title: Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  The authors previously reported the efficacy of a dose of 4 mg of zoledronic acid in reducing skeletal complications in patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate). In the current study, they update these results and report the long-term efficacy and safety of 21 months of treatment with zoledronic acid in a randomized, placebo-controlled trial.
  
  
  METHODS
  A total of 773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo via a 15-minute infusion every 3 weeks for 21 months. The 8-mg dose later was reduced to 4 mg (8/4-mg group). The primary efficacy endpoint was the percentage of patients at 21 months with >/= 1 skeletal-related event (SRE) (pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone). Secondary analyses (time to first SRE, annual incidence of SREs, and multiple-event analysis) included hypercalcemia of malignancy.
  
  
  RESULTS
  Fewer patients treated with zoledronic acid developed at least 1 SRE at 21 months compared with patients treated with placebo (39% of those treated at the 4-mg dose [P =0.127] and 36% of those treated at the 8/4-mg dose [P = 0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; P = 0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4-mg dose vs. 2.71 per year with placebo; P = 0.012). Moreover, the 4-mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003). Zoledronic acid was found to be well tolerated with long-term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute-phase reactions of nausea, anemia, and emesis.
  
  
  CONCLUSIONS
  To the authors' knowledge, zoledronic acid is the first bisphosphonate to demonstrate long-term safety and efficacy in this patient population.
authors.affiliation: Developmental Therapeutics, Cancer Institute Medical Group, Los Angeles, California 90025, USA. lrosen@targenix.com
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: N Simon
authors.initials: NS
authors.lastname: Tchekmedyian
authors.forename: Ronald
authors.initials: R
authors.lastname: Yanagihara
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzakowski
authors.forename: Marek
authors.initials: M
authors.lastname: Pawlicki
authors.forename: Paul
authors.initials: P
authors.lastname: De Souza
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Gladys
authors.initials: G
authors.lastname: Urbanowitz
authors.forename: Dirk
authors.initials: D
authors.lastname: Reitsma
authors.forename: John
authors.initials: J
authors.lastname: Seaman
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology* / Q000556:secondary*; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000473:pathology*; D010919:Placebos; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D010919:Placebos; D000077211:Zoledronic Acid