Bone Pain Palliation Research Articles

Pharmacopeial parametric release strategy in microbiological quality control of radiopharmaceuticals

Nuclear medicine is used to assess body functionality at various levels of biological organization and is increasingly employed for both diagnostic and therapeutic purposes. Nearly 5% of radiopharmaceuticals are used therapeutically, whereas approximately 95% are used for diagnosis. Diagnostic radiopharmaceuticals are generally considered safe because they are administered in subpharmacological doses, and the radiotracer components are employed in minimal doses. Consequently, the radiation exposure to the body during nuclear medicine investigations is typically low. However, when radiopharmaceuticals are used for therapeutic applications such as tumor ablation and bone pain palliation, the emitted radiation is highly localized and potent. Radiotracers and radiation doses are more carefully selected for young patients, as the radiation-induced risk of adverse health effects is greater in children than in adults. Radiopharmaceutical preparations should adhere to the established standards of pharmacopoeia worldwide to ensure safety and efficacy. Adherence to current good manufacturing practices, sterility, and good radiation practices are prerequisites for ensuring effective quality assurance and quality control systems during radiopharmaceutical preparation. The quality control test parameter for radiopharmaceuticals primarily involves physicochemical and biological tests. However, significant concerns exist regarding the biological testing of radiopharmaceuticals, necessitating their parametric release. The time-intensive traditional sterility test, bacterial endotoxin test, and rabbit pyrogen tests have been critical quality control issues due to the short half-lives of most radiopharmaceuticals, as they should be dispensed at the earliest to ensure optimal diagnostic/therapeutic benefit. Therefore, manufacturers of radiopharmaceuticals, dispensers, and nuclear medicine specialists should be cognizant of the issues posed by biological quality control as a primary obstacle to ensuring consistent quality through parametric release from a compendial test method standpoint.

Evaluation of 188Re- IBA as a novel radiopharmaceutical for bone marrow ablation

In this study, Ibandronate as a third generation of bisphosphonates was labeled with rhenium-188 radionuclide. Production and quality control of 188Re-IBA radiopharmaceutical was investigated. The radiation absorbed dose of this radiopharmaceutical was evaluated for adult male based on biodistribution data in mice using the RADAR and Sparks and Aydogan methodologies. The 188Re-IBA was produced with more than 96% radiochemical purity. The highest value of %ID/g was related to bone with 7.11% at 12 h post-injection. About 48% of injected activity was cumulated on the surface of bone tissue 48 h post-injection. The imaging studies confirmed the biodistribution pattern. Radiation absorbed doses of red bone marrow and osteogenic cells were estimated to about 0.39 and 0.71 mGy MBq-1, respectively. The maximum administrated activity was obtained 73.1 MBq kg-1 (2.0 mCi kg-1) of body weight. Effective dose was evaluated about 0.09 mSv MBq-1. The results were compared with other clinically used bone pain palliation radiopharmaceuticals. It was concluded that the 188Re-IBA radiopharmaceutical has a great tendency to be absorbed in bone tissue and it can provide sufficient care for bone marrow ablation with low undesired dose to other normal organs.

Efficacy of 153Sm-EDTMP on Bone Pain Palliation in Metastatic Patients: Breast and Prostate Cancers

Purpose: This study aimed to evaluate the effect of samarium-153-EDTMP (153Sm-EDTMP) on pain relief bone metastases of Breast Cancer (BC) and Prostate Cancer (PC) patients.
 Materials and Methods: Thirty patients aged 40-77 years (62.6±10.2 years) with intractable metastatic bone pain were included in the current study. A checklist of patient information and a standard questionnaire for the assessment of pain and quality of life were completed before and after four and eight week’s palliative treatment with 37 MBq/kg of 153Sm-EDTMP. To analyse the data, parametric and non-parametric tests were used in SPSS software.
 Results: Twelve females with BC (40%) and 18 males with PC (60%) were included. Four and eight weeks after palliative treatment of 153Sm-EDTMP, the mean pain score reduction and quality of life were statistically increased compared to before the intervention (P-value < 0.05). Notably, the amount of pain reduction in the fourth week was more than in the eighth week; however, the quality of life was better in the eighth week, without significant variation (P-value <0.05). In addition, there was no statistically significant relationship between pain reduction and the type of primary diseases, BC, and PC (P-value >0.05).
 Conclusion: The injection of 153Sm-EDTMP had therapeutic efficacy for bone pain palliation in patients with diffuse bone metastases at the end of the 4th and 8th week post-infusion.

