Palliation Of Metastatic Bone Pain Research Articles

ETCTN 10437: A single-arm phase II study of bone-targeted sn-117m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.

TPS5095 Background: Most patients with metastatic castration resistant prostate cancer (mCRPC) develop bone metastases with debilitating pain that is itself associated with shorter survival. Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain. To date, radium-223 dichloride is the first and only approved targeted alpha therapy for mCRPC; the major dose limitation is bone marrow toxicity with modest pain relief. Sn-117m-diethylenetriaminepentaacetic acid (DPTA), is a complex of a radioisotope of tin with DTPA. It emits a low-energy conversion electron and also yields a gamma emission. Sn-117m-DPTA localizes selectively in bone, and the limited range (0.2-0.3 mm) of its conversion electrons resulting in deeper tissue penetration with less radiation effects on bone marrow as compared to radium-223 dichloride. Srivastava et al. (1998) reported in a phase I/II study of patients with painful bone metastases from a variety of solid tumors, 45% of patients obtained reduction of pain by at least 50%, and 30% had complete relief of pain for more than two weeks after one injection. Thus, Sn-117m-DTPA has high palliative efficacy with little significant toxicity. Additional evaluation of this agent in mCRPC patients is urgently required. Methods: The study is a phase 2 single-arm clinical trial of Sn-117m-DPTA (20 mCi/70Kg or 0.28 mCi/kg) intravenously every 8 weeks for two injections for patients with mCRPC metastatic to at least two bone sites with at least one clinically meaningful pain site at baseline. Re-treatment with additional two cycles is allowed if patients meet re-treatment criteria. Key eligibility criteria include 1) refractory mCRPC patients who progressed on any lines of therapies 2) self-reported bone pain (≥4 on an 11-point pain intensity scale), and 3) must be on either regular pain medication or have undergone palliative radiation for bone pain within 12 weeks prior to starting study treatment. Key exclusion criteria include 1) visceral metastases and 2) malignant lymphadenopathy exceeding 3cm in short-axis diameter. Twenty-five patients will be enrolled with a primary objective to assess the efficacy of Sn-117m-DTPA on sustained pain response; defined as 1) achieving pain index ≤3 index within a 12-week period and 2) maintaining pain index ≤3 over a 16-week period. Secondary endpoints include patient reported outcomes, adverse events, progression-free survival and overall survival. Correlative aims include assessing blood (systemic inflammatory markers) and tissue biomarkers (gene sequencing and polo-like kinase-1) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 10 patients become evaluable. The study began enrolling patients in December 2021 and is ongoing. Clinical trial information: NCT04616547.

A single arm phase II study of bone-targeted Sn-117\xa0m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases

BackgroundSeveral bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need.MethodsThe study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5–10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival.DiscussionSn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline.Trial registration.ClincialTrials.gov Identifier: NCT04616547.

An automated synthesis of 177Lu-EDTMP as an efficient bone-seeking therapeutic radiopharmaceutical.

Radiolabeled bisphosphonates have found wide clinical use in nuclear medicine for palliative therapy of bone metastases. 177Lu-EDTMP was used to relieve metastatic bone pain in patients with breast or prostate cancer. The therapeutic efficacy of 177Lu-EDTMP at 1-, 3-, 6-, and 8-weeks post-therapy was evaluated using Standard Pain Scoring Assessment Criteria. In addition, toxicity was evaluated in terms of hematological parameters using the Common Terminology Criteria for Adverse Events V4.0. A fully automated synthesis of 177Lu-EDTMP was achieved in this study with high radiochemical efficiency and high radiochemical purity. During the study, 75 patients (57 M: 18 F, mean age: 68.0 ± 11.1 years) of breast/prostate cancer with documented skeletal metastases were included. Patients were administered intravenously with 177Lu-EDTMP at a dose rate of 22.2-37.0 MBq/kg following a fully automated synthesis of 177Lu-EDTMP using a disposable cassette system. Among the 75 patients all treated with 177Lu-EDTMP, 59 patients were responsive and the remaining 16 patients did not respond to the therapy. Mean pain score values in the responder group were 5.60 ± 0.5, 4.3 ± 0.1, 2.6 ± 0.4 and 1.4 ± 0.7 at weeks 1, 3, 6, and 8, respectively. Also, the mean pain score decreased from a baseline score of 7.6 ± 1.6 to 1.4 ± 0.7 at week 8 in the responder group. Statistical analysis of the pain score data showed a significant decrease in pain score after each radiopharmaceutical treatment, compared to the baseline scores (p <0.0001). Mild to severe toxicity was observed in two patients each treated with 177Lu-EDTMP. These findings demonstrated that the 177Lu-EDTMP radiopharmaceutical could be used safely to achieve considerable therapeutic efficacy, in metastatic bone pain palliation together with the safe clinical application and low radiation exposure during preparation.

