Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group

2003 ◽  
Vol 21 (16) ◽  
pp. 3150-3157 ◽  
Author(s):  
Lee S. Rosen ◽  
David Gordon ◽  
Simon Tchekmedyian ◽  
Ronald Yanagihara ◽  
Vera Hirsh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lung Cancer ◽  
Placebo Group ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Solid Tumors ◽  
Phase Iii ◽  
Morbidity Rate ◽  
Skeletal Metastases ◽  
Event Analysis

Purpose: To assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to solid tumors other than breast or prostate cancer. Patients and Methods: Patients were randomly assigned to receive zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group). The primary efficacy analysis was proportion of patients with at least one skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone. Secondary analyses (time to first SRE, skeletal morbidity rate, and multiple event analysis) counted hypercalcemia as an SRE. Results: Among 773 patients with bone metastases from lung cancer or other solid tumors, the proportion with an SRE was reduced in both zoledronic acid groups compared with the placebo group (38% for 4 mg and 35% for 8/4 mg zoledronic acid v 44% for the placebo group; P = .127 and P = .023 for 4-mg and 8/4-mg groups, respectively). Additionally, 4 mg zoledronic acid significantly increased time to first event (median, 230 v 163 days for placebo; P = .023), an important end point in this poor-prognosis population, and significantly reduced the risk of developing skeletal events by multiple event analysis (hazard ratio = 0.732; P = .017). Zoledronic acid was well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and vomiting. Conclusion: Zoledronic acid (4 mg infused over 15 minutes) is the first bisphosphonate to reduce skeletal complications in patients with bone metastases from solid tumors other than breast and prostate cancer.

Effect of the number of bone lesions on efficacy of zoledronic acid for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8529-8529 ◽  
Author(s):  
N. Shirina ◽  
R. E. Coleman ◽  
Y. M. Chen
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Lung Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Morbidity Rate ◽  
Bone Lesions ◽  
The Mean

8529 Background: It has been postulated that greater numbers of bone metastases and thus greater tumor burden may lead to increased skeletal morbidity. To assess the effect that the number of baseline bone metastases may have on the efficacy of zoledronic acid in patients with solid tumors, we conducted a retrospective analysis of 3 large, randomized, controlled trials. Methods: Data were evaluated from the intent-to-treat population with breast cancer (n = 739), prostate cancer (n = 397), or lung cancer and other solid tumors (n = 480) who were treated with zoledronic acid 4 mg, pamidronate 90 mg, or placebo and had information available on number of baseline bone lesions. Patients were stratified into 2 groups: those with ≤ 3 bone lesions or > 3 lesions. Results: In general, patients with > 3 lesions had a higher skeletal morbidity rate (SMR) compared with patients with ≤ 3 lesions (Table 1), and zoledronic acid reduced SREs regardless of the number of bone lesions, but the benefit of zoledronic acid appeared greater in patients with > 3 lesions. In patients with lung cancer and other solid tumors who had > 3 bone lesions, zoledronic acid significantly reduced the mean SMR (P = .008) and significantly prolonged time to first SRE (median, 171 vs 84 day; P = .005) compared with placebo. In prostate cancer patients with > 3 bone lesions, zoledronic acid also significantly reduced the mean SMR compared with placebo (Table 1). In breast cancer patients with > 3 bone lesions, the mean SMRs were similar for zoledronic acid and pamidronate groups (Table 1). Conclusions: Patients with a greater number of bone lesions are at higher risk for skeletal complications and receive greater clinical benefit from treatment with zoledronic acid. [Table: see text] [Table: see text]

Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: Report of RTOG 0517.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS9150-TPS9150 ◽  
Author(s):  
Michael J. Seider ◽  
Stephanie Shook ◽  
Corey J. Langer ◽  
Gwen Wyatt ◽  
William F. Demas ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Median Time ◽  
Standard Dose ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Relative Reduction