Safety and Efficacy of 68 Ga- or 177 Lu-Labeled DOTA-IBA as a Novel Theranostic Radiopharmaceutical for Bone Metastases : A Phase 0/I Study.

We designed and synthesized a novel theranostic bisphosphonate radiopharmaceutical ( 68 Ga- or 177 Lu-labeled DOTA-ibandronic acid [ 68 Ga/ 177 Lu-DOTA-IBA]) for bone metastasis. In this study, the dosimetry, safety, and efficacy of 68 Ga/ 177 Lu-DOTA-IBA as a theranostic radiopharmaceutical for bone metastases were evaluated in patients with malignancy based on 68 Ga- and 177 Lu-DOTA-IBA images, blood samples, and dosimetric analysis. Eighteen patients with bone metastasis and progression under conventional therapies were included in this study. Baseline 99m Tc-MDP SPECT and 68 Ga-DOTA-IBA PET/CT were performed for comparative purposes within 3 days. After receiving 891.5 ± 301.3 MBq 177 Lu-DOTA-IBA, serial 177 Lu-DOTA-IBA SPECT bone scan was performed over 14 days. Dosimetric evaluation was performed for main organs and tumor lesions. Safety was assessed by blood biomarkers. Karnofsky Performance Status, pain score, and follow-up 68 Ga-DOTA-IBA PET/CT were performed for response evaluation. Baseline 68 Ga-DOTA-IBA PET demonstrated a higher efficacy for detecting bone metastases compared with 99m Tc-MDP SPECT. The time-activity curves showed fast uptake and high retention of 177 Lu-DOTA-IBA in bone metastases (24 hours: 9.43 ± 2.75 %IA; 14 days: 5.45 ± 2.52 %IA). Liver, kidneys, and red marrow time-activity curves revealed a low uptake and fast clearance. The radiation-absorbed dose in bone metastasis lesions (6.40 ± 2.13 Gy/GBq) was significantly higher than that in red marrow (0.47 ± 0.19 Gy/GBq), kidneys (0.56 ± 0.19 Gy/GBq), or liver (0.28 ± 0.07 Gy/GBq), with all P 's < 0.001. Compared with baseline level, only one patient developed new grade 1 leukopenia (toxicity rate, 6%). The 177 Lu-DOTA-IBA therapy had no statistically significant effect on bone marrow hematopoietic function, liver function, and kidney function at any follow-up visit. Bone pain palliation was achieved in 82% (14/17) of patients. The 8-week follow-up 68 Ga-DOTA-IBA PET/CT demonstrated partial response in 3 patients, disease progression in 1 patient, and stable disease in 14 patients. 68 Ga/ 177 Lu-DOTA-IBA provides a set of potential theranostic radiopharmaceuticals and may have a good prospect for the management of bone metastasis.

Synthesis and Ready to Use Kit Formulation of EDTMP for the Preparation of 177Lu-EDTMP as a Bone Palliation Radiopharmaceutical.

With its suitable nuclear decay characteristics and large-scale production feasibility with adequate specific activity, 177Lu is regarded as an excellent radionuclide for developing bone pain palliation agent. Ethylenediamine-tetramethylene phosphonic acid (EDTMP) is a preferred carrier molecule for radiolanthanides, such as 177Lu. The present paper describes the synthesis of EDTMP and the development of a ready-to-use kit for the preparation of 177Lu-EDTMP and its quality control in accordance with the quality and safety criteria required for medicinal use. EDTMP was synthesized by a modified Mannich-type reaction, and the structure was characterized using NMR and IR spectroscopy. Optimization of radiolabeling conditions was done with two different salt forms of EDTMP. The labeling yield was checked by paper chromatography with radiation detection. Kit was developed as a lyophilized mixture of EDTMP and sodium bicarbonate in a maximum volume of 5 mL. Labeling efficiency, radionuclidic purity, radiochemical purity, sterility, and pyrogenicity analysis were performed as the quality control of the labeled kit. The analytical data for the structure determination and purity of the synthesized ligand were in agreement with authentic commercial samples used in radiopharmacy.177Lu-EDTMP complex was prepared using synthesized EDTMP ligand under optimized labeling conditions with high labelling yield (>99%). The radiolabeling yields of the EDTMP kit at room temperature after 30 min and 48 hours were 99.46% and 99.00%. The developed EDTMP kit enables an instant one-step preparation of the radiopharmaceutical of high radiochemical purity (>99%) and has a sufficiently long shelf life. This enables the routine production of the 177Lu-EDTMP in nuclear medicine clinics without requiring experienced staff.

