is a pure beta-emitting radionuclide with a half-life of 50.6 days. ...
... On the other hand, repetitive doses may be given at shorter intervals making it possible to titrate dose to response (Srivastava, 2004). [3] Strontium-89 is a pure beta-emitting radionuclide with a half-life of 50.6 days. The maximum beta energy is high and penetration (average) of Sr-89 in soft tissue is 2.4 mm. ...
... Hence Sr-89 is used in the therapy for multiple osseous metastases of prostate and breast cancer (Ebrahim et al., 2002 andRobinson et al.,1989). [2][3][4][5] emit principally nonpenetrating radiations such as beta particles. Zanzonico et al. (1999) [7] extended this for point source beta emitters. ...
There has been an increased interest in strontium-89 (Sr-89) therapy, which emits relatively high-energy (1.495 MeV) beta rays. The production in vivo bremsstrahlung radiation sufficient for external imaging and this radiation hazard warrants evaluation. The bremsstrahlung (secondary radiation) of Sr-89 has been traditionally ignored in internal dosimetry calculation. We have estimated the bremsstrahlung dose of Sr-89 source in the muscle and bone to body the various body organs (such as adrenals, brain, breasts, gallbladder wall, LLI wall, small intestine, stomach, ULI wall, heart wall, kidneys, liver, lungs, muscle, ovaries, pancreas, red marrow, bone surfaces, skin, spleen, testes, thymus, thyroid, urine bladder wall, uterus, fetus, placenta, and total body) from distributed sources of Sr-89 in the muscle and bone. In the present study, muscle and bone is considered as source organs. The bremsstrahlung dose of Sr-89 source in a muscle is less than that of cortical bone. In both muscle and bone medium, bremsstrahlung dose decreases with distance. These estimated values show that the bremsstrahlung radiation absorbed dose contribution from an organ to itself is very small, but contribution to other organs is not always negligible especially when large amounts of Sr-89 may be involved as in therapy applications.
... It is also successfully used for nerve endocrine tumour radioimmunotherapy. 111 In is produced by cyclotron from 112 Cd collision with protons of energy 2.8 MeV according to the nuclear reaction 112 Cd(p,2n) 111 In. The radioactive 111 In decays to 112 Cd with physical half-life time of 2.83 days. ...
... 111 In is produced by cyclotron from 112 Cd collision with protons of energy 2.8 MeV according to the nuclear reaction 112 Cd(p,2n) 111 In. The radioactive 111 In decays to 112 Cd with physical half-life time of 2.83 days. The type, energy and emission ratio for each decay are displayed at Table 2. ...
... mGy/MBq and the bladder receives 0.16 mGy/MBq. Consequently, this radioisotope gives the best bone to marrow ratio compared to other ones used for bone therapy [112]. It also presents a great advantage over the beta-emitter radioisotopes in the overall dosimetry. ...
Nuclear Medicine provides efficient tools for cancer therapy using compounds labelled with radionuclides that emit beta-particles, alpha-particles or Auger electrons. With their short path lengths, they destroy mainly targeted cancer cells with limited side effects. Ideal application for targeted radionuclide therapy demands radionuclides’ physical, radiobiological and radiochemical properties to be well known. These radionuclides are produced with the desirable characteristics for their application in Nuclear Medicine radiopharmaceutical therapy.
Furthermore, measurements of absorbed dose to the abnormal and to the normal tissue, in a patient-specific point of view, enhance therapy effectiveness. Dosimetry is a valuable tool for the decision of a successful treatment that will give impressive anti-tumour results and favourable tumour-to-normal tissue ratios.
This article will be a review of the contributions both in the production of the radionuclides – dedicated to radiopharmaceutical therapy – as well as in the individualized dosimetric methods referred in the literature for each radionuclide used in Nuclear Medicine therapy. Many dose-calculation methods and mathematical codes used will be referred in detail.
... Aunque, como se ha señalado el 32 P es raramente usado en Norteamérica y Europa para paliación del dolor óseo, la significativa ventaja económica y la facilidad de la administración oral ha renovado el interés en este agente como el radiofármaco de elección en otros lu-gares del mundo [14,15,24]. En un estudio de varias instituciones del Organismo Internacional de Energía Atómica (OIEA) se comparan el 89 Sr y el 32 P en 93 pacientes: 68 hombres y 25 mujeres con edad promedio de 62 años. ...
