The Experts below are selected from a list of 2592 Experts worldwide ranked by ideXlab platform
Sten Nilsson - One of the best experts on this subject based on the ideXlab platform.
-
Alpha-emitter Radium-223 in the management of solid tumors: current status and future directions.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 2020Co-Authors: Sten NilssonAbstract:Bone metastases, which are commonly seen in patients with advanced cancers, are a major cause of skeletal events, disability, and death. Radium-223 dichloride (Radium-223; Xofigo, formerly Alpharadin), a first-in-class, alpha-emitting radiopharmaceutical that selectively targets bone metastases with high-energy short-range alpha-particles, has been approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastases. Approval is based on results of the randomized phase III trial Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA), in which Radium-223 prolonged overall survival and time to first symptomatic skeletal event versus placebo among patients with CRPC with symptomatic bone metastases and was generally well tolerated, with low myelosuppression rates and manageable gastrointestinal adverse events. Long-term follow-up of the ALSYMPCA safety population showed that the incidence of myelosuppression remained low among patients treated with Radium-223, with no additional safety issues of acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, or primary bone cancer within approximately 1.5 years after treatment. The Radium-223 overall survival benefit and low toxicity make it an effective, well-tolerated, and novel treatment option for CRPC and symptomatic bone metastases and opens the possibility of exploring Radium-223 in the treatment of bone metastases from other cancers. A phase I clinical trial of patients with breast and prostate cancer with skeletal metastases demonstrated that Radium-223 was safe and well tolerated at all therapeutically relevant dosages. Moreover, a phase IIa trial of patients with advanced breast cancer and progressive bone-dominant disease demonstrated that Radium-223 targeted areas of increased bone metabolism and showed biologic activity.
-
Alpha-emitter Radium-223 in the management of solid tumors: current status and future directions.
2020Co-Authors: Sten NilssonAbstract:Bone metastases, which are commonly seen in patients with advanced cancers, are a major cause of skeletal events, disability, and death. Radium-223 dichloride (Radium-223; Xofigo, formerly Alpharad...
-
Disease Characteristics and Completion of Treatment in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Radium-223 in an International Early Access Program
Clinical Genitourinary Cancer, 2019Co-Authors: Fred Saad, Sten Nilsson, Silke Gillessen, Joe M. O'sullivan, Daniel Heinrich, Daniel Keizman, Kurt Miller, Manfred P. Wirth, John Reeves, Monica SegerAbstract:Abstract Background Radium-223 is approved by the US Food and Drug Administration and European Medicines Agency for the treatment of metastatic castration-resistant prostate cancer (mCRPC). There are currently no markers for selecting patients most likely to complete Radium-223 treatment. Patients and Methods In this phase IIIb, international, single-arm study, patients received Radium-223, 55 kBq/kg, every 4 weeks for ≤6 cycles. Primary end points were safety and overall survival. In post hoc analyses patients were grouped according to number of Radium-223 injections received (1-4 or 5-6). Associations between baseline covariates and number of injections were investigated. Results Of 696 eligible patients, 473 (68%) had received 5 to 6 Radium-223 injections and 223 (32%) 1 to 4 injections. Patients with less pain (moderate-severe vs. none-mild, odds ratio [OR], 0.41; P 141 μg/L vs. ≤141 μg/L, OR, 0.40; P Conclusion Patients with less advanced mCRPC are more likely to receive 5 to 6 Radium-223 injections and to achieve better overall survival. Consideration of baseline and disease characteristics is recommended before initiation of Radium-223 treatment.