Stability study of 188Re-HEDP as a radionuclide therapeutical for bone pain palliation

Stability study of 188Re-HEDP as a radionuclide therapeutical for bone pain palliation

Radiochemical quality control of the radiopharmaceutical, 89SrCl2 produced in FBTR

89SrCl2 radiopharmaceuticals is mainly used for bone pain palliation in the cancer patients, is being produced in FBTR via 89Y(n, p)89Sr using yttria target. The irradiated yttria target is chemically processed in high pure quartz distilled nitric acid medium in hot cell facility, to avoid the corrosion of components of hotcell due to chloride ions while using HCl medium. Being ionic species, the purified 89Sr(II) cation in aqueous solution containing bulk nitrate and other trace anions, exists as SrXn species where X: F−, Cl−, Br−, NO3−, PO43− and SO42−, n: stoichiometric anion content. The aim of the manuscript is to standardise an efficient ultra-low level anion purification method (ppb range) for the conversion of SrXn to SrCl2 and estimate the residual anionic impurities as recommended by the appropriate source specifications for its medical application. Various methods were standardised for the removal of anions in the SrCl2 source produced by the above process which include evaporation, calcination, anion exchange column, cation exchange column as well as its combination with pre-concentration column of ion chromatography (IC) technique using 89Sr tracers as well as FBTR produced 89Sr solution. Assay of 89Sr and other anions including nitrate for the above study were accomplished using Cerenkov counting and ion chromatography respectively. Thus evaporation-calcination-column chromatography mode was finalised to obtain pure SrCl2 source free from nitrate and other anionic impurities. This is the first ever systematic study for the Radiochemical quality control of nca 89SrCl2 radiopharmaceutical produced in a fast reactor. This study also finds its application to any analytical lab as well as industry where there is a requirement of anion purification in the ppb level.

177Lu-EDTMP radiation absorbed dose evaluation in man based on biodistribution data in Wistar rats

Skeletal metastases are common in patients suffering from various primary cancers. Radiopharmaceuticals are an effective option for bone pain palliation. In this work, the radiation absorbed dose of 177Lu-EDTMP radiopharmaceutical was estimated for adult man based on biodistribution data in Wistar rats. The MIRD dose calculation method and the Sparks and Aydogan methodology were applied. The results shows that about 46% of injected activity is cumulated on the surface of the trabecular and cortical bones. Radiation absorbed doses of red bone marrow and osteogenic cells were estimated to about 1.1 and 6.2 mGy/MBq, respectively. The maximum administrated activity was obtained 27 MBq/kg of body weight with an effective dose of 0.23 mSv/MBq. The results were compared with other available data from literature. This study indicated that 177Lu-EDTMP provides therapeutic efficacy for achieving bone pain palliation with low undesired dose to other normal organs.

Rhenium Radioisotopes for Medicine, a Focus on Production and Applications.