In this paper the prevalence of metastatic bone pain is estimated in our country in no less than 3 750 patients. Moreover, the role of -phosphate, which effectiveness is comparable to other radiopharmaceuticals, and the possible return to its previous general use, as it is cheaper, is examined. The fact that is considered more radiotoxic doesnt invalidate it as a treatment option, which is also evidenced by the Cuban experience. The Center of Isotopes (Centis) has established a production line of up to 37 GBq (1 Ci) per week of high quality . The fact of its being obtained through a radionuclide generator by electrochemical separation from makes the import of radioactive raw material practically not required for indefinite time. This implies that the radionuclide could be available in a sustainable way. By having the greater β- emission energy, it might be more radiotoxic than . Nevertheless, some evidences show that in the form of orthophosphate is more radiotoxic than 90Y citrate. In Europe, a radiopharmaceutical consisting of a lyophilized kit of EDTMP and Chloride solution was able to relief pain in 191 patients. Centis has registered the chloride solution for labeling. Then the task is to introduce in the market a radiopharmaceutical with this radioactive precursor and the imported lyophilized kit in order to increase the treatment to an important number of patients that, as a result, could be benefitted
... Table 1 lists the radionuclides which are currently used or being investigated for bone pain palliation and their nuclear and physical characteristics ( 89 Sr, 32 P, 153 Sm, 186 Re, 188 Re, 177 Lu, 166 Ho, 169 Er, 223 Ra, 90 Y, 117m Sn). The same radionuclides also have properties that make them useful for radiosynovectomy, an attractive alternative to chemical or surgical synovectomy for the treatment of inflammatory synovial disease, including rheumatoid arthritis (Srivastava, 2004). ...
The BR2 reactor is a 100 MW th high-flux 'materials testing reactor', which produces a wide range of radioisotopes for various applications in nuclear medicine and industry. Tin-117m (117m Sn), a promising radionuclide for therapeutic applications, and its production have been validated in the BR2 reactor. In contrast to therapeutic beta emitters, 117m Sn decays via isomeric transition with the emission of monoenergetic conversion electrons which are effective for metastatic bone pain palliation and radiosynovectomy with lesser damage to the bone marrow and the healthy tissues. Furthermore, the emitted gamma photons are ideal for imaging and dosimetry.
... Summary of the key clinical outcomes of different radiopharmaceuticals currently used in the clinical setting or under research for palliative treatment of bone metastases. 90 Y-EDTMP 45-50 Urinary -- -- -- -- -- -- (Khalid et al., 2014 Approved and commercially available (Serafini et al., 1998; Srivastava, 2004) 166 Ho-DOTMP 16-54 Urinary NE NE -- -- Moderate In clinical trails (Champlin et al., 2004; Ueno et al., 2009) 170 Tm-EDTMP 50-55 Urinary -- -- -- -- -- -- (Das et al., 2009) 177 Lu-DOTMP 70 Urinary NE NE -- -- Mild -- (Chakraborty et al., 2008 et al., 2013) Legend: NE – not established; WBC – white blood cells. Note: Data for 90 Y-EDTMP and 170 Tm-EDTMP is preclinical. ...
Purpose:
The present review article aims to provide an overview of the available radionuclides for palliative treatment of bone metastases beyond (89)Sr and (153)Sm. In addition, it aims to review and summarize the clinical outcomes associated with the palliative treatment of bone metastases using different radiopharmaceuticals.
Materials and methods:
A literature search was conducted on Science Direct and PubMed databases (1990 - 2015). The following search terms were combined in order to obtain relevant results: "bone", "metastases", "palliative", "care", "therapy", "treatment", "radiotherapy", "review", "radiopharmaceutical", "phosphorus-32", "strontium-89", "yttrium-90", "tin-117m", "samarium-153", "holmium-166", "thulium-170", "lutetium-177", "rhenium-186", "rhenium-188" and "radium-223". Studies were included if they provided information regarding the clinical outcomes.
Results and conclusions:
A comparative analysis of the measured therapeutic response of different radiopharmaceuticals, based on previously published data, suggests that there is a lack of substantial differences in palliative efficacy among radiopharmaceuticals. However, when the comparative analysis adds factors such as patient's life expectancy, radionuclides' physical characteristics (e.g. tissue penetration range and half-life) and health economics to guide the rational selection of a radiopharmaceutical for palliative treatment of bone metastases, (177)Lu and (188)Re-labeled radiopharmaceuticals appear to be the most suitable radiopharmaceuticals for treatment of small and medium/large size bone lesions, respectively.