An assessment of bone-seeking radionuclides for palliation of metastatic bone pain in a vertebral model.

Bone-seeking radiopharmaceuticals have the main role in the treatment of painful bone metastases. The aim of this study was to dosimetrically compare radiopharmaceuticals in use for bone pain palliation therapy and bone scan. The MCNPX code was used to simulate the radiation transport in a vertebral phantom. Absorbed fractions were calculated for monoenergetic electrons, photons and alpha particles. S values were obtained for radionuclides 32P, 33P, 89Sr, 90Y, 99mTc, 117mSn, 153Sm, 166Ho, 169Er, 177Lu, 186Re, 188Re, 223Ra, 224Ra and their progenies for target regions including the active marrow and the bone endosteum. The results demonstrated the dependence of dosimetric parameters on the source or target size, particle energy and location of the source. The electron emitters including 33P, 117mSn, 169Er and 177Lu and 223Ra as an α-emitter gave the lower absorbed dose to the active marrow. These radionuclides gave the highest values of the Relative Advantage Factor (RAF). According to the results,33P, 117mSn, 169Er, 177Lu and 223Ra have fewer side effects on the active marrow than other investigated radionuclides. Therefore, these radionuclides may be a better choice for use in palliative radiotherapy.

An electrochemical approach for removal of radionuclidic contaminants of Eu from 153Sm for effective use in metastatic bone pain palliation

IntroductionThermal neutron activation of 152Sm [152Sm(n,γ)153Sm] using natural or isotopically enriched (by 152Sm) samarium target is the established route for production of 153Sm used for preparation of 153Sm-EDTMP for pain palliation in cancer patients with disseminated bone metastases. However, some long-lived radionuclidic contaminants of Eu, such as, 154Eu (t½=8.6y) are also produced during the target activation process. This leads to detectable amount of Eu radionuclidic contaminants in patients' skeleton even years after administration with therapeutic doses of 153Sm-EDTMP. Further, the presence of such contaminants in 153Sm raises concerns related to radioactive waste management. The aim of the present study was to develop and demonstrate a viable method for large-scale purification of 153Sm from radionuclidic contaminants of Eu. MethodsA radiochemical separation procedure adopting electroamalgamation approach has been critically evaluated. The influence of different experimental parameters for the quantitative removal radionuclidic contaminants of Eu from 153Sm was investigated and optimized. The effectiveness of the method was demonstrated by purification of ~37 GBq of 153Sm in several batches. As a proof of concept, 153Sm-EDTMP was administered in normal Wistar rats and ex vivo γ-spectrometry of bone samples were carried out. ResultsAfter carrying out the electrolysis under the optimized conditions, the radionuclidic contaminants of Eu could not be detected in purified 153Sm solution by γ-spectrometry. The overall yield of 153Sm obtained after the purification process was >85%. The reliability of this approach was amply demonstrated in several batches, wherein the performance remained consistent. Ex vivo γ-spectrometry of bone samples of Wistar rats administered with 153Sm-EDTMP (prepared using electrochemically purified 153Sm) did not show photo peaks corresponding to radionuclidic contaminants of Eu. ConclusionsA viable electrochemical strategy for the large-scale purification of 153Sm from radionuclidic contaminants of Eu has been successfully developed and demonstrated.

Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons.

Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease. These patients are subjected to palliative care in order to improve the quality of their remaining life. With the gradually increasing number of cancer cases, palliation of metastatic bone pain is gaining importance. Bone-seeking radiopharmaceuticals play a pivotal role in the management of cancer pain, particularly in patients with multiple metastases, as these agents are proven to be effective in controlling the bone pain with minimum side effects. Although a plethora of such radiopharmaceuticals have been developed and evaluated in animal models, only a few are regularly used in clinics while some of these agents are at different stages of clinical evaluations. The present article describes only those bone-seeking radiopharmaceuticals, which have been reported to be clinically administered till date, along with their relative merits and drawbacks.

