Bone-seeking Radiopharmaceuticals Research Articles

Differences in the Renal Accumulation of Radiogallium-Labeled (Glu)14 Peptides Containing Different Optical Isomers of Glutamic Acid.

Acidic amino acid peptides have a high affinity for bone. Previously, we demonstrated that radiogallium complex-conjugated oligo-acidic amino acids possess promising properties as bone-seeking radiopharmaceuticals. Here, to elucidate the effect of stereoisomers of Glu in Glu-containing peptides [(Glu)14] on their accumulation in the kidney, the biodistributions of [67Ga]Ga-N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid-conjugated (l-Glu)14 ([67Ga]Ga-HBED-CC-(l-Glu)14), [67Ga]Ga-HBED-CC-(d-Glu)14, [67Ga]Ga-HBED-CC-(dl-Glu)14, and [67Ga]Ga-HBED-CC-(d-Glu-l-Glu)7 were compared. Although the accumulation of these compounds in the bone was comparable, their kidney accumulation and retention were strikingly different, with [67Ga]Ga-HBED-CC-(d-Glu-l-Glu)7 exhibiting the lowest level of kidney accumulation among these compounds. Repeated d- and l-peptides may be a useful method for reducing renal accumulation in some cases.

Synthesis and Evaluation of Radiogallium Labeled Bone-Imaging Probes Using Oligo-γ-Carboxy Glutamic Acid Peptides as Carriers to Bone.

We investigated the importance of the carboxy group density in bone affinity during the development of peptide-based bone-seeking radiopharmaceuticals and carriers. Oligo-γ-carboxy glutamic acid peptides [(Gla)n] with higher carboxy group density than oligo-glutamic acid peptides [(Glu)n] and oligo-aspartic acid peptides [(Asp)n] were chosen. Using the radiogallium chelator N,N'-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), we synthesized [67Ga]Ga-HBED-CC-(Gla)n (n = 1, 2, 5, 8, 11, or 14) with high yields. Hydroxyapatite-binding assays, biodistribution, and SPECT imaging showed higher affinity and bone accumulation for [67Ga]Ga-HBED-CC-(Gla)n compared to [67Ga]Ga-HBED-CC-(Glu)n. Notably, [67Ga]Ga-HBED-CC-(Gla)8 and [67Ga]Ga-HBED-CC-(Gla)11 exhibited superior bone accumulation and rapid blood clearance. SPECT/CT imaging with [67Ga]Ga-HBED-CC-(Gla)8 exclusively visualized the bone tissue. These findings support the potential use of [67Ga]Ga-HBED-CC-(Gla)n as excellent bone-imaging PET probes, suggesting (Gla)n peptides are superior bone-seeking carriers.

Ureteral Stone Mimicking Metastasis - Planar Bone Scan When Single-photon Emission Computed Tomography/Computed Tomography Is a Necessity.

In this case, we demonstrated a ureteric stone that resembled bone metastasis. Because bone-seeking radiopharmaceuticals are excreted into the urine by the kidneys, normal kidneys and bladder are well visualized on skeletal scintigraphs leading to incidental detection of urinary tract abnormalities. Bone tracer uptake related to ureteral stones has been reported [Figure 1] several times before. We present a right ureteral stone mimicking abnormal focal sacral uptake on planar scan in a patient with rectal cancer. This case emphasizes the importance of using single-photon emission computed tomography/computed tomography to determine the cause of abnormal uptake on a planar scan.

Prediction of radiation dose to adult human from radiopharmaceutical manufactured by third generation bisphosphonate labeled with Rhenium