... Radioactive isotopes of phosphorus (32 P) and strontium (89 Sr) were the first radiopharmaceuticals used for treatment of skeletal metastases in patients.[67] Other beta-emitting radionuclides such as 186Re, 153Sm, 177Lu, 117mSn, 166Ho, and 175Yb are recommended for this purpose.[891011121314] All agents have benefits and risks. ...
Bone metastasis is one of the most frequent causes of pain in cancer patients. Different radioisotopes such as P-32, Sm-153, Ho-166, Lu-177, and Re-186 with several chemical ligands as ethylenediaminetetramethylene phosphonic acid (EDTMP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP), and propylenediaminetetramethylene phosphonate (PDTMP) are recommended for bone pain palliation. In this work, (175)Yb-triethylenetetraminehexamethylene phosphonic acid (TTHMP) was produced as a proper alternative to other radiopharmaceuticals. Relatively long half-life (T1/2 = 4.18 days), maximum energy beta particle Eβ =470 keV (86.5%), low abundance gamma emission 396 keV (6.4%), 286 keV (3.01%), 113.8 keV (1.88%) and low cost are considered advantageous of Yb-175 are to wider usage of this isotope; in addition, TTHMP is an ideal carrier moiety for bone metastases. Production, quality control, and biodistribution studies of (175)Yb-TTHMP were targeted. Yb-175 chloride was obtained by thermal neutron bombardment of a natural Yb2O3 sample at Tehran Research Reactor (TRR), radiolabeling was completed in 1 h by the addition of TTHMP at the room temperature and pH was 7.5-8, radiochemical purity was higher than 95%. Biodistribution studies in normal rats were carried out. The results showed favorable biodistribution features of (175)Yb-TTHMP, indicating significant accumulation in bone tissues compared with clinically used bone-seeking radiopharmaceuticals. This research presents (175)Yb-TTHMP can be a good candidate for bone pain palliation and substitute of other radiopharmaceuticals, however, further biological studies in other mammals are still needed.
... The elemental dysprosium has a high thermal neutron absorption cross-section, which makes it interesting for making neutronabsorbing control rods in nuclear reactors (Kannan and Ganesan, 2010), and a resonance absorber to control the coolant void reactivity in Advanced Heavy Water Reactor (AHWR) (Kannan and Ganesan, 2010). In medical treating damaged joints, irradiation with 165 Dy has proved to be more effective than traditional surgery (Srivastava, 2004) and 159 Dy has been advocated for transmission imaging and bone mineral analysis (Rao et al., 1977). An alternative production route for radionuclides of lanthanides using high intensity lasers or light sources was studied recently by a group in Grenoble (Habs and Köster, 2012). ...
... Table 1 lists the radionuclides which are currently used or being investigated for bone pain palliation and their nuclear and physical characteristics ( 89 Sr, 32 P, 153 Sm, 186 Re, 188 Re, 177 Lu, 166 Ho, 169 Er, 223 Ra, 90 Y, 117m Sn). The same radionuclides also have properties that make them useful for radiosynovectomy, an attractive alternative to chemical or surgical synovectomy for the treatment of inflammatory synovial disease, including rheumatoid arthritis (Srivastava, 2004). ...
Tin-117m (T 14.0 d; 159 keV, 86%) is a promising radionuclide for therapeutic applications. In contrast to beta emitters, 117mSn emits low-energy conver-sion electrons that deposit their intense energy (127, 129, 152 keV) within a short range (0.22 - 0.29 mm) which can destroy tumors but not damage the bone marrow or other healthy tissues. The 159 keV gamma photons are ideal for imaging to monitor the cancer. This paper reports the results of 117mSn production yield calculations and measurements for several irradiation conditions which can be achieved in both the BR2 (Mol, Belgium) and HFIR (Oak Ridge, USA) High-Flux research reactors.
