Navigating through the coordination preferences of heavy alkaline earth metals: Laying the foundations for 223Ra- and 131/135mBa-based targeted alpha therapy and theranostics of cancer.

The clinical success of [223Ra]RaCl2 (Xofigo®) for the palliative treatment of bone metastases in patients with prostate cancer has highlighted the therapeutic potential of α-particle emission. Expanding the applicability of radium-223 in Targeted Alpha Therapy of non-osseous tumors is followed up with significant interest, as it holds the potential to unveil novel treatment options in the comprehensive management of cancer. Moreover, the use of barium radionuclides, like barium-131 and -135m, is still unfamiliar in nuclear medicine applications, although they can be considered as radium-223 surrogates for imaging purposes. Enabling these applications requires the establishment of chelators able to form stable complexes with radium and barium radionuclides. Until now, only a limited number of ligands have been suggested and these molecules have been primarily inspired by existing structures known for their ability to complex large metal cations. However, a systematic inspection of chelators specifically tailored to Ra2+ and Ba2+ has yet to be conducted. This work delves into a comprehensive investigation of a series of small organic ligands, aiming to unveil the coordination preferences of both radium-223 and barium-131/135m. Electronic binding energies of both metal cations to each ligand were theoretically computed via Density Functional Theory calculations (COSMO-ZORA-PBE-D3/TZ2P), while thermodynamic stability constants were experimentally determined for Ba2+-ligand complexes by potentiometry, NMR and UV-Vis spectroscopies. The outcomes revealed malonate, 2-hydroxypyridine 1-oxide and picolinate as the most favorable building blocks to design multidentate chelators. These findings serve as foundation guidelines, propelling the development of cutting-edge radium-223- and barium-131/135m-based radiopharmaceuticals for Targeted Alpha Therapy and theranostics of cancer.

ISIT-QA: In Silico Imaging Trial to Evaluate a Low-Count Quantitative SPECT Method Across Multiple Scanner-Collimator Configurations for 223Ra-Based Radiopharmaceutical Therapies.

Personalized dose-based treatment planning requires accurate and reproducible noninvasive measurements to ensure safety and effectiveness. Dose estimation using SPECT is possible but challenging for alpha (α)-particle-emitting radiopharmaceutical therapy (α-RPT) because of complex γ-emission spectra, extremely low counts, and various image-degrading artifacts across a plethora of scanner-collimator configurations. Through the incorporation of physics-based considerations and skipping of the potentially lossy voxel-based reconstruction step, a recently developed projection-domain low-count quantitative SPECT (LC-QSPECT) method has the potential to provide reproducible, accurate, and precise activity concentration and dose measures across multiple scanners, as is typically the case in multicenter settings. To assess this potential, we conducted an in silico imaging trial to evaluate the LC-QSPECT method for a 223Ra-based α-RPT, with the trial recapitulating patient and imaging system variabilities. Methods: A virtual imaging trial titled In Silico Imaging Trial for Quantitation Accuracy (ISIT-QA) was designed with the objectives of evaluating the performance of the LC-QSPECT method across multiple scanner-collimator configurations and comparing performance with a conventional reconstruction-based quantification method. In this trial, we simulated 280 realistic virtual patients with bone-metastatic castration-resistant prostate cancer treated with 223Ra-based α-RPT. The trial was conducted with 9 simulated SPECT scanner-collimator configurations. The primary objective of this trial was to evaluate the reproducibility of dose estimates across multiple scanner-collimator configurations using LC-QSPECT by calculating the intraclass correlation coefficient. Additionally, we compared the reproducibility and evaluated the accuracy of both considered quantification methods across multiple scanner-collimator configurations. Finally, the repeatability of the methods was evaluated in a test-retest study. Results: In this trial, data from 268 223RaCl2 treated virtual prostate cancer patients, with a total of 2,903 lesions, were used to evaluate LC-QSPECT. LC-QSPECT provided dose estimates with good reproducibility across the 9 scanner-collimator configurations (intraclass correlation coefficient > 0.75) and high accuracy (ensemble average values of recovery coefficients ranged from 1.00 to 1.02). Compared with conventional reconstruction-based quantification, LC-QSPECT yielded significantly improved reproducibility across scanner-collimator configurations, accuracy, and test-retest repeatability ([Formula: see text] Conclusion: LC-QSPECT provides reproducible, accurate, and repeatable dose estimations in 223Ra-based α-RPT as evaluated in ISIT-QA. These findings provide a strong impetus for multicenter clinical evaluations of LC-QSPECT in dose quantification for α-RPTs.