In recent decades, the use of alpha; pure beta; or beta/gamma emitters in oncology, endocrinology, and interventional cardiology rheumatology, has proved to be an important alternative to the most common therapeutic regimens. Among radionuclides used for therapy in nuclear medicine, two rhenium radioisotopes are of particular relevance: rhenium-186 and rhenium-188. The first is routinely produced in nuclear reactors by direct neutron activation of rhenium-186 via 185Re(n,γ)186Re nuclear reaction. Rhenium-188 is produced by the decay of the parent tungsten-188. Separation of rhenium-188 is mainly performed using a chromatographic 188W/188Re generator in which tungsten-188 is adsorbed on the alumina column, similar to the 99Mo/99mTc generator system, and the radionuclide eluted in saline solution. The application of rhenium-186 and rhenium-188 depends on their specific activity. Rhenium-186 is produced in low specific activity and is mainly used for labeling particles or diphosphonates for bone pain palliation. Whereas, rhenium-188 of high specific activity can be used for labeling peptides or bioactive molecules. One of the advantages of rhenium is its chemical similarity with technetium. So, diagnostic technetium analogs labeled with radiorhenium can be developed for therapeutic applications. Clinical trials promoting the use of 186/188Re-radiopharmaceuticals is, in particular, are discussed.

A solvent extraction-based procedure for removal of 46Sc impurity from reactor produced [45Ca]CaCl2 for its potential use in bone pain palliation

Calcium-45 [T½ = 163 d, Eβ (max) = 0.3 MeV] is a pure β− emitting radioisotope which can be envisaged for potential use in palliative care of pain due to skeletal metastases of primary cancer. During production of 45Ca in nuclear reactor via 44Ca (n,γ) 45Ca route, 46Sc is co-produced as a radionuclidic impurity. In this study, we have optimized a single-step solvent extraction procedure for complete removal of 46Sc impurity from [45Ca]CaCl2. The purified radiotracer was administered intravenously in normal Wistar rats and preferential bone uptake could be demonstrated by ex vivo biodistribution studies.

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.

Efficacy and safety of 177Lu-DOTMP in palliative treatment of symptomatic skeletal metastases: a prospective study.

Bone-seeking radiopharmaceutical 177Lu-DOTMP with favorable pharmacokinetics in the preclinical studies has been evaluated for its role in reducing bone pain and improving quality of life (QOL) in patients with symptomatic skeletal metastases. Patients with painful widespread skeletal metastases documented on 99mTc-MDP bone scintigraphy were intravenously administered 37 MBq/kg of 177Lu-DOTMP. Visual analogue score (VAS), analgesic score, European Cooperative Group of Oncology (ECOG) and the European Organization of Research and Treatment of Cancer QLQ-C30 of all the patients were assessed at baseline and posttherapy follow-up. Adverse effects were graded according to NCI-CTCAE V 5.0. Twenty-seven patients with painful widespread skeletal metastases (men 18; median age 61 years; range: 18-81) were studied for their responses as complete response, partial response, minimal response, no response and pain progression based on VAS and analgesic score. Overall response was seen in 77.8% of patients (complete, partial and minimal in 29.6, 33.3 and 14.8%, respectively) with significant improvement in median VAS and mean analgesic score at 2 months posttherapy from baseline (P < 0.001). The best response was seen in patients with breast cancer (100%) followed by prostate cancer (81%) and lung cancer (28%). Improvement in QOL was noted in 40% of patients, with change in ECOG score from 3.07 ± 0.67 at baseline to 2.6 ± 0.9 at 2 months posttherapy. Grade 2/3 anemia, grade 1/2 leukopenia and grade 1/3 thrombocytopenia were seen in 37, 11.1 and 18.5% patients respectively in the follow-up. 177Lu-DOTMP appears to be efficacious treatment for bone pain palliation with improvement in QOL though less effective in patients with lung cancer. The patients had transient mild-moderate hematotoxicity.

The radio-europium impurities in [153Sm]-EDTMP production: a review of isolation methods.

Many human cancers predominantly metastasize to the bone which causes bone pain and other symptoms. However, the management of bone metastases is challenging. Radionuclide therapy using low-energy beta-emitting radionuclides has yielded encouraging results. The aim of this therapy is to deliver the maximum dose to the metastatic sites but a minimal dose to the normal tissue. Samarium-153 [153Sm]Sm-Ethylenediamine tetramethylene phosphonate (EDTMP) is an FDA and European Medicine Agency approved (Quadramet) radionuclide and is widely used for bone pain palliation. 153Sm is reactor produced, and the presence of europium impurities is thus unavoidable. This in turn causes an increase in the hospital radioactive waste burden and in radiation absorbed doses to the patients, and therefore it is a concern. The effective removal of these impurities is thus highly desirable before its administration to the patients. In this article, we present a detailed review of the various methods described in the literature for separation of 153Sm and Eu, that is solvent extraction, ion-exchange chromatography, electrochromatography, electrochemical separation and supported ionic liquid phase.