... Emitted gamma photons with an energy in the range of 100–200 keV and a reasonable abundance (410%) allow in vivo dosimetric monitoring.Table 1 lists the radionuclides which are currently used or being investigated for bone pain palliation and their nuclear and physical characteristics ( 89 Sr, 32 P, 153 Sm, 186 Re, 188 Re, 177 Lu, 166 Ho, 169 Er, 223 Ra, 90 Y, 117m Sn). The same radionuclides also have properties that make them useful for radiosynovectomy , an attractive alternative to chemical or surgical synovectomy for the treatment of inflammatory synovial disease, including rheumatoid arthritis (Srivastava, 2004). In contrast to beta emitters, 117m Sn emits low-energy monoenergetic conversion electrons that deposit their intense energy (127, 129, 152 keV) within a short range (0.22–0.29 mm) and which can destroy tumors with less damage to the bone marrow and other healthy tissues. ...
... Table 1 lists the radionuclides which are currently used or being investigated for bone pain palliation and their nuclear and physical characteristics ( 89 Sr, 32 P, 153 Sm, 186 Re, 188 Re, 177 Lu, 166 Ho, 169 Er, 223 Ra, 90 Y, 117m Sn). The same radionuclides also have properties that make them useful for radiosynovectomy, an attractive alternative to chemical or surgical synovectomy for the treatment of inflammatory synovial disease, including rheumatoid arthritis (Srivastava, 2004). ...
The BR2 reactor is a 100MW(th) high-flux 'materials testing reactor', which produces a wide range of radioisotopes for various applications in nuclear medicine and industry. Tin-117m ((117m)Sn), a promising radionuclide for therapeutic applications, and its production have been validated in the BR2 reactor. In contrast to therapeutic beta emitters, (117m)Sn decays via isomeric transition with the emission of monoenergetic conversion electrons which are effective for metastatic bone pain palliation and radiosynovectomy with lesser damage to the bone marrow and the healthy tissues. Furthermore, the emitted gamma photons are ideal for imaging and dosimetry.
Therapeutic radioisotopes are generally artificially produced using research reactors or particle accelerators. Since most therapeutic radioisotopes are neutron rich and subsequently decay by beta (β−)-particle emission, the irradiation of stable nuclei under neutron bombardment is a major important strategy for production. Most reactors are owned and operated by federal governments, so the accessibility and support of these facilities continues to be an important factor to insure the availability of a wide variety of reactor-produced radioisotopes. In this chapter the principle reactor production and processing strategies are described for a wide variety of radioisotopes which have important therapeutic applications in nuclear medicine, oncology interventional cardiology/radiology, and related disciplines.
This chapter deals with systemic radionuclide treatment of otherwise refractory bone pain in patients with bone metastases caused by different tumour diseases. It describes the different radiopharmaceuticals approved in Europe, both the indications and contraindications and the application procedure. Clinical results with significant pain palliation in 70–80 % of patients are reported in many studies. Finally, some promising results of recent studies, shifting the therapeutic goal from pure pain palliation towards tumoricidal effects by using new radiopharmaceuticals, combining radionuclides with chemotherapy or application of other treatment protocols are discussed.
ABSTRAK PEMBUATAN DAN KARAKTERISASI SEDIAAN RADIOISOTOP 169 ErCl 3 HASIL IRADIASI BAHAN SASARAN ERBIUM-168 DIPERKAYA 97,75%. Erbium-169 (169 Er) merupakan salah satu radioisotop pemancar β yang dapat digunakan untuk radiosinovektomi. Pada penelitian ini dikembangkan pembuatan radioisotop 169 ErCl 3 dengan cara iradiasi bahan sasaran erbium oksida diperkaya dengan pengayaan 168 Er sebesar 97,75%. Sebelum digunakan dalam pembuatan radiofarmaka, larutan 169 ErCl 3 dikarakterisasi supaya memenuhi syarat aplikasinya. Karakterisasi fisiko-kimia radioisotop 169 ErCl 3 yang meliputi kejernihan; pH; muatan listrik; kemurnian radiokimia; dan kemurnian radionuklida; masing-masing ditentukan dengan cara visual; kertas indikator pH; metode elektroforesis kertas; kromatografi kertas dan elektroforesis kertas; serta spektrometer γ saluran ganda. Kestabilan larutan ditentukan dengan mengamati kemurnian radiokimia larutan 169 ErCl 3 setiap hari selama satu bulan penyimpanan pada temperatur kamar. Hasil penelitian menunjukkan bahwa 169 ErCl 3 