-
Current approaches to incorporation of Radium-223 in clinical practice
Prostate Cancer and Prostatic Diseases, 2018Co-Authors: Chris Parker, Sten Nilsson, Axel Heidenreich, Neal ShoreAbstract:Background Treatment options for metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years and include cytotoxic agents (e.g., docetaxel and cabazitaxel), immunotherapy (e.g., sipuleucel-T), oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), and targeted alpha therapy (e.g., Radium-223 dichloride (Radium-223)). Although treatment guidelines have been updated to reflect the availability of new agents, it is not easy to apply them in daily clinical practice because recommendations vary depending on patient comorbidities and disease characteristics. Furthermore, therapeutic accessibility, clinical judgment, and experience affect the selection of treatment options. Methods In this review, we provide practical guidance for the integration of Radium-223 into the management of patients with mCRPC based on our collective clinical experience, as well as the available clinical trial data. Results Radium-223 is a targeted alpha therapy; as a bone-seeking calcium mimetic, it accumulates in hydroxyapatite areas surrounding tumor lesions and selectively binds to the areas of increased bone turnover. Radium-223 prolongs overall survival and delays time to the first symptomatic skeletal events in men with mCRPC, and is indicated for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastases. We review its clinical efficacy and safety, practical guidance on identifying the appropriate patient, and recommendations for how best to educate and inform prospective patients regarding their treatment decision making. In addition, we review recent evidence for sequential and combination therapies with Radium-223, provide our experiences with these treatment approaches, and discuss their implications for the future treatment of patients with mCRPC. Conclusions Based on our clinical experience, Radium-223 should be considered relatively early in the treatment course in patients with mCRPC with bone metastases. Coordination of care among multidisciplinary team members, patients, and caregivers is essential for optimizing safe and effective treatment with all CRPC therapies.
-
Current approaches to incorporation of Radium-223 in clinical practice.
Prostate Cancer and Prostatic Diseases, 2018Co-Authors: Chris Parker, Sten Nilsson, Axel Heidenreich, Neal D. ShoreAbstract:Treatment options for metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years and include cytotoxic agents (e.g., docetaxel and cabazitaxel), immunotherapy (e.g., sipuleucel-T), oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), and targeted alpha therapy (e.g., Radium-223 dichloride (Radium-223)). Although treatment guidelines have been updated to reflect the availability of new agents, it is not easy to apply them in daily clinical practice because recommendations vary depending on patient comorbidities and disease characteristics. Furthermore, therapeutic accessibility, clinical judgment, and experience affect the selection of treatment options. In this review, we provide practical guidance for the integration of Radium-223 into the management of patients with mCRPC based on our collective clinical experience, as well as the available clinical trial data. Radium-223 is a targeted alpha therapy; as a bone-seeking calcium mimetic, it accumulates in hydroxyapatite areas surrounding tumor lesions and selectively binds to the areas of increased bone turnover. Radium-223 prolongs overall survival and delays time to the first symptomatic skeletal events in men with mCRPC, and is indicated for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastases. We review its clinical efficacy and safety, practical guidance on identifying the appropriate patient, and recommendations for how best to educate and inform prospective patients regarding their treatment decision making. In addition, we review recent evidence for sequential and combination therapies with Radium-223, provide our experiences with these treatment approaches, and discuss their implications for the future treatment of patients with mCRPC. Based on our clinical experience, Radium-223 should be considered relatively early in the treatment course in patients with mCRPC with bone metastases. Coordination of care among multidisciplinary team members, patients, and caregivers is essential for optimizing safe and effective treatment with all CRPC therapies.
Oliver Sartor - One of the best experts on this subject based on the ideXlab platform.
-
Radium‐223 Safety, Efficacy, and Concurrent Use with Abiraterone or Enzalutamide: First U.S. Experience from an Expanded Access Program
Oncologist, 2017Co-Authors: Oliver Sartor, Nicholas J. Vogelzang, Christopher Sweeney, Daniel Celestino Fernandez, Fabio Almeida, Andrei Iagaru, Alan Brown, Matthew R. Smith, Manish Agrawal, Adam P. DickerAbstract:BACKGROUND: In the phase III ALSYMPCA trial, metastatic castration-resistant prostate cancer (mCRPC) patients had few prior life-prolonging therapies. Following ALSYMPCA, which demonstrated Radium-223 survival benefit, and before Radium-223 U.S. commercial availability, an expanded access program (EAP) providing early-access Radium-223 allowed life-prolonging therapies in current use. SUBJECTS, MATERIALS, AND METHODS: This phase II, open-label, single-arm, multicenter U.S. EAP (NCT01516762) enrolled patients with symptomatic mCRPC, ≥2 bone metastases, and no lung, liver, or brain metastases. Patients received Radium-223 55 kBq/kg intravenously every 4 weeks × 6. Primary outcomes were acute and long-term safety. Additional analyses were done by number of Radium-223 injections, and prior or concomitant abiraterone or enzalutamide use. RESULTS: Of 252 patients, 184 received Radium-223: 165/184 (90%) had Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 183 (99%) had prior systemic anticancer therapy. Treatment-related adverse events occurred in 93/184 (51%) patients during treatment and 11 (6%) during follow-up. Median overall survival was 17 months, with 134/184 (73%) patients censored because of short follow-up due to Radium-223 approval. In post hoc analyses, patients with ≥3 prior anticancer medications, baseline ECOG performance status ≥2, and lower baseline hemoglobin were less likely to receive 5-6 Radium-223 injections and unlikely to benefit from Radium-223. Radium-223 was well tolerated regardless of concurrent or prior abiraterone or enzalutamide. CONCLUSION: Radium-223 was well tolerated, with no new safety concerns; safety was maintained with abiraterone or enzalutamide. Patients with more advanced disease were less likely to benefit from Radium-223. Clinicians should consider baseline characteristics and therapy sequence for greatest clinical value. IMPLICATIONS FOR PRACTICE: In this phase II U.S. expanded access program, Radium-223 was well tolerated, with a median overall survival of 17 months in metastatic castration-resistant prostate cancer patients. In post hoc analyses, Radium-223 was safe regardless of concurrent abiraterone or enzalutamide, and median overall survival appeared longer when Radium-223 was used earlier in patients with less prior treatment. Patients with more advanced disease were less likely to benefit from Radium-223. Clinicians should consider baseline clinical characteristics and therapy sequence to provide the greatest clinical value to patients.