IntroductionThe crucial step in preclinical process of radiopharmaceutical production is internal dosimetry evaluation by different ways to realize radiobiological dose-response relationships and to extract the results for clinical use. Till now several bone-seeking radiopharmaceuticals have been developed for bone metastasis. Interesting features of bisphosphonates attracted attentions to them in the field of radiopharmaceutical therapy and studies on new generation of them have been doing too. Materials and methodsIn this study, we used ZNA as representative of the third generation. The radiopharmaceutical 188Re-ZNA was produced and its radiochemical purity was investigated. Then, the biological distribution of the produced radiopharmaceutical at 1, 2, 4 and 24 h after injection on different organs of mice were investigated. Finally, the absorbed dose of organs in the human body was assessed using the RADAR method. ResultsThe results show 96% radiochemical purity of the 188Re-ZNA radiopharmaceutical. The amount of %ID/g in bone is 1.131% after 1 h and in 24 h it has a significant amount compared to other organs, that is 0.516%. Also dosimetric results show that the highest absorption dose is related to bone and the amount of this dose is 0.050 mGy/MBq. ConclusionConsidering the possibility of producing the 188Re-ZNA radiopharmaceutical, as well as the proper distribution of this radiopharmaceutical in target and non-target organs and increasing the absorbed dose in bone, it can be concluded that this radiopharmaceutical can be useful in the “radiopharmaceutical therapy” in metastases.

After Total Ankle Arthroplasty, When Does Bone Perfusion and Metabolic Activity at the Bone-Implant Interface Normalize? A PET/CT Study

Category: Ankle Arthritis Introduction/Purpose: Radionuclide bone scintigraphy in combination with computed tomography (CT) has been used to evaluate painful total hip and knee arthroplasties, and has also been used in the evaluation of the painful total ankle arthroplasty (TAA). Increased tracer uptake around implants may indicate loosening, but uptake characteristics of bone-seeking radiopharmaceuticals in asymptomatic total ankle patients have not been clarified. While findings of increased metabolic activity may prompt surgical intervention, there has been no work performed to define when postoperatively periprosthetic activity normalizes, if at all. In this study, we plan to establish normative data on 18F sodium fluoride (18F-NaF) positron emission tomography/CT (PET/CT) uptake ratios around TAA implants at various time intervals after surgery in asymptomatic TAA patients. Methods: The majority of the arthroplasty literature has investigated use of SPECT/CT performed with 99mTc-labeled bisphosphonates. However, data suggest that 18F-NaF PET/CT may be superior for this indication, with more favorable pharmacokinetics and similar sensitivity to detect aseptic loosening. In the present study, asymptomatic patients who underwent TAA with a modern fixed-bearing TAA prosthesis (either the Wright Infinity Adaptis or Exactech Vantage prosthesis) for posttraumatic arthritis were eligible for inclusion. Patients with ipsilateral hindfoot fusion and with any periprosthetic lucencies or cysts were excluded. Patients were enrolled at one of four time intervals following TAA: 6, 12, 18, or 24 months. Standard uptake values were measured at the bone-implant interface for the tibial and talar components on static PET, in regions of interest defined on axial CT scan slices. Periprosthetic bone blood flow (K1) and bone turnover (flux) were assessed at each time interval in each periprosthetic region using dynamic PET. Results: Sixteen asymptomatic patients underwent PET/CT: 4 patients at 6 months postoperatively, 6 at 12 months, and 6 at 24 months. We are currently still in data collection and at this time only 2 patients at 18 months have completed the scan, therefore their data were excluded. The average age was 65 years (range, 55 to 80) and 6 patients were female (38%), with individual patient data shown in the Table. Talar K1 and flux both appeared to increase from 6 to 12 months, and decrease between 12 and 24 months, although there was no statistically significant difference between timepoints. Overall tibial K1 and flux appeared to decrease slightly from 6 to 12 months, and stayed relatively stable between 12 and 24 months, again with no significant difference between timepoints (Figure). Conclusion: There is currently no normative data to help guide interpretation of radionuclide bone scintigraphy for the painful TAA. The present study utilizing 18F-NaF PET/CT scans demonstrates that even in asymptomatic patients, periprosthetic bone blood flow and bone turnover remain elevated up to 24 months following modern fixed-bearing TAA. Not only do these values remain elevated at 24 months, but we found that there does not appear to be any significant decrease in either measurement over time from 6 to 24 months postoperatively. Our findings suggest that radionuclide bone scintigraphy should be cautiously interpreted when performed within 2 years of TAA.