berupa larutan jernih, memiliki pH 1,5 – 2, tidak bermuatan, kemurnian radiokimia sebesar 99,51 ± 0,41% dan kemurnian radionuklida sebesar 99,84 ± 0,1%. Aktivitas jenis dan konsentrasi radioaktif larutan 169 ErCl 3 masing-masing sebesar 1,26 – 3,38 mCi/mg Er dan 11,05 – 29,59 mCi/mL pada saat end of irradiation (EOI). Uji stabilitas menunjukkan bahwa larutan 169 ErCl 3 masih stabil sampai satu bulan dengan kemurnian radiokimia sebesar 99,65 ± 0,09%. Larutan 169 ErCl 3 yang diperoleh dari bahan sasaran erbium oksida diperkaya 97,75% memiliki karakteristik fisiko-kimia yang memenuhi syarat untuk radiosinovektomi. ABSTRACT PREPARATION AND CHARACTERIZATION OF 169 ErCl 3 RADIOISOTOPE FROM IRRADIATED 97.75% ENRICHED ERBIUM-168 TARGET. Erbium-169 (169 Er) is one of radioisotopes that can be used for radiosynovectomy due to its β particle emission. The preparation of 169 ErCl 3 radioisotope has been developed by irradiation of enriched erbium oxide target with 97.75% of 168 Er enrichment. Before it is used in radiopharmaceuticals preparation, the 169 ErCl 3 solution was characterized to fulfil its application criteria. The physico-chemical characterization of 169 ErCl 3 , including solution clarity; pH; electric charge; the radiochemical purity; and the radionuclidic purity, were determined by visual observation; pH indicator paper; paper electrophoresis technique; paper chromatography and paper electrophoresis techniques; and multichannel γ spectrometry, respectively. The stability of 169 ErCl 3 solution was determined by daily observation of radiochemical purity during one month at room temperature. The present study has shown that 169 ErCl 3 was a clear solution, the pH of 1.5 – 2, neutral, the radiochemical purity of 99.51 ± 0.41% and radionuclidic purity of 99.84 ± 0.1%. The solution had specific activity and radioactive concentration of 1.26 – 3.38 mCi/mg Er and 11.05 – 29.59 mCi/mL at the end of irradiation (EOI), respectively. Stability evaluation indicated that 169 ErCl 3 solution was still stable for one month at room temperature with radiochemical purity of 99.65 ± 0.09%. Based on the results, 169 ErCl 3 solution from enriched erbium oxide target with 97.75% of 168 Er enrichment has suitable physico-chemical characteristics for radiosynovectomy.
This paper introduces a relatively novel paradigm that involves specific individual radionuclides or radionuclide pairs that have emissions that allow pre-therapy low-dose imaging plus higher-dose therapy in the same patient. We have made an attempt to sort out and organize a number of such theragnostic radionuclides and radionuclide pairs that may potentially bring us closer to the age-long dream of personalized medicine for performing tailored low-dose molecular imaging (SPECT/CT or PET/CT) to provide the necessary pre-therapy information on biodistribution, dosimetry, the limiting or critical organ or tissue, and the maximum tolerated dose (MTD), etc. If the imaging results then warrant it, it would be possible to perform higher-dose targeted molecular therapy in the same patient with the same radiopharmaceutical. A major problem that remains yet to be fully resolved is the lack of availability, in sufficient quantities, of a majority of the best candidate theragnostic radionuclides in a no-carrier-added (NCA) form. A brief description of the recently developed new or modified methods at BNL for the production of four theragnostic radionuclides, whose nuclear, physical, and chemical characteristics seem to show great promise for personalized cancer therapy are described.
The skeleton is a potential metastatic target of many malignant tumors. Up to 85% of prostate and breast cancer patients may develop bone metastases causing severe pain syndromes in many of them. In patients suffering from multilocular, mainly osteoblastic lesions and pain syndrome, radionuclide therapy is recommended for pain palliation. Low-energy beta-emitting radionuclides ((153)samarium-ethylenediaminetetrameth-ylenephosphonate (EDTMP) and (89)strontium) deliver high radiation doses to bone metastases and micrometastases in the bone marrow, but only negligible doses to the hematopoietic marrow. The response rate regarding pain syndrome is about 75%; about 25% of the patients may even become pain free. The therapy is repeatable, depending on cell counts. Concomitant treatment with modern bisphosphonates does not interfere with the treatment effects. Clinical trials using a new, not yet approved nuclide ((223)Radium) and/or combinations of chemotherapy and radionuclides are aiming at a more curative approach.