A comprehensive value-based method for new nuclear medical service pricing: with case study of radium [223Ra] bone metastases treatment.

IMPORTANCE: Innovative nuclear medicine services offer substantial clinical value to patients. However, these advancements often come with high costs. Traditional payment strategies do not incentivize medical institutes to provide new services nor determine the fair price for payers. A shift towards a value-based pricing strategy is imperative to address these challenges. Such a strategy would reconcile the cost of innovation with incentives, foster transparent allocation of healthcare resources, and expedite the accessibility of essential medical services. OBJECTIVE: This study aims to develop and present a comprehensive, value-based pricing model for new nuclear medicine services, illustrated explicitly through a case study of the radium [223Ra] treatment for bone metastases. In constructing the pricing model, we have considered three primary value determinants: the cost of the new service, associated service risk, and the difficulty of the service provision. Our research can help healthcare leaders design an evidence-based Fee-For-Service (FFS) payment reference pricing with nuclear medicine services and price adjustments. DESIGN, SETTING AND PARTICIPANTS: This multi-center study was conducted from March 2021 to February 2022 (including consultation meetings) and employed both qualitative and quantitative methodologies. We organized focus group consultations with physicians from nuclear medicine departments in Beijing, Chongqing, Guangzhou, and Shanghai to standardize the treatment process for radium [223Ra] bone metastases. We used a specially designed 'Radium Nuclide [223Ra] Bone Metastasis Data Collection Form' to gather nationwide resource consumption data to extract information from local databases. Four interviews with groups of experts were conducted to determine the add-up ratio, based on service risk and difficulty. The study organized consultation meeting with key stakeholders, including policymakers, service providers, clinical researchers, and health economists, to finalize the pricing equation and the pricing result of radium [223Ra] bone metastases service. MAIN OUTCOMES AND MEASURES: We developed and detailed a pricing equation tailored for innovative services in the nuclear medicine department, illustrating its application through a step-by-step guide. A standardized service process was established to ensure consistency and accuracy. Adhering to best practice guidelines for health cost data analysis, we emphasized the importance of cross-validation of data, where validated data demonstrated less variation. However, it required a more advanced health information system to manage and analyze the data inputs effectively. RESULTS: The standardized service of radium [223Ra] bone metastases includes: pre-injection assessment, treatment plan, administration, post-administration monitoring, waste disposal and monitoring. The average duration for each stage is 104 min, 39 min, 25 min, 72 min and 56 min. A standardized monetary value for medical consumables is 54.94 yuan ($7.6), and the standardised monetary value (medical consumables cost plus human input) is 763.68 yuan ($109.9). Applying an agreed value add-up ratio of 1.065, the standardized value is 810.19 yuan ($116.9). Feedback from a consultation meeting with policymakers and health economics researchers indicates a consensus that the pricing equation developed was reasonable and well-grounded. CONCLUSION: This research is the first study in the field of nuclear medicine department pricing methodology. We introduce a comprehensive value-based nuclear medical service pricing method and use radium[223Ra] bone metastases treatment pricing in China as a case study. This study establishes a novel pricing framework and provides practical instructions on its implementation in a real-world healthcare setting.

Advancements in the development of radiopharmaceuticals for nuclear medicine applications in the treatment of bone metastases.