-
An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with Radium-223.
Annals of Oncology, 2017Co-Authors: Oliver Sartor, Nicholas J. Vogelzang, Robert E. Coleman, Sten Nilsson, Joe M. O'sullivan, Daniel Heinrich, Svein Inge Helle, Oø Bruland, S. Kobina, Scott WilhelmAbstract:Background Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as Radium-223, is not established. Patients and methods The Radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy. Results Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (Radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning Radium-223, by week 12 declining in 87% of Radium-223 and 23% of placebo patients (P Conclusions Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning Radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during Radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.
-
Radium-223 Use in Clinical Practice and Variables Associated With Completion of Therapy.
Clinical Genitourinary Cancer, 2016Co-Authors: Rana R. Mckay, Oliver Sartor, Susanna Jacobus, Matthew Fiorillo, Elisa Ledet, Patrick M. Cotogna, Allie E. Steinberger, Heather A. Jacene, Mary-ellen TaplinAbstract:Abstract Background Radium-223 has shown clinical efficacy in metastatic castration-resistant prostate cancer. Despite improvement in quality of life and survival, practice patterns and utility of this agent outside the context of clinical trials have not been fully characterized. The primary objective in this study was to evaluate variables associated with completion of 5 to 6 Radium-223 doses. Patients and Methods We conducted retrospective analyses of patients who received Radium-223 (n = 135). Patients were classified into 3 cohorts: 1 to 2, 3 to 4, or 5 to 6 Radium-223 doses. We evaluated the association of clinical and laboratory variables with the number of cycles administered (5-6 vs. 1-4 doses). Results Twenty-five patients (18.5%) received 1 to 2 Radium-223 doses, 27 (20.0%) received 3 to 4, and 83 (61.5%) received 5 to 6. The most common reasons for treatment discontinuation included disease progression (61.5%, n = 40), patient preference (15.4%, n = 10), and toxicity (10.8%, n = 7). Factors associated with therapy completion in univariate analysis included previous sipuleucel-T treatment ( P = .068), no previous abiraterone or enzalutamide treatment ( P = .007), hemoglobin ≥ lower limit of normal (LLN; P = .006), white blood cell count ≥ LLN ( P = .045), absolute neutrophil count (ANC) ≥ LLN ( P = .049), lower alkaline phosphatase ( P = .029), and lower lactate dehydrogenase levels ( P = .014). Factors associated with therapy completion in multivariable analysis included previous sipuleucel-T treatment ( P = .009), hemoglobin ≥ LLN ( P = .037), and ANC ≥ LLN ( P = .029). Conclusion Several clinical parameters are associated with Radium-223 therapy completion. In general, these parameters reflect earlier disease stage. These data are hypothesis-generating and prospective testing of the optimal number of Radium-223 doses is warranted.