177Lu-EDTMP for Metastatic Bone Pain Palliation: A Systematic Review and Meta-Analysis.

Purpose: Painful metastatic bone involvement is common in advanced stages of many cancers. Between available radionuclides for bone pain palliation, no consensus has been reached on lutetium ethylenediaminetetramethylene phosphonate (177Lu-EDTMP) administration in this milieu. The aim of this study is to evaluate the treatment efficacy, safety profile, and toxicities of 177Lu-EDTMP in patients with metastatic bone involvement, according to the published literature. Methods: A comprehensive literature search of PubMed/MEDLINE, Scopus, and Google Scholar databases was carried out to retrieve pertinent articles published until January 2019, concerning the clinical efficacy and safety of 177Lu-EDTMP for bone pain palliative purposes. Results: Eight studies (172 patients) were included. This analysis revealed statistically significant effect of 177Lu-EDTMP therapy on the visual analog score (4.84% (95% CI: 3.88-5.81; p < 0.001), bone palliative pain response (84%, 95% CI: 75%-90%; p < 0.001), and Karnofsky performance status (21%, 95% CI: 18%-24%; p < 0.001) overall (as well as in the high-dose and low-dose subgroups). Complete palliative pain response to treatment was observed in 32% (95% CI: 16%-53%) of patients receiving 177Lu-EDTMP. Anemia was found to be the most common hematologic toxicity imposed by this therapeutic approach (grade I/II anemia in 24% (95% CI: 14%-38%; p < 0.001) and grade III/IV anemia in 19% (95% CI: 12%-28%; p < 0.001)). Conclusions: 177Lu-EDTMP seems to have comparable efficacy and safety profile as that of the frequently administered radiopharmaceuticals for bone palliation. Therefore, this agent can be a good option for bone pain palliative purposes, in case of limited access to other bone palliative radiopharmaceuticals.

177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results

Background[177Lu]Lu-DOTA-ZOL has shown promising results from the dosimetry and preclinical aspects, but data on its role in the clinical efficacy are limited. The objective of this study is to evaluate the efficacy and safety of [177Lu]Lu-DOTA-ZOL as a bone pain palliation agent in patients experiencing pain due to skeletal metastases from various cancers.MethodsIn total, 40 patients experiencing bone pain due to skeletal metastases were enrolled in this study. The patients were treated with a mean cumulative dose of 2.1 ± 0.6 GBq (1.3–2.7 GBq) [177Lu]Lu-DOTA-ZOL in a median follow-up duration of 10 months (IQR 8–14 months). The primary outcome endpoint was response assessment according to the visual analogue score (VAS). Secondary endpoints included analgesic score (AS), global pain assessment score, Eastern Cooperative Oncology Group Assessment performance status (ECOG), Karnofsky performance status, overall survival, and safety assessment by the National Cancer Institute’s Common Toxicity Criteria V5.0.ResultsIn total, 40 patients (15 males and 25 females) with a mean age of 46.6 ± 15.08 years (range 24–78 years) were treated with either 1 (N = 15) or 2 (N = 25) cycles of [177Lu]Lu-DOTA-ZOL. According to the VAS response assessment criteria, complete, partial, and minimal responses were observed in 11 (27.5%), 20 (50%), and 5 patients (12.5%), respectively with an overall response rate of 90%. Global pain assessment criteria revealed complete, partial, minimal, and no response in 2 (5%), 25 (62.5%), 9 (22.5%), and 4 (10%) patients, respectively. Twenty-eight patients died and the estimated median overall survival was 13 months (95% CI 10–14 months). A significant improvement was observed in the VAS, AS, and ECOG status when compared to baseline. None of the patients experienced grade III/IV haematological, kidney, or hepatotoxicity due to [177Lu]Lu-DOTA-ZOL therapy.Conclusion[177Lu]Lu-DOTA-ZOL shows promising results and is an effective radiopharmaceutical in the treatment of bone pain due to skeletal metastases from various cancers.