Bone metastases are a painful and complex condition that overwhelmingly impacts the prognosis and quality of life of cancer patients. Over the years, nuclear medicine has made remarkable progress in the diagnosis and management of bone metastases. This review aims to provide a comprehensive overview of the recent advancements in nuclear medicine for the diagnosis and management of bone metastases. Furthermore, the review explores the role of targeted radiopharmaceuticals in nuclear medicine for bone metastases, focusing on radiolabeled molecules that are designed to selectively target biomarkers associated with bone metastases, including osteocytes, osteoblasts, and metastatic cells. The applications of radionuclide-based therapies, such as strontium-89 (Sr-89) and radium-223 (Ra-223), are also discussed. This review also highlights the potential of theranostic approaches for bone metastases, enabling personalized treatment strategies based on individual patient characteristics. Importantly, the clinical applications and outcomes of nuclear medicine in osseous metastatic disease are discussed. This includes the assessment of treatment response, predictive and prognostic value of imaging biomarkers, and the impact of nuclear medicine on patient management and outcomes. The review identifies current challenges and future perspectives on the role of nuclear medicine in treating bone metastases. It addresses limitations in imaging resolution, radiotracer availability, radiation safety, and the need for standardized protocols. The review concludes by emphasizing the need for further research and advancements in imaging technology, radiopharmaceutical development, and integration of nuclear medicine with other treatment modalities. In summary, advancements in nuclear medicine have significantly improved the diagnosis and management of osseous metastatic disease and future developements in the integration of innovative imaging modalities, targeted radiopharmaceuticals, radionuclide production, theranostic approaches, and advanced image analysis techniques hold great promise in improving patient outcomes and enhancing personalized care for individuals with bone metastases.

An objective measure of response on whole-body MRI in metastatic hormone sensitive prostate cancer treated with androgen deprivation therapy, external beam radiotherapy, and radium-223.

OBJECTIVES: The aim of this study was to generate an objective method to describe MRI data to assess response in the vertebrae of patients with metastatic hormone sensitive prostate cancer (mHSPC), treated with external beam radiation therapy and systemic therapy with Radium-223 and to correlate changes with clinical outcomes. METHODS: Three sets of whole-body MRI (WBMRI) images were utilized from 25 patients from the neo-adjuvant Androgen Deprivation Therapy pelvic Radiotherapy and RADium-223 (ADRRAD) clinical trial: MRI1 (up to 28 days before Radium-223), MRI2, and MRI3 (2 and 6 months post completion of Radium-223). Radiological response was assessed based on post baseline MRI images. Vertebrae were semi-automatically contoured in the sagittal T1-weighted (T1w) acquisitions, MRI intensity was measured, and spinal cord was used to normalize the measurements. The relationship between MRI intensity vs time to biochemical progression and radiology response was investigated. Survival curves were generated and splitting measures for survival and biochemical progression investigated. RESULTS: Using a splitting measure of 1.8, MRI1 was found to be a reliable quantitative indicator correlating with overall survival (P = 0.023) and biochemical progression (P = 0.014). MRI (3-1) and MRI (3-2) were found to be significant indicators for patients characterized by progressive/non-progressive disease (P = 0.021, P = 0.004) and biochemical progression within/after 12 months (P = 0.007, P = 0.001). CONCLUSIONS: We have identified a potentially useful objective measure of response on WBMRI of vertebrae containing bone metastases in mHSPC which correlates with survival/progression (prognostic) and radiology response (predictive). ADVANCES IN KNOWLEDGE: Measurements of T1w WBMRI normalized intensity may allow identifying potentially useful response biomarkers correlating with survival, radiological response and biochemical progression.

Targeted Radium Alpha Therapy in the Era of Nanomedicine: In Vivo Results.

