Predictors of clinical outcome in patients with bone metastases from prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4555-4555
Author(s):  
F. Saad ◽  
R. E. Coleman ◽  
R. Cook ◽  
M. R. Smith ◽  
J. E. Brown ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Clinical Outcome ◽  
Bone Metastases ◽  
Bone Markers ◽  
Bone Lesion ◽  
Bone Marker ◽  
Risk Of Death ◽  
Pathologic Fractures ◽  
Increased Risk

4555 Background: Bone metastases are a significant cause of morbidity in patients with prostate cancer (PC). To assess the predictive value of bone markers and fractures for clinical outcome in patients with bone metastases from PC, we conducted a retrospective analysis of patients in a large, randomized, controlled trial of zoledronic acid. Methods: Data were analyzed in patients treated with 4 mg zoledronic acid or placebo who had bone marker (n = 411) or fracture (n = 640) information. Cox regression models, adjusted for treatment group, were used to assess the association between bone markers (urinary N-telopeptide [NTX] and bone alkaline phosphatase [BALP]) or fractures (time-dependent variable) and the risk of death or of experiencing a first skeletal-related event (SRE) on study. For bone marker analyses, patients were grouped by low (< 50 nmol/mmol creatinine), moderate (50 to 99), or high (≥ 100) NTX levels and by low (< 146 U/L) or high (≥ 146) BALP. Results: Patients who experienced a fracture on study (19%) had shorter survival compared with patients who did not; the hazard ratio for death was 1.29 (95% CI = 1.01, 1.65; P = .04), suggesting 29% increased risk of death among these patients. When adjusted for previous SRE and baseline ECOG performance status ≥ 2, the risk for death associated with fractures was increased by 23% and trended toward statistical significance (P = .10). Patients with high NTX levels had significantly increased risk of SREs and disease progression (P < .001) compared with patients with low NTX. Relative to low NTX levels, high and moderate NTX levels were associated with a 5.72-fold (95% CI = 4.04, 8.11; P < .001) and 4.10-fold (95% CI = 2.81, 5.97; P < .001) increased risk of death, respectively. High BALP also significantly correlated with an increased risk of a first on-study SRE (P = .028) and bone lesion progression (P < .001). Conclusions: These analyses suggest that pathologic fractures are associated with increased risk if death and that high bone marker levels are associated with increased risk of SREs, bone lesion progression, and shorter survival in patients with PC and bone metastases. The results support appropriate treatment for the prevention of fractures and to decrease bone marker levels. [Table: see text]

scholarly journals Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice

2012 ◽  
Vol 6 (6) ◽  
pp. 465 ◽  
Author(s):  
Alan So ◽  
Joseph Chin ◽  
Neil Fleshner ◽  
Fred Saad
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Therapy Monitoring ◽  
Standard Of Care ◽  
Negative Consequences ◽  
Risk Of Death ◽  
Increased Risk ◽  
Skeletal Related Events

Skeletal-related events (SREs) are a common complication of bone metastases, and have serious negative consequences for patients with castrate-resistant prostate cancer (CRPC). SREs can lead to severe pain, increased risk of death, increased health care costs and reduced quality of life. Until recently, zoledronic acid has been the sole standard of care for the prevention of SREs in men with CRPC with bone metastases. Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been recently approved for use in Canada for this indication, thus presenting another option for these patients. Denosumab was shown to be superior to zoledronic acid in delaying the time to first or subsequent SREs in CRPC patients with bone metastases. This review discusses current and previous trials examining agents designed to prevent SREs in men with CRPC and bone metastases. It also discusses the practical aspects of administering a bone-targeted therapy, including choosing a bone-targeted therapy, monitoring at the onset and during therapy, switching from one therapy to another, and assessing potential complications.

Effect of zoledronic acid (Z) treatment based on serum parathyroid hormone (PTH) levels in patients (pts) with malignant bone disease

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8610-8610 ◽  
Author(s):  
A. Berruti ◽  
L. Dogliotti ◽  
M. Tampellini ◽  
A. Lipton ◽  
V. Hirsh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lung Cancer ◽  
Bone Metastases ◽  
Solid Tumors ◽  
Bone Lesion ◽  
Small Subset ◽  
Prognostic Information ◽  
Risk Of Death ◽  
Increased Risk ◽  
Serum Pth