Palliative care of bone pain due to skeletal metastases: Exploring newer avenues using neutron activated 45Ca

IntroductionWith an objective to develop a cost-effective radiochemical formulation for palliation of pain due to skeletal metastases, we have demonstrated a viable method for large-scale production of 45Ca (t½=163days, Eβmax=0.3MeV) using moderate flux research reactor, its purification from radionuclidic impurities adopting electrochemical approach and preclinical evaluation of 45CaCl2. MethodsIrradiation parameters were optimized by theoretical calculations for production of 45Ca with highest possible specific activity along with minimum radionuclidic impurity burden. Based on this, the radioisotope was produced in reactor by irradiation of isotopically enriched (98% in 44Ca) CaO target at a thermal neutron flux of ~1×1014 n.cm−2.s−1 for 4months. Scandium-46 impurity co-produced along with 45Ca was efficiently removed adopting an electrochemical separation approach. The bone specificity of 45CaCl2 was established by in vitro studies involving its uptake in hydroxyapatite (HA) particles and also evaluating its biodistribution pattern over a period of 2weeks after in vivo administration in Wistar rats. ResultsThermal neutron irradiation of 100mg of enriched (98% in 44Ca) CaO target followed by radiochemical processing and electrochemical purification procedure yielded ~37GBq of 45Ca with a specific activity of ~370MBq/mg and radionuclidic purity>99.99%. The reliability and reproducibility of this approach were amply demonstrated by process demonstration in several batches. In vitro studies indicated significant uptake of 45CaCl2 (up to 65%) in HA particles. In vivo biodistribution studies in Wistar rats showed specific skeletal accumulation (40–46%ID) with good retention over a period of 2weeks. ConclusionsTo the best of our knowledge, this is the first study on utilization of 45CaCl2 in the context of nuclear medicine. The results obtained in this study hold promise and warrant further investigations for future translation of 45CaCl2 to the clinics, thereby potentially enabling a cost-effective approach for metastatic bone pain palliation especially in developing countries.

Formulation and evaluation of freeze-dried DOTMP kit for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP at the hospital radiopharmacy

Abstract Objective: The objective of the present work is to develop and evaluate freeze-dried DOTMP kit, which could be utilized for the convenient and single-step preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP, both of which have shown potential as alternative agents for metastatic bone pain palliation. Experimental: Freeze-dried DOTMP kits, each comprising a lyophilized mixture of 20 mg DOTMP and 8.75 mg NaOH, were prepared. The kits were used for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP complexes. The agents were prepared by dissolving the lyophilized powder in 1 mL of normal saline and incubating with 177LuCl3 or 153SmCl3, produced in-house, for 15 min at room temperature. Pharmacokinetic behavior and biological distribution of the agents were studied by carrying out biodistribution as well as scintigraphic studies in normal male Wistar rats. Shelf-life of the freeze-dried kits was also ascertained. Results: Clinical-scale 177Lu-DOTMP and 153Sm-DOTMP complexes, comprising up to 3.7 GBq (100 mCi) of activity, were prepared with &gt; 99% radiochemical purity using the freeze-dried kits. The complexes exhibited high in vitro stability when stored at room temperature. Biological studies showed selective skeletal accumulation and insignificant uptake of the radiotracers in any of the vital organs/tissue. The non-accumulated activity exhibited primary urinary clearance. The kits had a shelf-life of 2 years when stored at 4 ℃ temperature. Conclusion: Freeze-dried DOTMP kits, suitable for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP, have been developed and the radiochemical and biological behaviors of the radiolabeled agents have been studied. The use of the kit at the hospital radiopharmacy is expected to make the preparations easy and convenient. This in turn will enable the widespread dissemination of these promising agents towards their application for regular use.

177Lu-EDTMP for Treatment of Bone Pain in Patients with Disseminated Skeletal Metastases

