Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

Sartor, Oliver; Coleman, Robert E.; Nilsson, Sten; Heinrich, Daniel; Helle, Svein Inge; O’Sullivan, Joe M.; Fosså, Sophie D.; Chodacki, Aleš; Wiechno, Paweł; Logue, John P; Widmark, Anders; Johannessen, Dag Clement; Hoskin, Peter; James, Nicholas D.; Solberg, Arne; Syndikus, Isabel; Vogelzang, Nicholas J.; O'Bryan-Tear, C. Gillies; Shan, Minghua; Bruland, Øyvind S.; Parker, Christopher

doi:10.1016/s1470-2045(14)70183-4

Cited by 450 publications

(333 citation statements)

References 18 publications

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“…In addition, the use of administrative claims data for the identification and enumeration of SREs required several subjective decisions. Although our (28) 197 (22) 239 (27) . 1 291 (15) 144 (11) 57 (6) 79 (9) a 899 matched pairs; SRE-free patients sampled with replacement.…”

Section: Discussionmentioning

confidence: 99%

The Clinical and Economic Impacts of Skeletal-Related Events Among Medicare Enrollees With Prostate Cancer Metastatic to Bone

et al. 2016

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Background. Approximately 40% of men diagnosed with metastatic prostate cancer experience one or more skeletalrelated events (SREs), defined as a pathological fracture, spinal cord compression, or surgery or radiotherapy to the bone. Accurate assessment of their effect on survival, health care resource utilization (HCRU), and cost may elucidate the value of interventions to prevent SREs. Materials and Methods. Men older than age 65 years with prostate cancer and bone metastasis diagnosed between 2004 and 2009 were identified from linked Surveillance Epidemiology and End Results-Medicare records. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk for death associated with SREs were calculated by using Cox regression. HCRU and costs (in 2013 U.S. dollars) were evaluated in a propensity score-matched cohort by using Poisson regression and Kaplan-Meier sample average estimators, respectively.Results. Among 3,297 men with prostate cancer metastatic to bone, 40% experienced $1 SRE (median follow-up, 19 months). Compared with men who remained SRE-free, men with $1 SRE had a twofold higher risk for death (HR, 2.29; 95% CI, 2.09-2.51). Pathological fracture was associated with the highest risk for death (HR, 2.77; 95% CI, 2.38-3.23). Among men with $1 SRE, emergency department visits were twice as frequent (95% CI, 1.77-2.28) and hospitalizations were nearly four times as Conclusion. Among men with prostate cancer metastatic to bone, experiencing $1 SRE is associated with poorer survival, increased HCRU, and increased costs. These negative effects emphasize the importance of SRE prevention in this population. The Oncologist 2016;21:320-326Implications for Practice: This study confirms the substantial adverse clinical and economic effects of skeletal-related events (SREs) in men with prostate cancer. Compared with men who have prostate cancer metastatic to the bones and no SREs, men with prostate cancer metastatic to the bones experiencing $1 SRE had a twofold increase in the risk for death, a twofold increase in the number of emergency department visits, and a fourfold increase in the number of hospitalizations; they also incurred an additional $21,000 in direct medical costs attributed to SREs. Strategies to prevent SREs are potentially of high value in this patient population.

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Section: Discussionmentioning

confidence: 99%

The Clinical and Economic Impacts of Skeletal-Related Events Among Medicare Enrollees With Prostate Cancer Metastatic to Bone

et al. 2016

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“…2,3 The clinical observations that bone metastases from solid tumors from infancy to adulthood concord with the centripetal migration of hematopoiesis with aging suggest that bone metastases require subversion of the haematopoietic niche. Although endosteal, perivascular and other locations of the haematopoietic niche continue to be assessed, 4 mesenchymal stromal cells and their osteoblastic derivatives have been previously implicated as architects of the haematopoietic niche.…”

Section: Introductionmentioning

confidence: 99%

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

Joshi

Goihberg

Ren

et al. 2016

Cell Adhesion & Migration

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The haematopoietic niche is contributed to by bone marrow-resident mesenchymal stromal cells (BM-MSCs) and subverted by prostate cancer cells. To study mechanisms by which BM-MSCs and prostate cancer cells may interact, we assessed the migration, invasion, adhesion and proliferation of bone-derived prostate cancer cells (PC-3) in co-culture with pluripotent human BM-MSCs. We observed a strong adhesive, migratory and invasive phenotype of PC-3 cells with BM-MSC-coculture and set out to isolate and characterize the bioactive principle. Initial studies indicated that chemotaxis was secondary to a protein residing in the >100kDa fraction. Size-exclusion chromatography (SEC) recovered peak activity in a high-molecular weight fraction containing thrombospondin-1 (TSP1). While TSP1 immunodepletion decreased activity, put-back with purified TSP1 did not reproduce bioactivity. Further purification of the TSP1-containing high-molecular weight fraction of the BM-MSC secretome with heparin-affinity chromatography recovered bioactivity with highly restricted bands on polyacrylamide gel electrophoresis, determined by mass spectroscopy to be proteolytic fragments of fibronectin (FN). Put-back experiments with full-length FN permitted adhesion but failed to induce migration. Monospecific antibodies to FN blocked adhesion. Proteolytic cleavage of FN generated FN fragments which now induced migration. Neutralizing monoclonal antibodies to FN receptors a5 and b1 integrins, and a5 knockdown specifically blocked migration and adhesion. Conclusion: Fibronectin fragments (FNFr) function as matrikines driving the chemotactic affinity of prostate cancer cells via the a5b1 integrin. Taken together with the high-frequency of a5b1 expression in disseminated prostate cancer cells in bone marrow aspirates from patients, the FNFr/FN-a5b1 interaction warrants further study as a therapeutic target.

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“…46 In terms of symptomatic skeletal events, radium-233 treatment significantly delayed the median time to first event compared with placebo (15.6 vs 9.8 months, Po0.001). 47 In general, radium-233 was well tolerated. The most relevant adverse event was myelosuppression, suggesting that clinically relevant off-target effects do occur.…”

Section: Mtor Inhibitionmentioning

confidence: 95%

Cancer-targeted therapies and radiopharmaceuticals

Rachner¹,

Jakob

Hofbauer

2015

BoneKEy Reports

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The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed.

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Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

Cited by 450 publications

References 18 publications

The Clinical and Economic Impacts of Skeletal-Related Events Among Medicare Enrollees With Prostate Cancer Metastatic to Bone

The Clinical and Economic Impacts of Skeletal-Related Events Among Medicare Enrollees With Prostate Cancer Metastatic to Bone

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

Cancer-targeted therapies and radiopharmaceuticals

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