This article reintroduces and reinforces our proposed paradigm that involves specific individual "dual-purpose" radionuclides or radionuclide pairs with emissions suitable for both imaging and therapy and which, when molecularly (selectively) targeted using appropriate carriers, would allow pretherapy low-dose imaging as well as higher-dose therapy in the same patient. We have made an attempt to sort out and organize a number of such theragnostic radionuclides and radionuclide pairs that may thus potentially bring us closer to the age-long dream of personalized medicine for performing tailored low-dose molecular imaging (single-photon emission computed tomography/computed tomography or positron emission tomography/CT) to provide the necessary pretherapy information on biodistribution, dosimetry, the limiting or critical organ or tissue, the maximum tolerated dose, and so forth, followed by performing higher-dose targeted molecular therapy in the same patient with the same radiopharmaceutical. Beginning in the 1980s, our work at Brookhaven National Laboratory with such a "dual-purpose" radionuclide, tin-117m, convinced us that it is arguably one of the most promising theragnostic radionuclides, and we have continued to concentrate on this effort. Our results with this radionuclide are therefore covered in somewhat greater detail in this publication. A major problem that continues to be addressed, but remains yet to be fully resolved, is the lack of availability, in sufficient quantities, of a majority of the best candidate theragnostic radionuclides in a no-carrier-added form. A brief description of the recently developed new or modified methods at Brookhaven National Laboratory for the production of 5 theragnostic radionuclide/radionuclide pair items, whose nuclear, physical, and chemical characteristics seem to show great promise for personalized cancer and other therapies, is provided.
Internal radiotherapy is effective in the treatment of metastatic bone pain and can improve quality of life. A number of controlled studies using various agents have shown a mean response rate in pain relief of 70-80% of treated patients. Some investigators prefer radionuclides which emit low beta particles for the treatment of bone pain, because the assumption of lower bone marrow toxicity of this agents. However, neither dosimetric data for radiation absorbed dose to the bone marrow nor clinical blood count depression have shown any significant differences between these agents. Other researchers suggest enhanced antitumoral effects using high-energy beta emitters and propose aggressive first-line treatment in the early disease stage instead of using these radiopharmaceuticals only in end-stage patients suffering intractable bone pain. Another approach consists of including other treatment modalities such as autologous stem cell rescue or in combination with chemo or bisphosphonate therapy to a radionuclide treatment scheme. Future research should focus more on the curative effects of combination with radiosensitizer, for example, chemotherapy, or repeated treatments with bone seeking agents.
Hematological and biochemical parameters were evaluated in 31 patients receiving 150 MBq 89Strontium (89Sr) intravenously due to painful skeletal metastases from hormone resistant prostate cancer. Two and 3 months after the injection prostate specific antigen (PSA) had increased by a median of 36% and 100%, respectively, as compared to the pretreatment value whereas alkaline phosphatase (APHOS) had decreased by about 20% (median). The leucocyte and platelet counts were reduced by about 20-35%, without reaching grade greater than or equal to 2 toxicity. Pain relief was reported in 14 of 29 evaluable patients at 2 months and in 11 of 23 patients at 3 months. It is concluded that 89Sr represents a worthwhile therapeutic modality in the palliation treatment of patients with hormone resistant prostate cancer, though the biological significance of frequently increasing PSA and decreasing APHOS is not yet completely understood.
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Hydroxyapatite (HA), a natural constituent of bone, was studied as a particulate carrier for beta-emitting radionuclides in radiation synovectomy. Particles were radiolabeled with 153Sm or 186Re and their in vivo safety was investigated following intra-articular injection into knees of normal rabbits and rabbits with antigen-induced arthritis (AIA). Radiolabeling efficiency was greater than 95%; in vitro studies showed minimal (< or = 1%) loss of activity from particles over a 6-day period with 153Sm-labeled HA and about 5% loss of activity over a 5-day period with 186Re-labeled HA. The total cumulative extra-articular leakage of 153Sm over 6 days was 0.28% in normal rabbits and 0.09% in AIA rabbits. Leakage of 186Re from the joint was 3.05% over a 4-day period with 80% of extra-articular activity found in the urine. Histopathological evaluation of treated knees showed that HA particles are distributed throughout the synovium, embedded in the synovial fat pad. The ease and efficiency with which this HA carrier is labeled, coupled with observed extremely low leakage rates from the joint, make radiolabeled HA particles an attractive candidate as a radiation synovectomy agent for evaluation in rheumatoid arthritis patients.