Targeted alpha-particle therapy using radionuclides with alpha emission is a rapidly developing area in modern cancer treatment. To selectively deliver alpha-emitting isotopes to tumors, targeting vectors, including monoclonal antibodies, peptides, small molecule inhibitors, or other biomolecules, are attached to them, which ensures specific binding to tumor-related antigens and cell surface receptors. Although earlier studies have already demonstrated the anti-tumor potential of alpha-emitting radium (Ra) isotopes-Radium-223 and Radium-224 (223/224Ra)-in the treatment of skeletal metastases, their inability to complex with target-specific moieties hindered application beyond bone targeting. To exploit the therapeutic gains of Ra across a wider spectrum of cancers, nanoparticles have recently been embraced as carriers to ensure the linkage of 223/224Ra to target-affine vectors. Exemplified by prior findings, Ra was successfully bound to several nano/microparticles, including lanthanum phosphate, nanozeolites, barium sulfate, hydroxyapatite, calcium carbonate, gypsum, celestine, or liposomes. Despite the lengthened tumor retention and the related improvement in the radiotherapeutic effect of 223/224Ra coupled to nanoparticles, the in vivo assessment of the radiolabeled nanoprobes is a prerequisite prior to clinical usage. For this purpose, experimental xenotransplant models of different cancers provide a well-suited scenario. Herein, we summarize the latest achievements with 223/224Ra-doped nanoparticles and related advances in targeted alpha radiotherapy.

Alpha-Emitter Radium-223 Induces STING-Dependent Pyroptosis to Trigger Robust Antitumor Immunity.

Radium-223 (223 Ra) is the first-in-class alpha-emitter to mediate tumor eradication, which is commonly thought to kill tumor cells by directly cleaving double-strand DNA. However, the immunogenic characteristics and cell death modalities triggered by 223 Ra remain unclear. Here, it is reported that the 223 Ra irradiation induces the pro-inflammatory damage-associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223 Ra retards tumor progression by triggering pyroptosis, an immunogenic cell death. Mechanically, 223 Ra-induced DNA damage leads to the activation of stimulator of interferon genes (STING)-mediated DNA sensing pathway, which is critical for NLRP3 inflammasome-dependent pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha-emitter 223 Ra-induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy.

Tracing the Evolution of Prostate Brachytherapy in the 20th Century.

BACKGROUND: Prostate brachytherapy (BT) techniques have evolved over the past century. This paper aimed to preserve our collective memory of history and the early development of its technique. We searched articles in PubMed and Google Scholar using keywords referring to authors, dates, and BT technical details, including different radioactive sources and country-specific publications. We reviewed the work published by Holm and Aronowitz. The digital library Internet Archives was used to retrieve original journal articles, science newspaper printings, and government reports, which allowed us to situate the development of BT in its sociopolitical context in Europe and the USA. Our search was conducted in English, French, and German languages. SUMMARY: Early BT methods were developed by European physicians with early access to radium. Technical advancements were made by HH Young, who brought this practice to the USA, where Barringer pioneered the use of radon seeds and low-dose interstitial brachytherapy. While centralized radiotherapy centers, such as Memorial Hospital in New York, emerged for training and research, the high cost of radium and opposing interests made brachytherapy harder to implement in Germany. After World War II, the introduction of man-made radioisotopes allowed experiments with colloidal solutions and new seeds, including I-125. In the 1980s, transrectal ultrasound allowed for more accurate radioactive seed insertion and replaced the transrectal finger guidance.

A potential biomarker of radiosensitivity in metastatic hormone sensitive prostate cancer patients treated with combination external beam radiotherapy and radium-223.

