26 maart 2011: Zie ook dit bericht over denosumab  over zelfde studie als hieronder, waar nog veel meer informatie over denosumab - prolia is toegevoegd.

17 november 2010: Bron: J Clin Oncol. 2010 Nov 8

Denosumab geeft vergeleken met Zometa - Zoledronic Acid, minder bot gerelateerde problemen bij borstkankerpatienten met botuitzaaiingen. De tijd tot zich weer een probleem met een botuitzaaiinng voordeed was significant langer bij denosumab dan bij Zometa. Ook het aantal sterfgevallen direct gerelateerd aan botproblemen was bij denosumab minder dan bij Zometa. Dit blijkt uit een dubbelblinde gerandomiseerde studie bij ruim 2000 patienten. Het therapeutische effect bleek hetzelfde. Denosumab gaf minder nierproblemen dan Zometa, maar niet significant. Zometa gaf minder kaakproblemen dan denosumab maar ook dit was niet significant. Denosumab wordt een humaan antilichaam gericht tegen RANK ligand genoemd en is geen bisfosfonaaat maar werkt op een andere m,anier. Zie ook www.prolia.com

Medscape splitste de resultaten op deze manier:

Superiority of Denosumab

Dr. Stopeck and colleagues randomly assigned adult patients with breast adenocarcinoma and bone metastasis to receive either a subcutaneous injection of denosumab 120 mg plus an intravenous infusion of placebo every 4 weeks (n = 1026), or an intravenous injection of placebo and a subcutaneous dose of zoledronic acid 4 mg (n = 1020).

All approved cancer-specific therapies, such as chemotherapy and hormonal therapy, were allowed (except for bisphosphonate therapy), and daily calcium and vitamin D supplementation was strongly recommended.

The primary and secondary end points, designed to evaluate both noninferiority and superiority, were time to first and subsequent on-study SREs over the study period of approximately 34 months.

An SRE was defined as pathologic fracture, radiation therapy, or surgery to bone, or spinal cord compression.

The study found that, compared with zoledronic acid, denosumab significantly delayed the time to first on-study SRE by 18%, and time to multiple on-study SREs by 23%, with hazard ratios (HR) of 0.82 and 0.77, respectively. These results demonstrate both the noninferiority and superiority of denosumab over zoledronic acid.

The median time to first on-study SRE in the zoledronic acid group was 26.4 months; it "has not yet been reached" for the denosumab group, the authors report.

The mean skeletal morbidity rate (defined as the number of SREs per patient divided by the patient's time at risk) was 22% lower for denosumab than for zoledronic acid (0.45 vs 0.58 events per patient per year).

Markers of bone turnover at week 13 were significantly lower for denosumab than for zoledronic acid, with urine creatinine decreasing by a median of 80%, compared with 68%, and bone-specific alkaline phosphatase decreasing by a median of 44%, compared with 37%.

Overall survival, disease progression, and rates of severe adverse events were similar between the groups.

However, zoledronic acid was associated with a higher rate of adverse events potentially associated with renal toxicity (8.5% vs 4.9%), especially severe (2.2% vs 0.4%) and serious renal (1.5% vs 0.2%) adverse events.

"Denosumab elimination is likely through nonspecific catabolism in cells of the reticuloendothelial system similar to that of other therapeutic monoclonal antibodies and is not reliant on renal function," explain the authors.

Compared with denosumab, zoledronic acid was associated with a 2.7-fold increase in acute-phase reactions (flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias, and myalgias) in the first 3 days of treatment.

"These flu-like symptoms represent an added burden for patients and require greater monitoring and potential treatment following zoledronic acid therapy," the authors note.

Oral examinations conducted twice yearly during the study revealed that osteonecrosis of the jaw occurred infrequently and at a similar rate in both groups. However, there was a slightly higher incidence in the denosumab group (2.0% vs 1.4%; nonsignificant).

Known risk factors for osteonecrosis of the jaw, including previous dental extractions, poor oral hygiene, and dentures, were present in the vast majority of cases, and in a higher percentage of the denosumab-treated patients (90% vs 71%), "indicating that patients at risk may be identified," note the authors.


J Clin Oncol. 2010 Nov 8. [Epub ahead of print]

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study.

Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A.

University of Arizona, Arizona Cancer Center, Tucson, AZ; Penn State Milton S. Hershey Medical Center, Hershey, PA; Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Brussels, Belgium; Medical University of Vienna, Vienna, Austria; Cross Cancer Institute, Edmonton, Alberta, Canada; Western and Royal Melbourne Hospitals, Melbourne, Victoria, Australia; Blokhin Cancer Research Center, Moscow, Russia; National Cancer Center Hospital, Tokyo, Japan; Sarah Cannon Research Institute, Nashville, TN; Corporacion Medica de General San Martin, San Martin, Argentina; and Amgen, Thousand Oaks, CA.


PURPOSE This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases.

PATIENTS AND METHODS Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression).

Results Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39).

CONCLUSION Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

PMID: 21060033 [PubMed - as supplied by publisher]

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