-
Chemotherapy following Radium-223 dichloride treatment in ALSYMPCA
The Prostate, 2016Co-Authors: Oliver Sartor, Nicholas J. Vogelzang, Peter Hoskin, Robert E. Coleman, Sten Nilsson, Oana Petrenciuc, K. Staudacher, Marcus Thuresson, Chris ParkerAbstract:BACKGROUND. Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following Radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after Radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following Radium-223. METHODS. In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2: 1 to receive six injections of Radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed. RESULTS. Overall, 142 Radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% Radium-223, 72% placebo) and mitoxantrone (16% Radium-223, 20% placebo). The majority of patients (61% Radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In Radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3-4 hematologic values (
-
Patient-reported quality-of-life analysis of Radium-223 dichloride from the phase III ALSYMPCA study
Annals of Oncology, 2016Co-Authors: Sten Nilsson, Nicholas J. Vogelzang, Oliver Sartor, Robert E. Coleman, Joe M. O'sullivan, Paul Cislo, Jonathan Reuning-scherer, M. Shan, L. Zhan, Chris ParkerAbstract:Background Radium-223 dichloride (Radium-223), a first-in-class α-emitting radiopharmaceutical, is recommended in both pre- and post-docetaxel settings in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases based on overall survival benefit demonstrated in the phase III ALSYMPCA study. ALSYMPCA included prospective measurements of health-related quality of life (QOL) using two validated instruments: the general EuroQoL 5D (EQ-5D) and the disease-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P).
Arturo Chiti - One of the best experts on this subject based on the ideXlab platform.
-
Morphometric vertebral fractures in patients with castration-resistant prostate cancer undergoing treatment with Radium-223: a longitudinal study in the real-life clinical practice
Endocrine, 2020Co-Authors: Gherardo Mazziotti, Marcello Rodari, Fabrizia Gelardi, Giovanni Tosi, Paolo A. Zucali, Giovanna Pepe, Arturo ChitiAbstract:Purpose Radium-223 was associated with high incidence of non-vertebral fractures in patients with castration-resistant prostate cancer (CRPC). However, it is still unclear whether Radium-223 may induce skeletal fragility regardless of other therapies for CRPC. We aimed at evaluating the prevalence, incidence, and determinants of vertebral fractures (VFs), i.e., the most frequent complication of skeletal fragility, in CRCP patients undergoing Radium-223 therapy in the real-life clinical practice. Methods We retrospectively reviewed 49 CRPC patients with symptomatic bone metastases treated with Radium-223. Patients received median number of four Radium-223 doses (range: 2–6) and were followed-up for a median period of 11 months (range: 6–44). VFs were assessed by a quantitative morphometry using lateral images of spine 11C-Choline PET/CT, excluding from the analysis the vertebral bodies affected by bone metastases. Results Before Radium-223 administration, 24 patients (49%) had VFs significantly associated with duration of androgen deprivation therapy (ADT; odds ratio 1.29) and previous abiraterone therapy (odds ratio 3.80). During Radium-223 therapy, incident VFs occurred in 25% of patients, in relationship with prevalent VFs (hazard ratio 6.89) and change in serum total alkaline phosphatase values (hazard ratio 0.97), whereas the correlations with ADT and abiraterone therapy were lost. Noteworthy, the risk of VFs did not correlate with the therapeutic end points of Radium-223. Conclusions This study provides a first evidence that in real-life clinical practice, Radium-223 therapy may induce skeletal fragility with high risk of VFs, likely by inhibition of bone formation and independently of ADT and abiraterone therapy.
-
Morphometric vertebral fractures in patients with castration-resistant prostate cancer undergoing treatment with Radium-223: a longitudinal study in the real-life clinical practice
Endocrine, 2020Co-Authors: Gherardo Mazziotti, Marcello Rodari, Fabrizia Gelardi, Giovanni Tosi, Paolo A. Zucali, Giovanna Pepe, Arturo ChitiAbstract:PURPOSE: Radium-223 was associated with high incidence of non-vertebral fractures in patients with castration-resistant prostate cancer (CRPC). However, it is still unclear whether Radium-223 may induce skeletal fragility regardless of other therapies for CRPC. We aimed at evaluating the prevalence, incidence, and determinants of vertebral fractures (VFs), i.e., the most frequent complication of skeletal fragility, in CRCP patients undergoing Radium-223 therapy in the real-life clinical practice. METHODS: We retrospectively reviewed 49 CRPC patients with symptomatic bone metastases treated with Radium-223. Patients received median number of four Radium-223 doses (range: 2-6) and were followed-up for a median period of 11 months (range: 6-44). VFs were assessed by a quantitative morphometry using lateral images of spine 11C-Choline PET/CT, excluding from the analysis the vertebral bodies affected by bone metastases. RESULTS: Before Radium-223 administration, 24 patients (49%) had VFs significantly associated with duration of androgen deprivation therapy (ADT; odds ratio 1.29) and previous abiraterone therapy (odds ratio 3.80). During Radium-223 therapy, incident VFs occurred in 25% of patients, in relationship with prevalent VFs (hazard ratio 6.89) and change in serum total alkaline phosphatase values (hazard ratio 0.97), whereas the correlations with ADT and abiraterone therapy were lost. Noteworthy, the risk of VFs did not correlate with the therapeutic end points of Radium-223. CONCLUSIONS: This study provides a first evidence that in real-life clinical practice, Radium-223 therapy may induce skeletal fragility with high risk of VFs, likely by inhibition of bone formation and independently of ADT and abiraterone therapy.
