Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition ...to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.
In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval CI, 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
Summary Background Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone ...metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov , number NCT00699751. Findings Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months 95% CI 13·5–18·0 vs 9·8 months 7·3–23·7; hazard ratio HR=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding Algeta and Bayer HealthCare Pharmaceuticals.
In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with ...symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment.
To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection.
Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr.
All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics.
During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non–treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up.
Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns.
Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.
Three-year safety follow-up of Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial patients with castration-resistant prostate cancer and symptomatic bone metastases revealed a continued low incidence of myelosuppression, minimal nonhematologic adverse events, and secondary malignancies (none related to treatment) in four radium-223 patients and three placebo patients.
Idiopathic multicentric Castleman disease (iMCD) is characterized by constitutional symptoms, enlarged lymph nodes and laboratory test abnormalities, which are primarily related to the overproduction ...of interleukin-6 (IL-6). This form (iMCD) was treated earlier with cytostatics used for lymphoma, later with bio-logic therapy as rituximab, immunodulatory drugs and proteasome inhibitors, and in the last years with an anti-IL-6 antibody, siltuximab. Siltuximab is a human-mouse chimeric immunoglobulin G1k monoclonal antibody against human IL-6 approved in the European Union for the treatment of iMCD. In view of the limited treatment options for iMCD, this case report aimed to evaluate the efficacy and safety of siltuximab in the management of this condition.
We describe a young woman with iMCD diagnosed at the age of 25 years. For first line treatment, rituximab and dexamethasone were used without any cytostatic because the patient wished to give birth to a healthy child in the future. However, the response after this first line therapy was short. In addition, after 3 years from the start of rituximab + dexamethasone therapy, it was necessary to administer treatment for the relapse of iMCD. We decided for siltuximab in this young woman, still aged < 30 years, and started administration of siltuximab in 3-week intervals.
After administration of first two infusions of siltuximab, all inflammatory markers returned to normal value. Moreover, serum hemoglobin and albumin levels as well as C-reactive protein normalized after the first two administrations of siltuximab. The clinical response continue, siltuximab is still administered in 3-week intervals. PET/CT with fluorodeoxyglucose confirmed a very good anatomic and metabolic response to the treatment. Siltuximab demonstrated a favorable safety profile, and the prolonged treatment was well tolerated.
This result is encouraging and demonstrates the potential of siltuximab as treatment of CD. As earlier published, this case confirms that significantly elevated inflammatory markers in a patient with CD predict a good response to siltuximab.
(166)Ho is a beta-emitter (E(_max) = 1.84 MeV, T1/2 = 26.7 hours) with a mean penetration in the soft tissue of 2.2 mm and gamma-photons 81keV and 1380keV. In this paper, we present our experiences ...with preparation of (166)Ho-macroaggregates ((166)Ho-MA) for radiosynoviorhesis. Ho-MA were prepared by reacting the aqueous solution of holmium nitrate pentahydrate with sodium borohydride solution in 0.2 M NaOH. After centrifugation, washing, and drying at 105 degrees C, final fineness of 1-15 microm was attained using a homogenizer working at 70,000 rpm. Neutron activation was carried out in screwed titanium ampules in a nuclear reactor at the neutron flux 10E12-10E14 neutrons.cm-24.s-1. The irradiated samples were allowed to cool 24 hours before further manipulation. (166)Ho-MA were clinically tested on 20 patients suffering from gonarthrosis (15), rheumatoid arthritis (5), psoriatic arthritis (1), and gout arthropathy (1). (166)Ho-MA are currently produced under GMP and production facility allows producing radioactivity for 6 patients within one production run.
Abstract
Aim: Adherence to prescribed tx is an important factor in determining outcome in advanced CRPC pts, and is often driven by drug tolerability. In ALSYMPCA, the first-in-class α-emitter Ra-223 ...had a highly favorable safety profile and was well tolerated (Parker et al. NEJM 2013). Here we report results from a post hoc analysis identifying factors associated with ALSYMPCA study tx discontinuation to inform pt management and allow the full course of Ra-223 therapy.
Methods: ALSYMPCA pts had progressive, symptomatic CRPC with ≥ 2 bone mets, had no known visceral mets, and had received docetaxel or were unfit for or declined docetaxel. Pts were randomized 2:1 to 6 injections (inj) of Ra-223 (50 kBq/kg IV) q 4 wk or matching placebo (pbo). Pts who did not receive all 6 study inj were considered to have discontinued tx and withdrawn early from the study. A post hoc analysis of these pts was performed.
Results: Of the 921 pts enrolled, 901 were treated (Ra-223, n = 600; pbo, n = 301); 209 (35%) Ra-223 and 157 (52%) pbo pts discontinued tx after inj 1-5. Prior vs no prior docetaxel was associated with a greater percentage of pts discontinuing tx in both groups. Adverse events (AEs) were the primary reason for discontinuing tx across all categories (Table on following page). The most common AE was disease progression (Ra-223, 17%; pbo, 16%). Anemia was a more common reason for discontinuing Ra-223 (15% vs 3%), as was general physical health deterioration (9% vs 2%); bone pain was more common with pbo (11% vs 2%), as was fatigue (8% vs 4%).Pts (n) Discontinuing Treatment After Injections 1-5Pt Group Total Discontinued Reason for Discontinuing TreatmentTotal, n (%) RA N = 600Total, n (%) Pbo N = 301Ra Inj 1Pbo Inj 1Ra Inj 2Pbo Inj 2Ra Inj 3Pbo Inj 3Ra Inj 4Pbo Inj 4Ra Inj 5Pbo Inj 5All pts209 (35)157 (52)18213736483760344629AE92 (44)59 (38)7111412231027162110Death27 (13)28 (18)6453784548Inv Request25 (12)27 (17)1076399755Pt Request40 (19)22 (14)44769483125Other26 (12)21 (13)02496612341Prior Doce132 (22)92 (30)11121721312040203319AE60 (45)37 (40)38661352211167Death12 (9)12 (13)5212441113Inv Request17 (13)18 (20)1055245544Pt Request29 (22)15 (16)21337373105Other14 (11)10 (12)0125545020No Prior Doce77 (13)65 (21)792015171720141310AE32 (42)22 (35)43861055553Death15 (19)16 (25)1241343435Inv Request8 (10)9 (14)0021154211Pt Request11 (14)7 (11)2343211020Other12 (16)11 (17)0124127321
Conclusions: The percentage of pts discontinuing tx before the full course of therapy was smaller with Ra-223 than with pbo, which indicates a positive tx effect and safety profile. Supportive measures to improve the pts' general health and tx of anemia could help achieve the full course of Ra-223 therapy.
Disclosure: O. Sartor: has had a consultant or advisory relationship with and has received research funding from Algeta and Bayer; S. Nilsson: has had a consultant or advisory relationship with Algeta and has received remuneration from Bayer for travel costs and accommodations for study and writing meetings;
R.E. Coleman: has had a consultant or advisory relationship with Bayer, has received honoraria from Bayer and Amgen, and has provided expert testimony for Novartis; N. James: has had a consultant or advisory relationship with Algeta and Bayer; A. Aksnes: is employed by Algeta ASA (Bayer); M. Wahba: is employed by Bayer HealthCare; C. Parker: has had a consultant or advisory relationship with Algeta, Bayer, and BNIT, and has received honoraria from Amgen, Astellas, Bayer, Janssen, Sanofi-Aventis, and Takeda. All other authors have declared no conflicts of interest.
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