Census of Cardiac Uptake on Routine Bone Scintigraphy, a Methodology to Assess the Prevalence of the TTR Amyloidosis

Objective: Transthyretin cardiac amyloidosis is a rapidly progressive disease, remains underdiagnosed, and has long been considered a rare disease. Diagnosis decision making cannot be based on echography and MRI findings alone because they lack accuracy. However, it requires invasive test of myocardial or fat pad biopsies. Thus, the diagnosis is challenging, and the non-invasive scintigraphic technique using bone-seeking radiopharmaceuticals has become a cornerstone in the workup revealing a myocardial uptake. Our work consists of a single institution retrospective study aiming to estimate the bone scintigraphies, and the prevalence of the transthyretin cardiac amyloidosis in our population. Methods: We have carried out a census of the incidental cardiac uptake on routine bone scintigraphy in 2211 consecutive patients enrolled between 2009 and 2020, mostly performed for oncologic purposes. The visual analysis of the scintigraphic images classifies the cardiac uptake into 3 levels of gradation and evokes the diagnosis of the TTR cardiac amyloidosis in grades 2 and 3. Results: Different grades of myocardial uptake were observed in 1.37 % of all patients. Prevalence of uptake was 0.37% in the 50th, increased dramatically at the 60th (2.49%), and reached 4% above the age of 80. The diagnostic grades 2 and 3 cardiac uptakes were identified in 5 patients (0.23% of overall patients) ranging between 56- and 91-y-old. Our results concord with the trend of disease increases with age. Conclusion: The careful analysis of the bone scintigraphy of all incoming adult patients should allow to make the diagnosis of the TTR cardiac amyloidosis at a preclinical stage and establish new effective treatments. Our results provide an estimate of the number of patients that could be diagnosed and improve the awareness of the corresponding prevalence in our population. In this way, multicentric studies should be implemented by enrolling large cohorts of bone scintigraphy cases.

A phase III trial of docetaxel versus docetaxel and radium-223 (Ra-223) in patients with metastatic castration-resistant prostate cancer (mCRPC): DORA.

TPS5091 Background: Ra-223, a bone-targeted alpha therapy, prolongs survival in patients (pts) with symptomatic mCRPC to bone. Docetaxel targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. We hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. We previously determined the dose and schedule of co-administering Ra-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have improved declines in prostate specific antigen (PSA) and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone. We are now conducting a phase III study to determine the clinical benefit of the regimen. Methods: Randomization (1:1) of 738 men with mCRPC to docetaxel or docetaxel + Ra-223 is planned with a projected hazard ratio for treatment effect (15 vs 20 months median survival) of 0.75. Pts with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0–1 and normal organ function. Key exclusion criteria are: use of anticancer therapy ≤4 weeks (wks) before randomization and use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 wks). Subjects receive docetaxel 75 mg/m2 IV q3w for 10 doses or docetaxel 60 mg/m2 IV q3w for 10 doses + Ra-223 55 kBq/kg IV q6w for 6 doses. The primary endpoint is overall survival. Secondary and exploratory endpoints include: radiographic progression-free survival, symptomatic skeletal event-free survival, safety, markers of bone metabolism, alterations in circulating tumor cells and DNA, detection of androgen-receptor splice variant 7, changes in automated bone scan index (aBSI), and assessment of patient-reported outcome instruments (FACT-P, Brief Pain Inventory, Brief Fatigue Inventory). The study is open at 32 sites in the US and Netherlands and has 170 subjects enrolled. The study is sponsored by Memorial Sloan Kettering Cancer Center, and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT03574571.

Clinical Perspectives of Theranostics.

Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and treatment that target specific biological pathways or receptors. This review covers traditional theranostics for thyroid cancer and pheochromocytoma with radioiodine compounds. In addition, recent theranostics of radioimmunotherapy for non-Hodgkin lymphoma, and treatment of bone metastasis using bone seeking radiopharmaceuticals are described. Furthermore, new radiopharmaceuticals for prostatic cancer and pancreatic cancer have been added. Of particular, F-18 Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography (PET) is often used for treatment monitoring and estimating patient outcome. A recent clinical study highlighted the ability of alpha-radiotherapy with high linear energy transfer (LET) to overcome treatment resistance to beta--particle therapy. Theranostics will become an ever-increasing part of clinical nuclear medicine.