(177)Lu-labeled ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP) is an agent that concentrates in areas of enhanced osteoblastic activity. The potential of (177)Lu-EDTMP for palliation of metastatic bone pain has been documented in the recent literature. The objective of the present work was to study the efficacy and safety of the agent after administration to a limited number of patients. Ten patients (median age, 68.5 y) with disseminated skeletal metastases received a single bolus infusion of (177)Lu-EDTMP (3.7 GBq). All patients had painful bone metastases in more than one anatomic region that were not relieved by narcotic analgesics. The efficacy of the agent was studied by following pain scores assessed at baseline and at 4, 8, and 12 wk after therapy, by using Karnofsky indices and mobility scores, and by determining the requirement for analgesics at baseline and 4 wk after therapy. The toxicity of the agent was assessed by analyzing complete blood counts. A significant reduction in the mean pain score was noted in all patients. The initial mean pain score of 8.44 dropped to 5.73 within 1 mo of treatment. Six patients who required analgesics for pain management had either reduced or completely withdrawn from their use by 4 wk. Compared with initial scans, scans obtained 1 mo after therapy also showed a decreased uptake of the radiotracer. The mobility scores of all patients were higher at 4 wk. The mean Karnofsky performance score of all patients was initially 45 and increased markedly to 69 at 4 wk. None of the patients experienced blood-related toxicity. (177)Lu-EDTMP, with only low bone marrow toxicity, provided significant pain relief to patients and considerably increased their mobility, resulting in an overall improvement in the quality of life. The results of the preliminary clinical studies indicate that (177)Lu-EDTMP can be considered an effective and safe therapeutic radiopharmaceutical for pain palliation of patients with disseminated skeletal disease.

Efficacy and Safety of 177Lu-EDTMP in Bone Metastatic Pain Palliation in Breast Cancer and Hormone Refractory Prostate Cancer

(177)Lu-labeled ethylenediamine-N,N,N',N'-tetrakis methylene phosphonic acid ((177)Lu-EDTMP), was used to palliate metastatic bone pain as a new bone-seeking radiopharmaceutical. In this phase II study, we assessed the efficacy and safety of (177)Lu-EDTMP for bone pain palliation in patients with breast cancer and hormone refractory prostate cancer with bone metastases. Sixteen patients were enrolled in the trial and were subsequently divided into 2 groups, the low-dose group (1295 MBq) and the high dose group (2590 MBq) to determine differences in toxicities and response rates. Pain scores, Karnofsky indices, mobility scores, and requirement of analgesic administration were assessed at 0, 2, 4, 6, 8, and 12 weeks after injection of (177)Lu-EDTMP. Toxicity was assessed by analyzing hemoglobin, leukocyte, and platelet counts. An obvious reduction in the mean pain score was observed at 2 to 6 weeks after the administration of (177)Lu-EDTMP. The rate of complete responses in bone pain palliation was 55% in group 1 and 80% in group 2 at 6 weeks after treatment. Of the 5 patients who required additional analgesics, all were able to reduce or completely stop taking these medications by 4 weeks after therapy. Mean (SD) Karnofsky indices of 58.18 (9.82) (range, 50-70) and 56.00 (8.94) (range, 50-70) at baseline increased to 82.73 (9.05) (range, 60-90) at 6 weeks after (177)Lu-EDTMP treatment in group 1 and 85.00 (5.77) (range, 80-90) at 8 weeks after injection in group 2, respectively. Mobility scores decreased from 2.91 (1.04) (range, 1-4) and 2.80 (0.84) (range, 2-4) at baseline to 1.00 (0.67) (range, 0-2) and 0.50 (0.58) (range, 0-1) at 8 weeks after administration of (177)Lu-EDTMP in groups 1 and 2, respectively, primarily owing to improved mobility. In group 1, 1 patient experienced grade III toxicity in both hemoglobin and platelet counts. No grade IV toxicities were observed. In group 2, there were no grade III or IV toxicities found in hemoglobin, platelets, or leukocytes counts. Moreover, no clinically significant adverse effects were observed, and no significant differences in either efficacy or safety were detected between the 2 dose levels. This study indicated that (177)Lu-EDTMP was an effective and safe treatment for palliation of metastatic bone pain in patients with prostate or breast cancer. A dose of 1295 MBq (35 mCi) was sufficient for bone pain palliation therapy, and doses as high as 2590 MBq (70 mCi) were well tolerated.

Development of Radiopharmaceuticals for Diagnosis and Therapy of Metastatic Bone Cancer