Chris Parker - One of the best experts on this subject based on the ideXlab platform.
-
Current approaches to incorporation of Radium-223 in clinical practice
Prostate Cancer and Prostatic Diseases, 2018Co-Authors: Chris Parker, Sten Nilsson, Axel Heidenreich, Neal ShoreAbstract:Background Treatment options for metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years and include cytotoxic agents (e.g., docetaxel and cabazitaxel), immunotherapy (e.g., sipuleucel-T), oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), and targeted alpha therapy (e.g., Radium-223 dichloride (Radium-223)). Although treatment guidelines have been updated to reflect the availability of new agents, it is not easy to apply them in daily clinical practice because recommendations vary depending on patient comorbidities and disease characteristics. Furthermore, therapeutic accessibility, clinical judgment, and experience affect the selection of treatment options. Methods In this review, we provide practical guidance for the integration of Radium-223 into the management of patients with mCRPC based on our collective clinical experience, as well as the available clinical trial data. Results Radium-223 is a targeted alpha therapy; as a bone-seeking calcium mimetic, it accumulates in hydroxyapatite areas surrounding tumor lesions and selectively binds to the areas of increased bone turnover. Radium-223 prolongs overall survival and delays time to the first symptomatic skeletal events in men with mCRPC, and is indicated for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastases. We review its clinical efficacy and safety, practical guidance on identifying the appropriate patient, and recommendations for how best to educate and inform prospective patients regarding their treatment decision making. In addition, we review recent evidence for sequential and combination therapies with Radium-223, provide our experiences with these treatment approaches, and discuss their implications for the future treatment of patients with mCRPC. Conclusions Based on our clinical experience, Radium-223 should be considered relatively early in the treatment course in patients with mCRPC with bone metastases. Coordination of care among multidisciplinary team members, patients, and caregivers is essential for optimizing safe and effective treatment with all CRPC therapies.
-
Current approaches to incorporation of Radium-223 in clinical practice.
Prostate Cancer and Prostatic Diseases, 2018Co-Authors: Chris Parker, Sten Nilsson, Axel Heidenreich, Neal D. ShoreAbstract:Treatment options for metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years and include cytotoxic agents (e.g., docetaxel and cabazitaxel), immunotherapy (e.g., sipuleucel-T), oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), and targeted alpha therapy (e.g., Radium-223 dichloride (Radium-223)). Although treatment guidelines have been updated to reflect the availability of new agents, it is not easy to apply them in daily clinical practice because recommendations vary depending on patient comorbidities and disease characteristics. Furthermore, therapeutic accessibility, clinical judgment, and experience affect the selection of treatment options. In this review, we provide practical guidance for the integration of Radium-223 into the management of patients with mCRPC based on our collective clinical experience, as well as the available clinical trial data. Radium-223 is a targeted alpha therapy; as a bone-seeking calcium mimetic, it accumulates in hydroxyapatite areas surrounding tumor lesions and selectively binds to the areas of increased bone turnover. Radium-223 prolongs overall survival and delays time to the first symptomatic skeletal events in men with mCRPC, and is indicated for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastases. We review its clinical efficacy and safety, practical guidance on identifying the appropriate patient, and recommendations for how best to educate and inform prospective patients regarding their treatment decision making. In addition, we review recent evidence for sequential and combination therapies with Radium-223, provide our experiences with these treatment approaches, and discuss their implications for the future treatment of patients with mCRPC. Based on our clinical experience, Radium-223 should be considered relatively early in the treatment course in patients with mCRPC with bone metastases. Coordination of care among multidisciplinary team members, patients, and caregivers is essential for optimizing safe and effective treatment with all CRPC therapies.
-
The safety and efficacy of Radium-223 dichloride for the treatment of advanced prostate cancer.