TPS9150 Background: Skeletal related events (SREs) diminish quality of life (QOL) as well as overall survival (OS) in patients with bone metastases, a common event in breast, lung and prostate cancer. SREs can be reduced or delayed by the use of bisphosphonates. It is postulated that the radiopharmaceuticals, Strontium-89 (Sr89) and Samarium-153 (Sm153), when added to a bisphosphonate can decrease the incidence of SREs. Methods: RTOG 0517 randomized patients with breast, lung and prostate cancer and blastic bone metastases to either Zoledronic acid (ZA) alone or ZA plus a single standard dose of either Sr89 or Sm153. No limitations were placed on additional therapy such as chemotherapy or hormonal treatment. The projected median time to SRE [pathological bone fracture, spinal cord compression, surgery to bone, or radiation to bone] for the ZA arm was 10.4 months requiring 257 SRE events to detect a 33% relative reduction for the radiopharmaceutical arm in the time to development of an SRE with 90% power. Other study objectives included quality of life, pain control, OS and toxicity. Results: 261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued from July 2006 through February 2011 (4.6 patients/month). Due to a lower than expected rate of SREs in the control (ZA) arm, the study was closed early and therefore did not reach the targeted accrual. 28 (17.4%) patients in the ZA arm and 27 (16.8%) in the radiopharmaceutical arm experienced an SRE. Median time to development of an SRE in the ZA and radiopharmaceutical arms was 11.60 and 16.74 months, respectively (p=.47). Median OS in the ZA arm and radiopharmaceutical arm was 15.95 and 11.18 months, respectively (p=0.12). Cox proportional hazards regression model showed that baseline characteristics, including gender, race, ethnicity, primary disease site or number of bone metastases, had no significant impact on OS. There was no difference in QOL parameters or toxicities between the two arms. Conclusion: Patients receiving ZA only experienced a much lower SRE rate than was hypothesized. The addition of Sr89 or Sm153 did not result in a difference in SREs, OS, or QOL

Efficacy and safety of zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results of CALGB 90202 (Alliance).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 27-27 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Susan Halabi ◽  
Charles J. Ryan ◽  
Walter Michael Stadler ◽  
Arif Hussain ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Statistical Power ◽  
Phase Iii ◽  
Rank Test ◽  
Rank Statistic ◽  
Type I ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer

27 Background: Zoledronic acid (ZA) decreases risk of skeletal-related events (SREs) in men with castration-resistant prostate cancer (CRPC) and bone metastases. This phase III study evaluated efficacy and safety of earlier treatment with ZA in men with castration-sensitive metastatic prostate cancer. Methods: CALGB 90202 was a randomized, double-blinded, placebo-controlled phase III trial in men with castration-sensitive prostate cancer and bone metastases who had initiated androgen deprivation therapy within six months of study entry. Subjects were randomized 1:1 in blinded manner to receive ZA (4 mg intravenously every 4 weeks) or placebo (P). After progression to CRPC, all patients crossed over to open-label ZA. The primary endpoint was time to first SRE. Target sample size was 680. Time to SRE was defined as interval between date of randomization and date of first SRE (radiation to bone, or clinical fracture, or surgery to bone, or death due to prostate cancer). With 470 SRE events, the log-rank test has 88% power to detect a 23% decrease in hazard rate of SRE event assuming a one-sided type I error rate of 0.05. The study was discontinued prematurely after the corporate supporter withdrew study drug supply. Primary analysis was based on the stratified log-rank statistic adjusting on the stratification factors following observation of 284 SREs (60% of total events). Results: Between June 2004 and April 2012, 645 patients were randomly assigned to ZA or P. Median time to first SRE was 32.5 months in the ZA group and 29.8 months in the P group (hazard ratio (HR) 0.96 [0.76-1.22]; stratified log-rank P=0.74). A total of 271 deaths were observed; median follow-up time for surviving patients was 24.4 months (20.6, 28.3). Overall survival was similar between groups (HR= 0.89 [0.70-1.14]; stratified P=0.34). Rates of grade 3 or higher adverse events were similar between groups (15% vs. 12% in ZA and P). Conclusions: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs or death. Early termination limited statistical power of the study. Clinical trial information: NCT00079001.

Alpha-Emitter Radium-223 in the Management of Solid Tumors: Current Status and Future Directions

2014 ◽  
pp. e132-e139 ◽  
Author(s):  
Sten Nilsson
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Bone Metastases ◽  
High Energy ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Current Status ◽  
Skeletal Metastases ◽  
Radium 223 ◽  
Alpha Emitter

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.

scholarly journals Randomized Controlled Trial of Early Zoledronic Acid in Men With Castration-Sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance)

2014 ◽  
Vol 32 (11) ◽  
pp. 1143-1150 ◽  
Author(s):  
Matthew R. Smith ◽  
Susan Halabi ◽  
Charles J. Ryan ◽  
Arif Hussain ◽  
Nicholas Vogelzang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Controlled Trial ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Primary Analysis ◽  
Open Label ◽  
Castration Resistant

Purpose Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer. Patients and Methods Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply. Results Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups. Conclusion In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer.