PURPOSE: The ADRRAD trial reported the safety and feasibility of the combination of external beam radiotherapy and radium-223 in the treatment of de novo bone metastatic prostate. This study aimed to determine if any biomarkers predictive of response to these treatments could be identified. EXPERIMENTAL DESIGN: 30 patients with newly diagnosed bone metastatic hormone sensitive prostate cancer were recruited to the ADRRAD trial. Blood samples were taken pre-treatment, before cycles 2 to 6 of radium-223, and 8 weeks and 6 months after treatment. Mononuclear cells were isolated and DNA damage was assessed at all timepoints. RESULTS: DNA damage was increased in all patients during treatment, with bigger increases in foci observed in patients who relapsed late compared to those who relapsed early. Increases in DNA damage during the radium-223 only cycles of treatment were specifically related to response in these patients. Analysis of hematology counts also showed bigger decreases in red blood cell and hemoglobin counts in patients who experienced later biochemical relapse. CONCLUSIONS: While some patients responded to this combination treatment, others relapsed within one year of treatment initiation. This study identifies a biomarker based approach that may be useful in predicting which patients will respond to treatment, by monitoring both increases in DNA damage above baseline levels in circulating lymphocytes and decreases in red blood cell and hemoglobin counts during treatment.

Radium-223 in metastatic castration-resistant prostate cancer: whole-body diffusion-weighted magnetic resonance imaging scanning to assess response.

BACKGROUND: Radium-223 is a bone-seeking, ɑ-emitting radionuclide used to treat men with bone metastases from castration-resistant prostate cancer. Sclerotic bone lesions cannot be evaluated using Response Evaluation Criteria in Solid Tumors. Therefore, imaging response biomarkers are needed. METHODS: We conducted a phase 2 randomized trial to assess disease response to radium-223. Men with metastatic castration-resistant prostate cancer and bone metastases were randomly allocated to 55 or 88 kBq/kg radium-223 every 4 weeks for 6 cycles. Whole-body diffusion-weighted magnetic resonance imaging (DWI) was performed at baseline, at cycles 2 and 4, and after treatment. The primary endpoint was defined as a 30% increase in global median apparent diffusion coefficient. RESULTS: Disease response on DWI was seen in 14 of 36 evaluable patients (39%; 95% confidence interval = 23% to 56%), with marked interpatient and intrapatient heterogeneity of response. There was an association between prostate-specific antigen response and MRI response (odds ratio = 18.5, 95% confidence interval = 1.32 to 258, P = .013). Mean administered activity of radium-223 per cycle was not associated with global MRI response (P = .216) but was associated with DWI response using a 5-target-lesion evaluation (P = .007). In 26 of 36 (72%) patients, new bone metastases, not present at baseline, were seen on DWI scans during radium-223 treatment. CONCLUSIONS: DWI is useful for assessment of disease response in bone. Response to radium-223 is heterogeneous, both between patients and between different metastases in the same patient. New bone metastases appear during radium-223 treatment.The REASURE trial is registered under ISRCTN17805587.

Effect of Intraperitoneal 224Radium-Labelled Microparticles on Compartmentalized Inflammation After Cytoreductive Surgery and Hypertherm Intraperitoneal Chemotherapy.

Despite extensive treatment with surgery and chemotherapy many patients with peritoneal metastases from colorectal cancer experience intraperitoneal disease relapse. The α-emitting 224radium-labelled microparticle radionuclide therapeutic Radspherin® is being explored as a novel treatment option for these patients. Radspherin® is specially designed to give local radiation to the surface of the peritoneal cavity and potentially kill remaining attached micrometastases as well as free-floating cancer cells, thus preventing future relapse. The effect of Radspherin® on the immune system is not known. Systemic and local inflammatory responses were analyzed in plasma, intraperitoneal fluid and urine collected prospectively as part of a phase 1 dose-escalation study of intraperitoneal instillation of the α-emitting therapeutic radiopharmaceutical Radspherin®, at baseline and the first 7 postoperative days from nine patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. All patients additionally received intraperitoneal instillation of Radspherin® on postoperative day 2. Complement activation products C3bc and the terminal complement complex were analyzed using enzyme-linked immunosorbent assay. Cytokines (n = 27), including interleukins, chemokines, interferons and growth factors, were analyzed using multiplex technique. The time course and magnitude of the postoperative cytokine response after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy displayed a modest systemic response in plasma, in contrast to a substantial local intraperitoneal response. After administration of Radspherin®, a significant increase (P < 0.05) in TNF and MIP-1ß was observed in both plasma and peritoneal fluid, whereas IL-9 increased only in plasma and IFNγ and IL1-RA only in peritoneal fluid. Only minor changes were seen for the majority of the inflammatory markers after Radspherin® administration. Our study showed a predominately local rather than systemic inflammatory response to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Radspherin® had overall modest impact on the inflammation.