Expert Review of Anticancer Therapy, 2016Co-Authors: James M. Wilson, Chris ParkerAbstract:ABSTRACTIntroduction: A number of drugs have been shown to extend life expectancy in castration-resistant prostate cancer (CRPC). Skeletal related events (SREs) secondary to bone metastases cause significant morbidity for men with CRPC. The α-emitting radiopharmaceutical Radium-223 dichloride has been shown to improve overall survival, time to symptomatic skeletal events (SSEs) and quality of life in CRPC.Areas covered: The development of Radium-223 from pre-clinical studies to the evidence of efficacy and safety from a phase 3 trial is discussed as well as its pharmacokinetics and metabolism. The integration of Radium-223 into routine care for patients with advanced prostate cancer is included including a comparison with other agents in this setting.Expert commentary: The risk/benefit ratio for Radium-223 is very similar to that of other agents used in the CRPC setting and is a treatment option for men unsuitable for cytotoxic chemotherapy because of comorbidities. The ALSYMPCA trial demonstrated an impr...
-
Hematologic Safety of Radium-223 Dichloride: Baseline Prognostic Factors Associated With Myelosuppression in the ALSYMPCA Trial
Clinical Genitourinary Cancer, 2016Co-Authors: Nicholas J. Vogelzang, Robert E. Coleman, Sten Nilsson, Marcus Thuresson, Chris Parker, Jeff M. Michalski, Joe M. O'sullivan, Anders Widmark, Lei Xu, Joseph GerminoAbstract:BACKGROUND: Myelosuppression is common in patients with progressive castration-resistant prostate cancer and bone metastases. Radium-223 prolongs overall survival in these patients but may cause myelosuppression; understanding risk factors will improve clinical decision making. We describe hematologic safety of Radium-223 in ALSYMPCA and post hoc analyses identifying patients at increased risk for hematologic toxicity. PATIENTS AND METHODS: Hematologic parameters and adverse events were analyzed. Multivariate analyses assessing baseline risk factors for hematologic toxicities were performed separately for Radium-223 and placebo patients. RESULTS: Nine hundred one patients received Radium-223 (n = 600) or placebo (n = 301); 65% of Radium-223 and 48% of placebo patients had the full 6 cycles. Grade 3/4 thrombocytopenia was more common in Radium-223 versus placebo patients (6% vs. 2%). Logistic regression analyses identified significant baseline predictors for grade 2-4 hematologic toxicities related to Radium-223 treatment: extent of disease (6-20 vs. < 6 bone metastases; odds ratio [OR] = 2.76; P = .022) and elevated prostate-specific antigen (OR = 1.65; P = .006) for anemia; prior docetaxel (OR = 2.16; P = .035), decreased hemoglobin (OR = 1.35; P = .008), and decreased platelets (OR = 1.44; P = .030) for thrombocytopenia. Neutropenia events were too few in placebo patients for a comparative analysis. There were no significant associations between hematologic toxicities and number of Radium-223 injections received (4-6 vs. 1-3). CONCLUSION: Radium-223 has a favorable safety profile with a low myelosuppression incidence. Understanding baseline factors associated with myelosuppression may assist clinicians in avoiding severe myelosuppression events with Radium-223.
-
Chemotherapy following Radium-223 dichloride treatment in ALSYMPCA
The Prostate, 2016Co-Authors: Oliver Sartor, Nicholas J. Vogelzang, Peter Hoskin, Robert E. Coleman, Sten Nilsson, Oana Petrenciuc, K. Staudacher, Marcus Thuresson, Chris ParkerAbstract:BACKGROUND. Radium-223 prolongs overall survival in patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, regardless of prior docetaxel. Whether or not chemotherapy can be safely administered following Radium-223 treatment is of clinical importance. An exploratory analysis of prospectively collected data, from the ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) patient subgroup who received chemotherapy after Radium-223 or placebo treatment, was conducted to evaluate the safety and efficacy of chemotherapy following Radium-223. METHODS. In ALSYMPCA, CRPC patients with symptomatic bone metastases and no visceral metastases were randomized 2: 1 to receive six injections of Radium-223 (50 kBq/kg IV) or placebo plus best standard of care, stratified by prior docetaxel, baseline alkaline phosphatase, and current bisphosphonate use. In this exploratory analysis, chemotherapy agents administered following study treatment were identified; timing and duration were calculated. Hematologic safety was reviewed, and overall survival analyzed. RESULTS. Overall, 142 Radium-223 and 64 placebo patients received subsequent chemotherapy; most common were docetaxel (70% Radium-223, 72% placebo) and mitoxantrone (16% Radium-223, 20% placebo). The majority of patients (61% Radium-223, 58% placebo) had received prior docetaxel. Radium-223 patients started subsequent chemotherapy later than placebo patients; chemotherapy duration was similar between groups. In Radium-223 and placebo patients receiving subsequent chemotherapy, median hematologic values (hemoglobin, neutrophils, and platelets) remained nearly constant up to 18 months following start of chemotherapy, regardless of prior docetaxel treatment. A low percentage of patients in both groups had grades 3-4 hematologic values (
Nicholas J. Vogelzang - One of the best experts on this subject based on the ideXlab platform.