8610 Background: Z prevents skeletal-related events (SREs) in pts with bone metastases or multiple myeloma. However, secondary hyperparathyroidism and increased PTH may stimulate osteoclast activity and tumor growth, thus potentially limiting the efficacy of Z. Methods: Serum PTH was assessed at baseline and every 3 months in 1,068 pts enrolled in 3 randomized trials: 547 received Z, and 521 received placebo or pamidronate. Results: 213 (20%) pts had elevated PTH at baseline, and 105 of 547 (19%) pts had elevated PTH during Z treatment. In patients with normal baseline PTH, Z significantly reduced the incidence of SREs and delayed time to first SRE compared with control, whereas the risk of SREs was not reduced in patients with elevated baseline PTH. In prostate cancer patients, Z significantly decreased the risk of death compared with placebo in pts with normal baseline PTH (relative risk [RR] = 0.72; 95% confidence interval [CI]: 0.55, 0.94; P = .015). No survival advantage was observed in this subpopulation among pts with lung cancer or other solid tumors. In the small subset of pts with elevated PTH during Z treatment, there was an increased risk of death (for breast cancer pts, RR = 1.68 [95% CI: 1.10, 2.56]; P = .016; for prostate cancer pts, RR = 2.92 [95% CI: 1.83, 4.67]; P < .001). Additionally, elevated PTH during Z treatment in prostate cancer pts also significantly correlated with an increased risk of bone lesion progression (RR = 1.54 [95% CI: 1.09, 2.17]; P = .015). Elevated PTH during treatment did not affect the incidence or time to onset of SREs. Among pts with lung cancer or other solid tumors, elevated PTH during Z treatment did not provide any predictive or prognostic information. Conclusions: PTH levels either at baseline or during Z treatment appear to correlate with disease progression and the clinical benefit of Z in pts with bone metastases from certain types of cancer. This retrospective analysis suggests the importance of PTH status in patients undergoing Z treatment. Normalization of PTH levels may increase the benefit of Z. [Table: see text]

Bisphosphonates for Treatment and Prevention of Bone Metastases

2005 ◽  
Vol 23 (32) ◽  
pp. 8219-8224 ◽  
Author(s):  
M. Dror Michaelson ◽  
Matthew R. Smith
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Cord Compression ◽  
Optimal Timing ◽  
Duration Of Treatment ◽  
Treatment And Prevention ◽  
Increased Risk ◽  
Skeletal Complications ◽  
Cancer Complications

Bone metastases are a major cause of morbidity for men with prostate cancer. Complications of bone metastases include pain, fractures, and spinal cord compression. Although they appear osteoblastic by radiographic imaging, most bone metastases are characterized by excess osteoclast number and activity. In addition, pathologic osteoclast activation is associated with increased risk of skeletal complications. Zoledronic acid, a potent inhibitor of osteoclast activity, differentiation, and survival, decreases the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Other bisphosphonates, including pamidronate and clodronate, seem to be ineffective in this setting. The reduction in risk of skeletal complications with zoledronic acid must be weighed against potential adverse effects. Additional studies are needed to determine the optimal timing, schedule, and duration of treatment in men with bone metastases as well as the potential role of bisphosphonates in other settings including the prevention of bone metastases.

Predictive Value of Bone Resorption and Formation Markers in Cancer Patients With Bone Metastases Receiving the Bisphosphonate Zoledronic Acid

2005 ◽  
Vol 23 (22) ◽  
pp. 4925-4935 ◽  
Author(s):  
Robert E. Coleman ◽  
Pierre Major ◽  
Allan Lipton ◽  
Janet E. Brown ◽  
Ker-Ai Lee ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Zoledronic Acid ◽  
Bone Resorption ◽  
Bone Metastases ◽  
Clinical Outcomes ◽  
Bone Alkaline Phosphatase ◽  
Bone Resorption Marker ◽  
Risk Of Death ◽  
Increased Risk ◽  
Time Varying Covariates

PurposeThree large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy.Patients and MethodsUrinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients—1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non–small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (≥ 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (≥ 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates.ResultsPatients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes.ConclusionThe bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Rate of pathologic fractures associated with zoledronic acid treatment in both breast and prostate cancer patients with bone metastases: Findings from real-world clinical practice.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19615-e19615
Author(s):  
David H. Regan ◽  
Dennis J Wollschleger ◽  
William N. Harwin ◽  
Stephen Szabo ◽  
Joseph DiBenedetto ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Randomized Controlled Trial ◽  
Clinical Practice ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Pathological Fracture ◽  
Controlled Trial ◽  
Randomized Controlled ◽  
Pathologic Fractures ◽  
Cancer Specialists

e19615 Background: Recent papers by Stopeck et al (J Clin Oncol, 2010), and by Fizazi et al (Lancet, 2011) evaluated rates of pathologic fractures (PF) in breast cancer (BC) and prostate cancer (PC) patients with bone metastases, and concluded that 23% and 15% of the patients on zoledronic acid (ZOL) respectively had a PF. Since these results were obtained within a randomized controlled trial environment, it is very important to compare these rates to those observed in actual practice. The objective of this study was therefore to determine the rate of PF among both BC and PC patients with bone metastases treated with ZOL in clinical practice. Methods: A patient chart review was conducted in two institutions, Florida Cancer Specialists (FCS) and Georgia Cancer Specialists (GCS) to determine the rate of PF in BC and PC patients with bone metastases initiating ZOL. BC and PC patients with confirmed diagnoses who initiated ZOL treatment from 2005 thru 2007 were included in the study. The patients were required to have been on ZOL for a minimum of 18 months following initiation of treatment. Demographic information, baseline clinical characteristics, and outcomes related to the treatment of bone metastases were assessed. Results: A total of 207 BC patients and 178 PC patients were included in the sample. Median age in the BC group was 65, and in the PC group was 74. In the BC cohort, of the 207 patients, only 17 (8.2%) patients had a PF. In the PC cohort, of the 178 patients, only 8 (4.5%) patients had a pathological fracture. When evaluated by institution, only 5 (4.7%) BC patients, and 4 (4%) PC patients from FCS had a pathological fracture; and only 12 (12%) BC and 4 (5.2%) PC patients from GCS had a pathological fracture. Conclusions: The findings from this study indicate that the rate of pathological fractures associated with ZOL treatment in clinical practice is very different from that observed in a randomized controlled trial setting. Physicians, payers and policy makers should carefully consider these findings in both clinical pathway decisions and formulary inclusion.