Examining the sensitivity of 18F-NaF PET for the imaging of cardiac amyloidosis

BackgroundConventional nuclear imaging with bone-seeking radiopharmaceuticals has been shown to be a sensitive test for the detection of transthyretin cardiac amyloidosis (ATTR); however, to date, few data exist on the utility of 18F-sodium fluoride (NaF) positron emission tomography (PET) in subjects with cardiac amyloidosis (CA). MethodsMyocardial perfusion imaging and cardiac 18F-NaF PET/CT of 7 subjects with ATTR, four with light-chain CA (AL), and four controls were retrospectively reviewed. Qualitative interpretation and quantitative analyses with average left ventricular standardized uptake values (SUVmean) and target-to-background ratios (TBRmean) were performed. ResultsAverage TBRmean was significantly increased in subjects with ATTR (0.98 ± 0.09) compared to AL (0.85 ± 0.08, P = .026) and CTL (0.82 ± 0.07, P = .020), while SUVmean was not (P = .14). Receiver-operator characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.91, with a sensitivity/specificity of 75%/100% for TBRmean using a cutoff value of 0.89 for the diagnosis of ATTR. Qualitative interpretation resulted in a sensitivity/specificity of 57%/100% for ATTR. ConclusionsWhile 18F-NaF PET/CT demonstrates good diagnostic accuracy for ATTR, particularly when using quantitative analysis, the low TBRmean values observed in ATTR indicate poor myocardial signal. 18F-NaF PET/CT is not yet ready for clinical use in CA until further comparison studies are performed with 99mTc-DPD/PYP.

68Ga-Labeled bismacrocyclic methylene phosphonate as potential bone seeking PET radiopharmaceutical

Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of 68Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent.

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.

Targeted Radionuclide Therapy of Painful Bone Metastases: Past Developments, Current Status, Recent Advances and Future Directions

Bone pain arising from secondary skeletal malignancy constitutes one of the most common types of chronic pain among patients with cancer which can lead to rapid deterioration of the quality of life. Radionuclide therapy using bone-seeking radiopharmaceuticals based on the concept of localization of the agent at bone metastases sites to deliver focal cytotoxic levels of radiation emerged as an effective treatment modality for the palliation of symptomatic bone metastases. Bone-seeking radiopharmaceuticals not only provide palliative benefit but also improve clinical outcomes in terms of overall and progression-free survival. There is a steadily expanding list of therapeutic radionuclides which are used or can potentially be used in either ionic form or in combination with carrier molecules for the management of bone metastases. This article offers a narrative review of the armamentarium of bone-targeting radiopharmaceuticals based on currently approved investigational and potentially useful radionuclides and examines their efficacy for the treatment of painful skeletal metastases. In addition, the article also highlights the processes, opportunities, and challenges involved in the development of bone-seeking radiopharmaceuticals. Radium-223 is the first agent in this class to show an overall survival advantage in Castration-Resistant Prostate Cancer (CRPC) patients with bone metastases. This review summarizes recent advances, current clinical practice using radiopharmaceuticals for bone pain palliation, and the expected future prospects in this field.

A phase III trial of docetaxel versus docetaxel and radium-223 (Ra-223) in patients with metastatic castration-resistant prostate cancer (mCRPC): DORA.

TPS5594 Background: Ra-223, a bone-targeted alpha therapy, prolongs survival in patients (pts) with symptomatic mCRPC to bone. Docetaxel targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. We hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. We previously determined the dose and schedule of co-administering Ra-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have improved declines in prostate specific antigen (PSA) and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone. We are now conducting a phase III study to determine the clinical benefit of the regimen. Methods: Randomization (1:1) of 738 men with mCRPC to docetaxel or docetaxel + Ra-223 is planned with a projected hazard ratio for treatment effect (15 vs 20 months median survival) of 0.75. Pts with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0-1 and normal organ function. Key exclusion criteria are: use of anticancer therapy ≤4 weeks (wks) before randomization and use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 wks). Subjects receive docetaxel 75 mg/m2 IV q3w for 10 doses or docetaxel 60 mg/m2 IV q3w for 10 doses + Ra-223 55 kBq/kg IV q6w for 6 doses. The primary endpoint is overall survival. Secondary and exploratory endpoints include: radiographic progression-free survival, symptomatic skeletal event-free survival, safety, markers of bone metabolism, alterations in circulating tumor cells and DNA, detection of androgen-receptor splice variant 7, changes in automated bone scan index (aBSI), and assessment of patient-reported outcome instruments (FACT-P, Brief Pain Inventory, Brief Fatigue Inventory). The study is open at 25 sites in the US and Netherlands, sponsored by Memorial Sloan Kettering Cancer Center, and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT03574571 .