-
Radium‐223 Safety, Efficacy, and Concurrent Use with Abiraterone or Enzalutamide: First U.S. Experience from an Expanded Access Program
Oncologist, 2017Co-Authors: Oliver Sartor, Nicholas J. Vogelzang, Christopher Sweeney, Daniel Celestino Fernandez, Fabio Almeida, Andrei Iagaru, Alan Brown, Matthew R. Smith, Manish Agrawal, Adam P. DickerAbstract:BACKGROUND: In the phase III ALSYMPCA trial, metastatic castration-resistant prostate cancer (mCRPC) patients had few prior life-prolonging therapies. Following ALSYMPCA, which demonstrated Radium-223 survival benefit, and before Radium-223 U.S. commercial availability, an expanded access program (EAP) providing early-access Radium-223 allowed life-prolonging therapies in current use. SUBJECTS, MATERIALS, AND METHODS: This phase II, open-label, single-arm, multicenter U.S. EAP (NCT01516762) enrolled patients with symptomatic mCRPC, ≥2 bone metastases, and no lung, liver, or brain metastases. Patients received Radium-223 55 kBq/kg intravenously every 4 weeks × 6. Primary outcomes were acute and long-term safety. Additional analyses were done by number of Radium-223 injections, and prior or concomitant abiraterone or enzalutamide use. RESULTS: Of 252 patients, 184 received Radium-223: 165/184 (90%) had Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 183 (99%) had prior systemic anticancer therapy. Treatment-related adverse events occurred in 93/184 (51%) patients during treatment and 11 (6%) during follow-up. Median overall survival was 17 months, with 134/184 (73%) patients censored because of short follow-up due to Radium-223 approval. In post hoc analyses, patients with ≥3 prior anticancer medications, baseline ECOG performance status ≥2, and lower baseline hemoglobin were less likely to receive 5-6 Radium-223 injections and unlikely to benefit from Radium-223. Radium-223 was well tolerated regardless of concurrent or prior abiraterone or enzalutamide. CONCLUSION: Radium-223 was well tolerated, with no new safety concerns; safety was maintained with abiraterone or enzalutamide. Patients with more advanced disease were less likely to benefit from Radium-223. Clinicians should consider baseline characteristics and therapy sequence for greatest clinical value. IMPLICATIONS FOR PRACTICE: In this phase II U.S. expanded access program, Radium-223 was well tolerated, with a median overall survival of 17 months in metastatic castration-resistant prostate cancer patients. In post hoc analyses, Radium-223 was safe regardless of concurrent abiraterone or enzalutamide, and median overall survival appeared longer when Radium-223 was used earlier in patients with less prior treatment. Patients with more advanced disease were less likely to benefit from Radium-223. Clinicians should consider baseline clinical characteristics and therapy sequence to provide the greatest clinical value to patients.
-
Optimal usage of Radium-223 in metastatic castration-resistant prostate cancer.
Journal of the Formosan Medical Association, 2017Co-Authors: Tony T. Wu, Nicholas J. Vogelzang, Chao-yuan Huang, Shu-pin Huang, Yen-chuan Ou, See-tong Pang, Daniel Heung-yuan Shen, Wen-jeng WuAbstract:Abstract Radium-223 is a first-in-class α-emitting radiopharmaceutical that targets bone metastases associated with metastatic castration-resistant prostate cancer (mCRPC). In the pivotal phase III trial ALSYMPCA, Radium-223 significantly increased overall survival (OS), compared with placebo (median 14.9 vs 11.3 months; hazard ratio 0.70; 95% CI 0.58–0.83; p To optimize treatment outcomes, selection of appropriate patients is important. As well as osteoblastic bone metastases, mCRPC patients should be well enough to receive six doses of Radium-223 as this treatment duration has been shown to greatly improve OS outcomes compared with administration of four or fewer doses. Additionally, alkaline phosphatase and lactate dehydrogenase are emerging as important biomarkers during Radium-223 treatment. Optimal concomitant standard-of-care therapies (such as abiraterone or enzalutamide) to be administered with Radium-223 have yet to be defined as does the most efficacious dose and duration of Radium-223 treatment. In conclusion, Radium-223 is an important addition to the mCRPC treatment landscape and marks a paradigm shift in the treatment of bone metastases.