A double-blind study was made on the effectiveness of erbium169 synoviorthesis in the digital joints of 7 patients with erosive, seropositive rheumatoid arthritis. The study involved 70 joints observed over a 12-month period: 20 pairs of metacarpophalangeal joints (MCP) and 15 pairs of proximal interphalangeal joints (PIP) were injected with erbium169 in one joint and saline in the other one. All joints had radiological lesions corresponding to Stage I and II of the Steinbroker classification. Six months after synoviorthesis, good and excellent results were observed in 71 % of the articulations treated with erbium169 and in only 40 % of those injected with saline (placebo) (p
This paper summarizes the results of our mechanistic studies on {sup 117m}Sn(4+)- DTPA to determine (i) the effect of oxidation state and specific activity of {sup 117m}Sn, (ii) effect of the addition of calcium, (iii) the nature of chemical species of tin in blood and urine, and (iv) kinetics of uptake and washout of radioactivity from bone relative to technetium, rhenium, and samarium bone agents.
The therapeutic application of 89strontium for the relief of pain in 11 cases of carcinoma of the prostate with skeletal metastases is reported. A significant clinical improvement could be observed in 8 of the 11 patients with generalized osseous metastases of prostatic carcinoma after the application of 30 muCi. 89strontium per kg. The effect was long lasting. At the same time an increase of alkaline phosphatase was observed, which was interpreted as an indication of the reactivation of osteoblasts and osteoid peripheral zones owing to beta-emission of the radioisotope in the affected areas. The indications for such therapy are discussed.
Two hundred and two patients with bone pain from metastatic cancer were treated with 40 microCi/kg of Sr-89. Patients were followed with pain diaries, records of medication taken, sleep patterns, serial bone scans and a Karnofsky Index. One hundred and thirty-seven patients with adequate followup survived at least 3 months, including 100 with prostate and 28 with breast carcinoma. Eighty of the 100 patients with prostate cancer responded, and 25 of the 28 breast cancer patients improved. Ten patients with prostate cancer and five with breast cancer became pain free. Little hematologic depression was noted. Sr-89 kinetic studies showed that strontium taken up in osteoblastic areas remained for 100 days. The tumor-to-marrow absorbed dose ratio was 10:1.
We have utilized 89Sr as palliative treatment for bone pain secondary to metastatic cancer in the skeleton of over 200 patients. The best results have been in patients with carcinoma of the prostate (80% response rate) and breast (89%). Results in a small number of patients with a variety of other cell types were not nearly as encouraging. Strontium-89 provides excellent palliation in the management of bone pain secondary to prostate and breast carcinoma.
Various 117mSn (2+ and 4+) compounds in well defined oxidation states were studied in normal mice using whole body autoradiography (WBARG), tissue distribution and scintigraphy in animal models of vitamin A induced bone disease, fracture, infected fracture and ischemic muscle lesions. The 117mSn4+-DTPA showed high affinity to normal bone with low soft tissue concentration. Increased deposition of this compound in fractures and ischemic lesions in muscle was also demonstrated. In hypervitaminosis A, reduced bone uptake of 117mSn4+-DTPA was shown to occur. Nude mice bearing osteogenic sarcoma of human origin showed uptake in spiculated pattern. The similar distribution of 117mSn4+-DTPA which does not contain phosphate or phosphonate groups, and the 99mTc(Sn) skeletal imaging compounds may indicate that tin is important in binding to bone. 117mSn4+-DTPA may not be ideal for routine imaging except when long term follow up is required. It should however be considered for therapy of bone tumors because of the long physical half-life of 117mSn (t1/2 = 14.03 days), abundance of short-range conversion and Auger electrons and its preferential deposition in cortical bone as indicated by our results.
Tin is an essential ingredient of most technetium-99m radiopharmaceutical preparations but its in-vivo distribution and long-term fate are not well understood. Tin-117m (t1/2 14d; gamma 159 keV, 86%) is an ideal tracer for studying biological behavior of tin compounds as well as for developing clinically-useful radiopharmaceuticals. This work describes the preparation and in-vivo distribution in mice of a number of tin-117m labeled compounds with commonly used ligands. High bone uptake of most compounds studied as well as the unexpectedly high bone uptake of Sn4+-DTPA indicates a high bone affinity of tin bound to chemically diverse ligands. Various compounds show subtle but significant differences in blood clearance, excretion, and soft-tissue uptake. Differences among Sn2+ and Sn4+ compounds with the same ligand are particularly noteworthy. For stannic chelates, higher bone uptake, faster blood clearance, and reduced soft-tissue concentration were observed. It appears that tin compounds bind to bone predominantly through the tin atom and that the differences in biodistribution depend on factors such as the net charge on the complex, the oxidation state of tin, and hydrolytic and kinetic stabilities of the complexes. The results indicate that the favorable half-life and decay characteristics of tin-117m in various stannic compounds, especially stannic-DTPA, make it potentially useful as an agent for skeletal scintigraphy and radiotherapy of bone tumors.