Остеотропные радиофармацевтические препараты на основе фосфоновых кислот и Ga-68 (обзор)

Остеотропные радиофармацевтические препараты на основе фосфоновых кислот и Ga-68 (обзор)

Radiopharmaceuticals for Treatment of Osteosarcoma.

Although trace amounts of radioactivity are routinely used to detect osteosarcoma, the use of larger therapeutic amounts of radiation is often an unrecognized opportunity to treat metastatic osteosarcoma. This chapter will review a number of approaches to use ionizing radiation in the form of injectable radiopharmaceuticals. Since bone metastases are a common pattern of metastatic spread of cancer in general, a number of bone-seeking radiopharmaceuticals have been developed and FDA approved for treatment of bone metastases. Although osteosarcoma, a bone-forming cancer, would seem ideally suited to be treated with bone seekers, patterns of relapse involving non-ossifying metastases remain a major problem to be overcome. Thus, this review will not only describe experience using a number of bone-seeking radiopharmaceuticals such as 153-samarium-EDTMP, 153-samarium-DOTMP, and 223-radium against osteosarcoma, but also approaches to identify patients who may benefit as well as some means to the improve overall efficacy including combination therapy with routine agents and using nuclear imaging to develop best strategy for use. These include imaging with not only 99mTc-MDP standard bone scans, but also 99mTc-MDP bone scans with SPECT CT, bone-specific sodium fluoride PET-CT (Na18F), and 18FDG-PET-CT. Accurate knowledge of oligometastatic active disease can facilitate more effective use of combination therapy, including radiosensitizers and local control measures, for example, stereotactic body radiotherapy (SBRT) and/or cryoablation to reduce disease burden as well as manage and prevent micrometastatic disease from growing and metastasizing. Finally, a new tumor-specific radiopharmaceutical, CLR 131, may also provide another radiopharmaceutical to treat both osteoblastic and non-ossifying areas of osteosarcoma.

Investigation of 177Lu-labeled HEDP, DPD, and IDP as potential bone pain palliation agents

Application of bone-seeking radiopharmaceuticals is one of the modalities in the management of metastatic bone pain. The present study aimed to investigate the potential of 177Lu-labeled phosphate/...

Abstract CT145: Repeated radium-223-chloride versus rhenium-188-HEDP in patients with metastatic castration-resistant prostate cancer: RaRe study

Abstract Background: For patients with castration-resistant prostate cancer (CRPC) metastatic to bone, treatment with bone seeking radiopharmaceuticals is an important treatment option, both for pain palliation and improvement of survival. Radium-223-chloride (an alpha-emitter) has a proven survival benefit. Some small clinical studies suggest that rhenium-188-HEDP, a beta-emitter that is well-known for its effect on pain palliation, may have a beneficial effect on survival as well. A major advantage of rhenium-188-HEDP, compared to radium-223-chloride is the production on-site at a healthcare institute, resulting in rapidly availability and lower costs. Other advantages of rhenium-188-HEDP includes more favorable physical characteristics (shorter half-life and longer penetration depth) and being more patient-friendly (3 instead of 6 administrations) compared to radium-223-chloride. Despite some promising data in small randomized studies, the potential effect on patient survival of rhenium-188-HEDP needs to be established in a randomized phase III study. Methods: The RaRe trial is a multicenter, randomized, open-label, controlled phase III study comparing the efficacy of repeated treatment with radium-223-chloride and repeated treatment with rhenium-188-HEDP in patients with CRPC metastatic to bone. The aim of the trial is to include 402 participants who are randomized to one of the two treatment groups in a 1:1 ratio. The primary endpoint is overall survival (OS), and the secondary endpoints are pain response, quality of life (QoL), time to first occurrence of skeletal related event (SRE), prostate specific antigen (PSA) progression, total alkaline phosphatase (tALP) progression, and incremental cost-effectiveness. An interim analysis for futility will be performed after the inclusion of 90 patients in each treatment group. Discussion: In this randomized phase III trial we hypothesize that treatment with rhenium-188-HEDP results in an improved survival in patients with CRPC metastatic to bone as compared to the current standard treatment with radium-223-chloride. We also expect to demonstrate that treatment with rhenium-188-HEDP improves pain response and quality of life of CRPC patients. Results coming from this study may help to find a better treatment for CRPC patients, while reducing costs. In current times of exponential growth of healthcare costs, we believe that this study is meaningful from the perspective of cost-effectiveness. Clinicaltrials.gov identifier: NCT03458559. Registered 8 March 2018. Trial status: recruiting. Citation Format: Jessica C. Notohardjo, Esther W. Bouman-Wammes, Joyce M. van Dodewaard - de Jong, Haiko J. Bloemendal, Rogier Lange, Rob ter Heine, Henk M. Verheul, John M. de Klerk, Alfons J. van den Eertwegh. Repeated radium-223-chloride versus rhenium-188-HEDP in patients with metastatic castration-resistant prostate cancer: RaRe study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT145.