scholarly journals Retrospective Toxicological Profiling of Radium-223 Dichloride for the Treatment of Bone Metastases in Prostate Cancer Using Adverse Event Data

Medicina ◽  
2019 ◽  
Vol 55 (5) ◽  
pp. 149 ◽  
Author(s):  
Theodoros G. Soldatos ◽  
Ioannis Iakovou ◽  
Christos Sachpekidis
Keyword(s):  
Prostate Cancer ◽  
Adverse Event ◽  
Bone Metastases ◽  
Cancer Patients ◽  
Safety Profile ◽  
Adverse Event Reporting System ◽  
Castration Resistant Prostate Cancer ◽  
Risk Of Death ◽  
Radium 223 ◽  
Increased Risk

Background and Objective: Radium-223 dichloride (Xofigo®) is a calcium mimetic agent approved for the treatment of castration-resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease. This targeted, α-particle-emitting therapy has demonstrated significant survival benefit accompanied by a favorable safety profile. Nevertheless, recent evidence suggests that its combined use with abiraterone and prednisone/prednisolone may be associated with increased risk of death and fractures. While the precise pathophysiologic mechanisms of these events are not yet clear, collecting evidence from more clinical trials and translational studies is necessary. The aim of our present study is to assess whether accessible sources of patient outcome data can help gain additional clinical insights to radium-223 dichloride’s safety profile. Materials and Methods: We performed a retrospective analysis of cases extracted from the FDA Adverse Event Reporting System and characterized side effect occurrence by using reporting ratios. Results: A total of ~1500 prostate cancer patients treated with radium-223 dichloride was identified, and side effects reported with the use of radium-223 dichloride alone or in combination with other therapeutic agents were extracted. Our analysis demonstrates that radium-223 dichloride may often come with hematological-related reactions, and that, when administered together with other drugs, its safety profile may differ. Conclusions: While more prospective studies are needed to fully characterize the toxicological profile of radium-223 dichloride, the present work constitutes perhaps the first effort to examine its safety when administered alone and in combination with other agents based on computational evidence from public real-world post marketing data.

Correlation of N-telopeptide of type I collagen (NTX) with survival and fractures in patients (pts) with bone metastases from renal cell carcinoma (RCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16016-e16016
Author(s):  
J. E. Brown ◽  
A. Lipton ◽  
R. J. Cook ◽  
D. Michaelson ◽  
R. E. Coleman ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Solid Tumors ◽  
Prognostic Significance ◽  
Small Sample ◽  
Phase Iii ◽  
Bone Lesions ◽  
Type I ◽  
Risk Of Death ◽  
Pathologic Fractures ◽  
Increased Risk

e16016 Background: The osteolysis marker NTX has shown prognostic significance in pts with bone metastases from a broad range of solid tumors, but its potential in pts with RCC has not been investigated. Methods: This was an exploratory correlative analysis of NTX levels and outcomes in the RCC subset of pts treated with zoledronic acid (ZOL) in a 21-month phase III trial (Rosen et al. J Clin Oncol. 2002). In North American pts in this study, urinary NTX was measured approximately every 3 mo and was expressed per mmol creatinine (CR). Endpoints included overall survival (OS), disease progression in bone, and pathologic fractures. Relative risks and 95% confidence intervals for pts with elevated NTX (NTX ≥ 64 nmol/mmol CR) versus normal NTX (< 64 nmol/mmol CR) were calculated by Cox regression for baseline and most recent (≤ 6 mo prior) NTX assessments. Results: Among 55 ZOL-treated RCC pts, 29 had baseline NTX data (median = 60 nmol/mmol CR). Whereas baseline NTX levels showed trends for outcomes, recent NTX levels profoundly correlated with outcomes ( Table ). An elevated recent NTX measurement correlated with a > 13-fold increased risk of death and a > 11-fold increased risk of progression in bone. Correlations were also significant for first and all on-study fractures. Conclusions: In pts with RCC receiving ZOL, serial NTX assessments may provide important prognostic insight. Although based on a small sample size, correlations between recent NTX levels and outcomes in RCC pts are more profound than those previously reported in pts with other solid tumors (Brown et al. J Natl Cancer Inst. 2005). Elevated NTX could alert physicians to the need to more closely monitor bone lesions and intervene to prevent fractures in RCC pts. This may be especially important in the context of new systemic therapies that are improving the outlook in the advanced RCC setting. [Table: see text] [Table: see text]

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