The physical and biological attributes of 117mSn(4+)-DTPA indicate that it should be an effective agent for palliative therapy of painful bony metastatic disease. The aim of this study was to evaluate whether or not this agent could effectively reduce pain while sparing the hemopoietic marrow from adverse effects.
Fifteen patients (10 males and 5 females) with painful bony metastases from various primary cancers were included in the study. Seven patients received 1.22 to 3.11 MBq/kg of 117mSn intravenously (Group 1) and eight patients received 4.85 to 5.77 MBq/kg (Group 2). All but one were treated as outpatients and followed for a minimum of 2 mo.
In the first group, pain relief was non-assessable in four patients because of death or additional treatment of soft-tissue disease by another modality. One patient had no relief of pain, one had complete relief of pain and one had transient relief of pain. No myelotoxicity was observed. For Group 2, three patients achieved complete relief of pain, two good relief, two partial relief and one began to experience pain relief when he suffered a pathological fracture 2 mo post-treatment. None of these patients had myelotoxicity.
Tin-117m(4+)-DTPA can reduce pain from metastatic disease to bone without inducing adverse reactions related to bone marrow. Further studies are needed to assess tolerance levels for the bone marrow and to evaluate response rates and duration of effect.
Radiation synovectomy is a potential weapon in the therapeutic armamentarium of nuclear medicine. It is an attractive alternative to surgical or chemical synovectomy for the treatment of rheumatoid arthritis. In this article the clinical results obtained with radiation synovectomy from the 1950s through 1992 are summarized and reviewed. Even after taking into account the paucity of well-controlled trials and rigorous clinical follow-up, it is clear that radiation synovectomy is efficacious in controlling the symptoms of rheumatoid arthritis. However, the procedure is not widely used because of concerns about leakage of radioactivity from the treated joint, and the resulting high doses that can be delivered to nontarget organs. New approaches to the preparation of radiolabeled particles for use in radiation synovectomy promise to minimize this leakage and thus allow the full potential of this important radiotherapy to be realized.
Purpose:
A large proportion of the practice of radiotherapy in the management of metastatic adenocarcinoma of the prostate is associated with palliation of pain from osseous metastases and improving quality of life. Radiation therapy is well known to be effective in treating painful sites and may also be effective in reducing the propensity for adjuvantly treated disease to become symptomatic. Strontium-89 is a systemic radionuclide that has clinical efficacy in the palliation of pain from bony metastases.
Methods and materials:
The study was a Phase-III randomized placebo control trial performed in eight Canadian Cancer Centers to evaluate the effectiveness of strontium-89 as an adjunct to local field radiotherapy. Patients with endocrine refractory metastatic prostate cancer received local field radiotherapy and either strontium-89 as a single injection of 10.8 mCi or placebo.
Results:
One hundred twenty-six patients were recruited. No significant differences in survival or in relief of pain at the index site where noted. Intake of analgesics over time demonstrated a significant reduction in the arm treated with strontium-89. Progression of pain as measured by sites of new pain or the requirement for radiotherapy showed statistically significant differences between the arms in favor of strontium-89. Tumor makers including prostate specific antigen, acid phosphatase, and alkaline phosphatase were also reduced in patients receiving strontium-89. A Quality-of-Life analysis was performed as a multivariate data set and demonstrated an overall superiority of strontium-89 with alleviation of pain and improvement in physical activity being statistically significant. Toxicity was evaluated and demonstrated increased hematological toxicity in the group receiving strontium-89.
Conclusions:
It is concluded that the addition of strontium-89 is an effective adjuvant therapy to local field radiotherapy reducing progression of disease as evidenced by new sites of pain and the requirement of further radiotherapy and improving quality-of-life and need for analgesic support in this group of patients.
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 therapeutic 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.