In Situ In Vivo radiolabeling of polymer-coated hydroxyapatite nanoparticles to track their biodistribution in mice.

The imaging of healthy tissues and solid tumors benefits from the application of nanoparticle probes with altered pharmacokinetics, not available to low molecular weight compounds. However, the distribution and accumulation of nanoprobes in vivo typically take at least tens of hours to be efficient. For nanoprobes bearing a radioactive label, this is contradictory to the requirement of minimizing the radiation dose for patients by using as-short-as-feasible half-life radionuclides in diagnostics. Thus, we developed a two-stage diagnostic concept for monitoring long-lasting targeting effects with short-lived radioactive labels using bone-mimicking biocompatible polymer-coated and colloidally fully stabilized hydroxyapatite nanoparticles (HAP NPs) and bone-seeking radiopharmaceuticals. Within the pretargeting stage, the nonlabeled nanoparticles are allowed to circulate in the blood. Afterward, 99mTc-1-hydroxyethylidene-1.1-diphosphonate (99mTc-HEDP) is administered intravenously for in situ labeling of the nanoparticles and subsequent single-photon emission computed tomography/computed tomography (SPECT/CT) visualization. The HAP NPs, stabilized with tailored hydrophilic polymers, are not cytotoxic in vitro, as shown by several cell lines. The polymer coating prolongs the circulation of HAP NPs in the blood. The nanoparticles were successfully labeled in vivo with 99mTc-HEDP, 1 and 24 h after injection, and they were visualized by SPECT/CT over time in healthy mice.

The influence of carrier addition on the biodistribution of bone-seeking agent «188Re-oxa-bis(ethylenenitrilo)- tetramethylenephosphonic acid»

Bone-seeking radiopharmaceuticals are known to be the most promising agents for the palliative treatment of the pain of bone metastases. A generator-produced radionuclide rhenium-188 (188Re) is an attractive candidate for therapeutic use due to its nuclear characteristics. The goal of the current work was the investigation of the biodistribution of 188Re-oxa-bis(ethylenenitrilo)tetramethylenephosphonic acid (188Re-OENTMP) with gallium carrier and without carrier and to compare them. A comparative accumulation study of both 188Re-OENTMP formulations was performed in normal rats after intravenous administration up to 48 hours. It was revealed that for carrier-added 188Re-OENTMP the bone samples from femur, skull, ribs, spine and knee joint all had higher uptake in comparison to that of 188Re-OENTMP without carrier. The values of carrier-added 188Re-OENTMP in skeleton were ranged from 7,82% to 57,37% of injected dose (ID), when the amount of 188Re-OENTMP without carrier varied from 5,76% to 22,75% of ID. Among the soft tissue organs, only thyroid gland and kidneys had a relatively high uptake. Most of the activity excreted via the urinary tract. In conclusion, it should be pointed out that carrier addition strongly affects bone uptake of 188Re-OENTMP, so carrier-added 188Re-OENTMP could be useful to deliver radiation to skeletal metastases from soft tissue cancer.