title: Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: a randomized first-line phase II trial.
abstract: BACKGROUND
  Bone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.
  
  
  METHODS
  Thirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.
  
  
  RESULTS
  After 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P < .0001) and 76.2% (95% CI, 67.3%-82.7%; P < .0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).
  
  
  CONCLUSIONS
  In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.
authors.affiliation: Regional Cancer and Blood Centre, Auckland City Hospital, Auckland, New Zealand. Electronic address: ReubenB@adhb.govt.nz.
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Broom
authors.affiliation: Cancer Trials New Zealand, Discipline of Oncology, University of Auckland, New Zealand.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hinder
authors.affiliation: Cancer Trials New Zealand, Discipline of Oncology, University of Auckland, New Zealand; Department of Preventative and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Katrina
authors.initials: K
authors.lastname: Sharples
authors.affiliation: Cancer Trials New Zealand, Discipline of Oncology, University of Auckland, New Zealand.
authors.forename: Janie
authors.initials: J
authors.lastname: Proctor
authors.affiliation: Cancer Trials New Zealand, Discipline of Oncology, University of Auckland, New Zealand.
authors.forename: Steven
authors.initials: S
authors.lastname: Duffey
authors.affiliation: Cancer Trials New Zealand, Discipline of Oncology, University of Auckland, New Zealand.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pollard
authors.affiliation: Regional Cancer and Blood Centre, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Peter C C
authors.initials: PC
authors.lastname: Fong
authors.affiliation: Midcentral Regional Cancer Treatment Service, Palmerston North Hospital, Palmerston North, New Zealand.
authors.forename: Garry
authors.initials: G
authors.lastname: Forgeson
authors.affiliation: Oncology Service, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: Dean L
authors.initials: DL
authors.lastname: Harris
authors.affiliation: Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jameson
authors.affiliation: Wellington Blood and Cancer Centre, Wellington Hospital, Wellington, New Zealand.
authors.forename: Anne
authors.initials: A
authors.lastname: O'Donnell
authors.affiliation: Tauranga Hospital, Tauranga, New Zealand.
authors.forename: Richard T
authors.initials: RT
authors.lastname: North
authors.affiliation: Regional Cancer and Blood Centre, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Deva
authors.affiliation: Regional Cancer and Blood Centre, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Fritha J
authors.initials: FJ
authors.lastname: Hanning
authors.affiliation: Department of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: Andrew
authors.initials: A
authors.lastname: Grey
authors.affiliation: Cancer Trials New Zealand, Discipline of Oncology, University of Auckland, New Zealand.
authors.forename: Michael P N
authors.initials: MP
authors.lastname: Findlay
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D024042:Collagen Type I / Q000097:blood / Q000652:urine; D004164:Diphosphonates / Q000008:administration & dosage*; D000068338:Everolimus; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000097:blood / Q000652:urine; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000077211:Zoledronic Acid; D000068338:Everolimus; D020123:Sirolimus
keywords: Bisphosphonates; Neoplasm metastasis; Randomized controlled trial; Skeletal-related events; Targeted therapy