Rhemium-186-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP) has been used for the palliation of metastatic bone pain. However, delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP. We designed, synthesized and evaluated a stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl] carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP). The stability of (186)Re-MAG3-HBP and (186)Re-HEDP in phosphate buffer were compared. No measurable decomposition of (186)Re-MAG3-HBP occurred, while only approximately 30% of (186)Re-HEDP remained intact 24 hours post-incubation. In biodistribution experiments, the radioactivity level of (186)Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of (186)Re-MAG3-HBP was faster than that of (186)Re-HEDP. In addition, the gastric accumulation of (186)Re-MAG3-HBP radioactivity was lower. To evaluate the therapeutic effects of (186)Re-MAG3-HBP, an animal model of bone metastasis was prepared. In the rats treated with (186)Re-HEDP, tumor growth was comparable to that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Bone pain was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent of metastatic bone pain. Moreover, based on the similar concept, we designed, synthesized, and evaluated a (99m)Tc-6-hydrazinopyridine-3-carboxylic acid-conjugated bisphosphonate ((99m)Tc-HYNIC-HBP) as a bone scintigraphic agent. (99m)Tc-HYNIC-HBP gave higher levels of radioactivity in bone than (99m)Tc-HMDP. There was no significant difference in clearance from blood between (99m)Tc-HYNIC-HBP and (99m)Tc-HMDP. Consequently, (99m)Tc-HYNIC-HBP showed a higher bone-to-blood ratio than (99m)Tc-HMDP. The findings indicate that (99m)Tc-HYNIC-HBP holds great potential for bone scintigraphy.

1424P - Comparison of 8GY Single Fraction Radiotherapy Versus 20GY in Five Fractions or 30GY in 10 Fractions for the Treatment of Metastatic Bone Pain

ABSTRACT Introduction In 1974 the Radiation Therapy Oncology Group (RTOG) initiated a randomized clinical trial comparing various dose-fractionation schedules in the palliation of cancer metastatic to bone. The trial was closed in February of 1980 and results have been published in 1982, with the conclusion that: “low-dose short schedules are as effective as more aggressive protracted programs. Since that time, different radiotherapy schedules had been employed for palliation of bone metastasis: 40 Gy in 20 fractions, 30 Gy in 10 fractions and single fractions of 8 Gy, 6 Gy or 4 Gy. Several randomized prospective trials and meta-analyses have been reported showing the same results in pain relief when comparing single doses vs protracted treatments. Objectives The aim of this study was to compare the most common fractionation used in oncology to treat bone metastases which are 8Gy single fraction, 20Gy in five fractions and 30Gy in 10 fractions. Method A total dose of 120 patients who is known to have stage VI cancer with bone metastasis at King Hussein Medical Center between January 2007 and December 2009, were allocated to receive either 8Gy single fraction, 20Gy in five fractions or 30Gy in 10 fractions for the treatment of their pain. Patient recorded pain severity and analgesic requirements on questionnaire which was filled by the main investigator before treatment, at 2 weeks and at 1,2,3,4,5,6,8,10, and 12 months after radiotherapy. Pain relief was the primary endpoint of treatment benefit. Results There was no difference in the time to first improvement in pain, time to complete pain relief or in time to first increase in pain at any time up to 12 months after randomization, nor in the class of analgesic used. Retreatment was twice as common after 8Gy than after multifraction radiotherapy, although retreatment for residual or recurrent pain did not reflect a difference between the three groups in the probability of pain relief. Conclusion A single fraction of 8 Gy when used for the treatment of bone metastasis is as safe and effective as a multifraction regimen for the palliation of metastatic bone pain for at least 12 months. This may make it suitable alternative to the multifraction radiotherapy regimens. Keywords: Bone metastases; Radiotherapy; Pain relief; Palliation Disclosure All authors have declared no conflicts of interest.

Elderly Patients With Painful Bone Metastases Should be Offered Palliative Radiotherapy

To investigate the efficacy of palliative radiotherapy (RT) in relieving metastatic bone pain in elderly patients. The response to RT for palliation of metastatic bone pain was evaluated from a prospective database of 558 patients between 1999 and 2008. The pain scores and analgesic intake were used to calculate the response according to the International Bone Metastases Consensus Working Party palliative RT endpoints. Subgroup analyses for age and other demographic information were performed. No significant difference was found in the response rate in patients aged >or=65, >or=70, and >or=75 years compared with younger patients at 1, 2, or 3 months after RT. The response was found to be significantly related to the performance status. Age alone did not affect the response to palliative RT for bone metastases. Elderly patients should be referred for palliative RT for their painful bone metastases, regardless of age, because they receive equal benefit from the treatment.

Production of Sn-117m in the BR2 high-flux reactor

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 ( 117mSn), a promising radionuclide for therapeutic applications, and its production have been validated in the BR2 reactor. In contrast to therapeutic beta emitters, 117mSn 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.