Bone-modifying agents are protective for symptomatic skeletal events in Radium-223 treatment.

INTRODUCTION: Radium-223 (Ra-223) dichloride therapy increases overall survival and delays time to the first symptomatic skeletal event (SSE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Bone-modifying agents (BMA) reduce SSE in patients with bone metastasis, but there is little information on their use with Ra-223. This study aimed to investigate the effect of BMA on SSE in patients with bone metastatic CRPC treated with Ra-223 in real-world practice. METHODS: We included 73 patients treated with Ra-223 from 10 institutions in Japan. Time to the first SSE was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. We used univariate analysis to ascertain the association between variables and SSE. RESULTS: During a median follow-up of 12.7 months (interquartile range, 7-21.7), 12 (16.4%) patients presented SSE. Age and BMA use were different between men with and without SSE. The 1-year SSE-free survival rate from Ra-223 treatment initiation was 82.4% (95% CI, 69.4%-90.2%). BMA use was associated with favorable SSE-free survival (hazard risk, 0.23; 95% confidence interval, 0.061-0.85; p = 0.027). Two (4.7%) and seven (23.3%) patients presented symptomatic pathological bone fracture in groups with and without BMA use, respectively (p = 0.017). CONCLUSION: This study stresses the importance of BMA use in patients with CRPC and bone metastases in Ra-223 treatment.

Treatment outcomes of radium-223 in patients with metastatic castration-resistant prostate cancer: An experience before National Health Insurance reimbursement in Taiwan.

BACKGROUND: Radium-223 (Ra-223), an α-particle-emitting isotope, inhibits bony metastases and prevents patients from skeletal-related events in metastatic castration-resistant prostate cancer (mCRPC). We retrospectively reviewed the treatment response, predictive factors, and adverse events (AEs) of Ra-223 before the National Health Insurance reimbursement in a Taiwanese tertiary institute. METHODS: Patients treated with Ra-223 before January 2019 were enrolled and categorized into progressive disease (PD) and clinical benefits (CB) groups. Laboratory data before and after the treatment were collected, and spider plots concerning percentage changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) were prepared and calculated statistically. CB/PD, baseline ALP, LDH, and PSA levels were also adopted as stratification factors for overall survival (OS). RESULTS: Among 19 patients included, 5 (26.3%) and 14 (73.4%) belonged to the PD and CB groups, respectively, with no significant difference observed in the baseline laboratory data. The percentage changes in ALP, LDH, and PSA levels after Ra-223 treatment were statistically significant among the two groups (ALP: CB 54.3 ± 21.4% vs PD 77.6 ± 11.8%, p = 0.044; LDH: CB 88.2 ± 22.8% vs PD 138.3 ± 49.0%, p = 0.046; PSA: CB 97.8 ± 61.7% vs PD 277.0 ± 101.1%, p = 0.002). The trends of LDH between the two groups in spider plot were separated significantly. There were no differences in the AEs between the two groups. CB had a longer median OS than the PD group (20.50 months vs 9.43 months, p = 0.009). Patients with LDH <250 U/L at baseline tended to have longer OS but without significance. CONCLUSION: The CB rate of Ra-223 was 73.7%. No predictive factor for treatment response was obtained from pretreatment data. The mean percentage changes in ALP, LDH, and PSA levels compared with baseline significantly differed between the CB and PD groups, especially the LDH levels. The CB and PD groups showed different OS, with LDH levels exhibiting the potential to predict OS.

Pain Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with 223Ra: PARABO, a Prospective, Noninterventional Study.