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA4507-LBA4507 ◽  
Author(s):  
K. Fizazi ◽  
M. A. Carducci ◽  
M. R. Smith ◽  
R. Damião ◽  
J. E. Brown ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Cancer Progression ◽  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Bone Destruction ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

LBA4507 Background: Bone metastases from hormone-refractory (castration-resistant) prostate cancer (CRPC) are associated with RANKL-mediated osteoclast activation resulting in bone destruction and skeletal-related events (SRE). Denosumab is a fully human monoclonal antibody against RANKL. This phase III, randomized, double-blind, active-controlled trial compared the efficacy and safety of denosumab vs. zoledronic acid (ZA) in patients with metastatic CRPC. Methods: Patients (n = 1,901) with CRPC and at least 1 bone metastasis, but no prior IV bisphosphonate use, received either SC denosumab 120 mg and IV placebo (n = 950), or SC placebo and IV ZA 4 mg (n = 951) adjusted for creatinine clearance every 4 weeks. All patients were instructed to take supplemental calcium and vitamin D. The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. Results: Denosumab significantly delayed the time to first on-study SRE compared with ZA, (HR 0.82 ; 95% CI: 0.71, 0.95 ; p = 0.008.) The median time to first on-study SRE was 20.7 mo denosumab vs. 17.1 mo ZA, a difference of 3.6 months. Denosumab also significantly delayed the time to first and subsequent on-study SRE (multiple event analysis) (HR 0.82 ; 95% CI: 0.71, 0.94 ; p = 0.004). Greater suppression of the bone turnover markers uNTx and BSAP occurred in denosumab patients compared with ZA (p < 0.0001 for both). Overall, adverse event (AE) rates (97% each) and serious AEs (63% denosumab, 60% ZA) were similar, irrespective of potential relationship to study drugs. AEs of hypocalcemia were reported in 13% and 6% of denosumab and ZA patients. Osteonecrosis of the jaw occurred in 22 (2.3%) denosumab compared with 12 (1.3%) ZA patients (p = 0.09). Overall survival (HR 1.03 ; 95% CI: 0.91, 1.17 ; p = 0.65) and time to cancer progression (HR 1.06; 95% CI: 0.95, 1.18; p = 0.30) were similar between treatment arms. Conclusions: Denosumab demonstrated superiority over ZA in delaying or preventing SREs in patients with bone metastases from CRPC. Adverse events were consistent in both treatment groups with those previously reported in advanced cancer populations. [Table: see text]

A phase III, multicenter, randomized, controlled study of maximum androgen blockade with versus without zoledronic acid in treatment-naïve prostate cancer patients with bone metastases: Results of ZAPCA study.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 150-150 ◽  
Author(s):  
Tomomi Kamba ◽  
Toshiyuki Kamoto ◽  
Yousuke Shimizu ◽  
Shunichi Namiki ◽  
Kiyohide Fujimoto ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Hormonal Treatment ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Controlled Study ◽  
Treatment Naïve ◽  
Lh Rh ◽  
Baseline Psa

150 Background: Zoledronic acid (ZA) is proved to be useful for the prevention of skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases, but its early use combined with androgen deprivation therapy (ADT) in men with hormonal treatment-naïve prostate cancer and bone metastases is controversial. Methods: A total of 227 men with hormonal treatment-naïve prostate cancer and bone metastases were randomly assigned in a 1:1 ratio to receive zoledronic acid (4mg intravenously every 4 weeks up to 2 years) along with ADT (LH-RH analogue + bicalutamide, MZ group) or ADT alone (MAB group). Stratification factors were PSA (<200ng/ml vs. ≥200ng/ml), EOD (extent of diseases) grade (1,2 vs. 3,4) and Gleason score (<7 vs. ≥8). The primary end point was time to treatment failure (TTTF), defined as 3 consecutive rise of PSA from the nadir, clinical progression, SRE, death or cessation of protocol therapy for any reason. Results: The median follow-up was 41.1 months. The median TTTF was 12.4 months in MZ group (95% CI, 10.6 to 16.6) and 9.7 months in MAB group (95% CI, 8.9 to 12.6; hazard ratio, 0.754; 95% CI, 0.567 to 1.003; log-rank P= .051). In a subset of men with baseline PSA levels <200ng/mL, the median TTTF was 23.7 months in MZ group (95% CI, 15.2 to 31.3) and 9.8 months in MAB group (95% CI, 6.6 to 17.0; hazard ratio, 0.575; 95% CI, 0.354 to 0.933; log-rank P= .023). An exploratory multivariate analysis using Cox proportional hazards model identified MZ group, age less than 80, and EOD ≤2 as independent factors associated with better TTTF. Conclusions: In men with hormonal treatment naïve prostate cancer with bone metastases, concurrent use of ZA with ADT did not show a significant advantage over ADT alone regarding TTTF. However, in a subgroup of men with lower baseline PSA levels, ZA significantly prolonged TTTF, compared with ADT alone. Clinical trial information: NCT00685646.

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