-
Radium-223 dichloride for the treatment of castration-resistant prostate cancer with symptomatic bone metastases.
Expert Review of Clinical Pharmacology, 2017Co-Authors: Nicholas J. VogelzangAbstract:ABSTRACTIntroduction: Castration-resistant prostate cancer (CRPC) is associated with the development of bone metastases, increased mortality, and a reduction in the patient’s quality of life (QOL). The management of metastatic CRPC (mCRPC) has rapidly evolved over the past decade, with a number of available therapeutic agents improving overall survival. Radium-223 dichloride (Radium-223), the first targeted alpha therapy, improves survival accompanied by QOL benefits with a favorable safety profile. It is approved in over 40 countries for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease.Areas covered: The current management of CRPC in men with bone metastases, and in particular the role of Radium-223 in this setting, is reviewed and discussed. A search of bibliographic databases for peer-reviewed literature and major meetings was conducted.Expert commentary: In treating patients with mCRPC, the best sequencing and/or combination of Radium-223 wi...
-
An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with Radium-223.
Annals of Oncology, 2017Co-Authors: Oliver Sartor, Nicholas J. Vogelzang, Robert E. Coleman, Sten Nilsson, Joe M. O'sullivan, Daniel Heinrich, Svein Inge Helle, Oø Bruland, S. Kobina, Scott WilhelmAbstract:Background Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as Radium-223, is not established. Patients and methods The Radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy. Results Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (Radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning Radium-223, by week 12 declining in 87% of Radium-223 and 23% of placebo patients (P Conclusions Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning Radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during Radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.
-
Hematologic Safety of Radium-223 Dichloride: Baseline Prognostic Factors Associated With Myelosuppression in the ALSYMPCA Trial
Clinical Genitourinary Cancer, 2016Co-Authors: Nicholas J. Vogelzang, Robert E. Coleman, Sten Nilsson, Marcus Thuresson, Chris Parker, Jeff M. Michalski, Joe M. O'sullivan, Anders Widmark, Lei Xu, Joseph GerminoAbstract:BACKGROUND: Myelosuppression is common in patients with progressive castration-resistant prostate cancer and bone metastases. Radium-223 prolongs overall survival in these patients but may cause myelosuppression; understanding risk factors will improve clinical decision making. We describe hematologic safety of Radium-223 in ALSYMPCA and post hoc analyses identifying patients at increased risk for hematologic toxicity. PATIENTS AND METHODS: Hematologic parameters and adverse events were analyzed. Multivariate analyses assessing baseline risk factors for hematologic toxicities were performed separately for Radium-223 and placebo patients. RESULTS: Nine hundred one patients received Radium-223 (n = 600) or placebo (n = 301); 65% of Radium-223 and 48% of placebo patients had the full 6 cycles. Grade 3/4 thrombocytopenia was more common in Radium-223 versus placebo patients (6% vs. 2%). Logistic regression analyses identified significant baseline predictors for grade 2-4 hematologic toxicities related to Radium-223 treatment: extent of disease (6-20 vs. < 6 bone metastases; odds ratio [OR] = 2.76; P = .022) and elevated prostate-specific antigen (OR = 1.65; P = .006) for anemia; prior docetaxel (OR = 2.16; P = .035), decreased hemoglobin (OR = 1.35; P = .008), and decreased platelets (OR = 1.44; P = .030) for thrombocytopenia. Neutropenia events were too few in placebo patients for a comparative analysis. There were no significant associations between hematologic toxicities and number of Radium-223 injections received (4-6 vs. 1-3). CONCLUSION: Radium-223 has a favorable safety profile with a low myelosuppression incidence. Understanding baseline factors associated with myelosuppression may assist clinicians in avoiding severe myelosuppression events with Radium-223.