223Ra, a targeted α-therapy, is approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have bone metastases. In the phase 3 ALSYMPCA study, 223Ra prolonged survival and improved quality of life versus placebo. Our real-world study, PARABO, investigated pain and bone pain-related quality of life in patients with mCRPC and symptomatic bone metastases receiving 223Ra in clinical practice. Methods: PARABO was a prospective, observational, noninterventional single-arm study conducted in nuclear medicine centers across Germany (NCT02398526). The primary endpoint was a clinically meaningful pain response (≥2-point improvement from baseline for the worst-pain item score in the Brief Pain Inventory-Short Form). Results: The analysis included 354 patients, who received a median of 6 223Ra injections (range, 1-6). Sixty-seven percent (236/354) received 5-6 injections, and 33% (118/354) received 1-4 injections. Of 216 patients with a baseline worst-pain score of more than 1, 59% (128) had a clinically meaningful pain response during treatment. Corresponding rates were 67% (range, 98/146) with 5-6 223Ra injections versus 43% (range, 30/70) with 1-4 injections, 60% (range, 60/100) in patients with no more than 20 lesions versus 59% (range, 65/111) in those with more than 20 lesions, and 65% (range, 69/106) in patients without prior or concomitant opioid use versus 54% (range, 59/110) in those with prior or concomitant opioid use. Mean subscale scores (pain severity and pain interference) on the Brief Pain Inventory-Short Form improved during treatment. Conclusion: 223Ra reduced pain in patients with mCRPC and symptomatic bone metastases, particularly in patients who received 5-6 injections. The extent of metastatic disease did not impact pain response.

Complete Cycles of Radium-223 Improve Overall Survival in Patients With Metastatic Castration-resistant Prostate Cancer: A Retrospective Study.

BACKGROUND/AIM: The aim of this study was to investigate whether complete cycles of Radium-223 (Ra-223) improved survival in patients with metastatic castration resistant prostate cancer (mCRPC). PATIENTS AND METHODS: We retrospectively analyzed mCRPC patients treated with Ra-223 at Taichung Veterans General hospital. Patient and disease characteristics, laboratory results, number of bone metastases, mCRPC treatment sequence, Ra-223 treatment cycles and survival outcomes were collected. Overall survival and progression-free survival (PFS) were analyzed with Kaplan-Meier analysis. Uni- and multivariate analysis was used to identify clinical-radiologic factors that influence outcomes. RESULTS: From October 2016 to December 2020, 42 patients with mCRPC were enrolled. Twenty-three patients received <4 cycles of Ra-223 for mCRPC and 19 patients received 5-6 cycles. The median PSA progression free survival was 2.07 months in the <4 cycles group, compared to 3.93 months in the 5-6 cycles group (log rank p=0.006). The median overall survival was 3.93 months in the <4 cycles group, compared to 28.5 months in the 5-6 cycles group (log rank p<0.001). In the multivariate model, the course number of Ra-223 and pre-treatment alkaline phosphatase (ALP) levels were independent risk factors for overall survival. CONCLUSION: Patients who complete 5-6 cycles of Ra-223 had significantly better overall survival than those who didn't. Patients with a lower pre-treatment ALP were more likely to benefit from Ra-223 treatment.

Integrating radium-223 therapy into the management of metastatic prostate cancer care: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Few life-prolonging treatment options are available for patients with metastatic castration-resistant prostate cancer (mCRPC). This article provides an overview of the current systemic treatments available for mCRPC and reviews studies that investigate the optimal timing for the use of radium-223. The aim is to illustrate possible systemic treatment sequences to maximize benefit from radium-223 therapy. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER & HOW IS IT TREATED?: Prostate cancer is called mCRPC when it spreads to organs outside of the prostate (such as the lymph nodes, bones, liver, or lungs) and no longer responds to hormonal therapy. There are several treatment options available for mCRPC, such as abiraterone, enzalutamide, radium-223, docetaxel, cabazitaxel, olaparib, rucaparib, sipuleucel-T, and 177Lu-PSMA. It is important to understand the risks and benefits associated with each treatment and whether current use may have an impact on future treatment options, including eligibility in certain clinical trials. Maintaining bone health is also an important part of prostate cancer care. WHAT IS RADIUM-223?: Radium-223 is a radioactive molecule that releases strong radiation within a very small range around itself. It mainly travels to the bone where the prostate cancer has spread and kills the cancer cells in that area. Results from a clinical study named ALSYMPCA showed that men who received radium-223 lived longer in addition to having less bone pain. The most common side effects of radium-223 are nausea, vomiting, and diarrhea. Radium-223 minimally suppresses the bone marrow, which means that it slightly reduces the levels of red and white blood cells.