Internal dosimetry studies of 170Tm-EDTMP complex, as a bone pain palliation agent, in human tissues based on animal data

Radiopharmaceuticals with therapeutic applications are designed to deliver high doses of radiation to target organs with minimizing unwanted radiation to healthy tissues. Owing to the potential of targeted radiotherapy to treat a wide range of malignancies, 170Tm -EDTMP was developed for possible therapeutic applications. This study describes absorbed dose prediction of 170Tm-EDTMP in human organs after animal injection which is determined via medical internal radiation dose (MIRD) and MCNP-4C code methods. It was estimated that a 1-MBq administration of 170Tm-EDTMP into the human body would result in an absorbed dose of 37.9 mGy (MIRD method) and 38.02 mGy (MCNP-4C code) in the bone surface after 60 days post injection. Highest and lowest difference between MIRD and MCNP results are for lung and bone surface respectively. Finally, the results show that there is a good agreement between MIRD method and MCNP-4C simulation code for absorbed dose estimation.

Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain.

Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance the quality of life. Radiopharmaceuticals are mainly used in the latest courses of the disease. Bone-pain palliation with easy-to-administer radionuclides offers advantages, including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other therapies. Several β¯- and α-emitters as well as pharmaceuticals, from the very first [89Sr]strontium-dichloride to recently introduced [223Ra]radium-dichloride, are investigated to identify an optimum agent. In addition, the combination of bone-seeking radiopharmaceuticals with chemotherapy or radiotherapy has been employed to enhance the outcome. Radiopharmaceuticals demonstrate an acceptable response rate in pain relief. Nevertheless, survival benefits have been documented in only a limited number of studies. In this review, we provide an overview of bone-seeking radiopharmaceuticals used for bone-pain palliation, their effectiveness and toxicity, as well as the results of the combination with other therapies. Bone-pain palliation with radiopharmaceuticals has been employed for eight decades. However, there are still new aspects yet to be established.

Dosimetry of Bone-Seeking Radiopharmaceuticals for Palliative Therapy of Bone Metastases: A Simulation Study Using GATE Monte Carlo Code

Purpose: Radiopharmaceutical Therapy (RPT) is one of the effective methods for pain palliation of bone metastases. Bone marrow is a critical organ in bone structure whose absorbed dose should be kept below a certain threshold. The purpose of this study was to calculate and compare absorbed doses of bone-seeking radiopharmaceuticals used in the palliative treatment of bone metastases. Materials and Methods: In this study, the GATE Monte Carlo code was used to simulate a femur bone, which consists of bone marrow, endosteal layer, bone, and soft tissue phantom model. Absorbed doses of the 153Sm-EDTMP, 89SrCl2, 177Lu-EDTMP, 188Re-HEDP, and 223RaCl2 radiopharmaceuticals were calculated in the femur phantom compartments. Results: bone absorbed doses per disintegration from alpha particles of 223RaCl2 is approximately 24 times higher than absorbed doses from beta particles of 89SrCl2. Also, absorbed dose per disintegration from beta particles of 89SrCl2 in the bone is approximately 12, 6 and 1.5 times higher than 177Lu-EDTMP, 153Sm-EDTMP, and 188Re-HEDP, respectively. Moreover, the bone and bone marrow absorbed dose from beta particles of 153Sm-EDTMP is 1.9 times higher than 177Lu-EDTMP. Besides, absorbed dose per disintegration from beta particles of 188Re-HEDP in the bone marrow is approximately 40, 30, 7, and 4 times higher than 223RaCl2, 89SrCl2, 177Lu-EDTMP and 153Sm-EDTMP, respectively. Conclusion: Our results show that 223RaCl2 could be a more efficient radiopharmaceutical for radionuclide therapy of bone metastases. Also, 177Lu-EDTMP, due to low marrow toxicity and comparable bone absorbed dose with 153Sm-EDTMP, can be used for achieving bone pain palliation. Moreover, significantly high bone marrow absorbed dose of 188Re-HEDP should be considered for palliative therapy of metastatic bone patients.