Development of [90Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

Based on the concept of bifunctional radiopharmaceuticals, we have previously developed (186)Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed (90)Y-labeled radiopharmaceutical could be developed. In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [(90)Y]DOTA-complex-conjugated bisphosphonate ([(90)Y]DOTA-HBP) was prepared by coordination with (90)Y, and its biodistribution was studied in comparison to [(90)Y]citrate. In biodistribution experiments, [(90)Y]DOTA-HBP and [(90)Y]citrate rapidly accumulated and resided in the bone. Although [(90)Y]citrate showed a higher level of accumulation in the bone than [(90)Y]DOTA-HBP, the clearances of [(90)Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [(90)Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [(90)Y]DOTA-HBP were lower than those of [(90)Y]citrate. [(90)Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [(90)Y]citrate. Since the DOTA ligand forms a stable complex not only with (90)Y but also with lutetium ((177)Lu), indium ((111)In), gallium ((67/68)Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging.

Hypocalcemia Associated with Strontium-89 Administration in a Patient with Diffuse Bone Metastases from Neuroendocrine Carcinoma

Metastatic bone disease is often associated with severe pain in cancer patients, and has become an increasingly important quality-of-life issue. Radionuclides, such as strontium-89 (Sr-89), have provided effective palliation of metastatic bone pain. Although strontium follows the biochemical pathways of calcium in the body, changes in calcium homeostasis related to Sr-89 therapy have rarely been reported. We present a case of a 32-year-old male with poorly differentiated neuroendocrine carcinoma and extensive skeleton metastases who developed profound hypocalcemia after Sr-89 administration.

Europium-154 contamination levels in Samarium-153-EDTMP for radionuclide therapy

153Sm-EDTMP, a useful non toxic bone seeking isotope in the palliative radionuclide therapy for bone metastases, is produced by neutron activation of enriched of 152Sm2O3 targets. During the large-scale formation of 153Sm, however, there is a co-production of some long-lived radio nuclides, among which 154Eu is a major and inevitable radionuclide impurity. The level of 154Eu contamination was evaluated performing a gamma-ray spectrometry of a radiopharmaceutical sample and the urine of an administered patient. As expected, gamma-ray spectra revealed the presence of 153Eu in all the samples. The specific activity of 153Eu in the urine sample collected at 6 hours after injection is 21 Bq/ml and is less than 1 Bq/ml in 24 hr. The contamination levels of 153Eu, normalized to the corresponding activity of 153Sm, were 0.0012% in the residual and in the first urine sample and 0.0017% and 0.0031% at 30 and 54 hours after administration, respectively. The results of this study show that the level of the long-lived 153Eu impurity is not a limitation in the metastatic bone pain palliation due to the additional radiation dose burden, but could pose a cause of concern in case of discharging.

Loading-dose ibandronate with maintenance dosing for the palliation of metastatic bone pain: The Bon-I-Pain and Bon-O-Pain trials

Loading-dose ibandronate with maintenance dosing for the palliation of metastatic bone pain: The Bon-I-Pain and Bon-O-Pain trials

Development of a Rhenium-186-Labeled MAG3-Conjugated Bisphosphonate for the Palliation of Metastatic Bone Pain Based on the Concept of Bifunctional Radiopharmaceuticals

Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate]oxorhenium(V) (186Re-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, 186Re-labeling was performed by reacting 186ReO4- with SnCl2 in citrate buffer. After purification by HPLC, 186Re-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of 186Re-MAG3-HBP and 186Re-HEDP, these (186)Re complexes were incubated in phosphate buffer. No measurable decomposition of 186Re-MAG3-HBP occurred over a 24-h period, while only approximately 30% of 186Re-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower than that of 186Re-HEDP. In conclusion, 186Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.

Analytical and radioanalytical quality control of purity and stability of radiopharmaceutical compound [&lt;Superscript&gt;186g&lt;/Superscript&gt;Re]Re-HEDP for bone metastases pain palliation

The nuclear properties of 186g Re make it a useful agent for radionuclide therapy and imaging. The coordination compound ( 186g Re)Re-HEDP has proved to be a successful bone seeking agent for palliation of metastatic bone pain. Chemical, radiochemical and radionuclidic purity of commercial radiopharmaceutical ( 186g Re)Re-HEDP have been checked by means by �- and �-spectrometries, INAA and paper radio- chromatography. The results indicate a good radionuclidic purity, with levels of contamination from the short-lived 188 Re well below the required specifications. After injection of the radiopharmaceutical, the radiochemical measurements conducted in vivo, on biological matrices, blood, plasma and urine, have shown that, entering the systemic circulation, 186g Re dissociates from the bis-phosphonate complex as hydrosoluble ( 186g Re)ReO4 - , and the two chemical species follow different biokinetics.