Ultrastructural Analysis of Cancer Cells Treated with the Radiopharmaceutical Radium Dichloride ([223Ra]RaCl2): Understanding the Effect on Cell Structure.

The use of alpha-particle (α-particle) radionuclides, especially [223Ra]RaCl2 (radium dichloride), for targeted alpha therapy is steadily increasing. Despite the positive clinical outcomes of this therapy, very little data are available about the effect on the ultrastructure of cells. The purpose of this study was to evaluate the nanomechanical and ultrastructure effect of [223Ra] RaCl2 on cancer cells. To analyze the effect of [223Ra]RaCl2 on tumor cells, human breast cancer cells (lineage MDA-MB-231) were cultured and treated with the radiopharmaceutical at doses of 2 µCi and 0.9 µCi. The effect was evaluated using atomic force microscopy (AFM) and transmission electron microscopy (TEM) combined with Raman spectroscopy. The results showed massive destruction of the cell membrane but preservation of the nucleus membrane. No evidence of DNA alteration was observed. The data demonstrated the formation of lysosomes and phagosomes. These findings help elucidate the main mechanism involved in cell death during α-particle therapy.

Enhanced Antitumor Efficacy of Radium-223 and Enzalutamide in the Intratibial LNCaP Prostate Cancer Model.

Radium-223 dichloride and enzalutamide are indicated for metastatic castration-resistant prostate cancer and their combination is currently being investigated in a large phase 3 clinical trial. Here, we evaluated the antitumor efficacy of radium-223, enzalutamide, and their combination in the intratibial LNCaP model mimicking prostate cancer metastasized to bone. In vitro experiments revealed that the combination of radium-223 and enzalutamide inhibited LNCaP cell proliferation and showed synergistic efficacy. The combination of radium-223 and enzalutamide also demonstrated enhanced in vivo antitumor efficacy, as determined by measuring serum PSA levels in the intratibial LNCaP model. A decreasing trend in the total area of tumor-induced abnormal bone was associated with the combination treatment. The serum levels of the bone formation marker PINP and the bone resorption marker CTX-I were lowest in the combination treatment group and markedly decreased compared with vehicle group. Concurrent administration of enzalutamide did not impair radium-223 uptake in tumor-bearing bone or the ability of radium-223 to inhibit tumor-induced abnormal bone formation. In conclusion, combination treatment with radium-223 and enzalutamide demonstrated enhanced antitumor efficacy without compromising the integrity of healthy bone. The results support the ongoing phase 3 trial of this combination.

Nano-hydroxyapatite radiolabeled with radium dichloride [223Ra] RaCl2 for bone cancer targeted alpha therapy: In vitro assay and radiation effect on the nanostructure.

The use of targeted alpha therapy (TAT) for bone cancer is increasing each year. Among the alpha radionuclides, radium [223Ra]Ra+2 is the first one approved for bone cancer metastasis therapy. The development of novel radiopharmaceutical based on [223Ra]Ra+2 is essential to continuously increase the arsenal of new TAT drugs. In this study we have developed, characterized, and in vitro evaluated [223Ra] Ra-nano-hydroxyapatite. The results showed that [223Ra] Ra-nano-hydroxyapatite has a dose-response relationship for osteosarcoma cells and a safety profile for human fibroblast cells, corroborating the application as a radiopharmaceutical.