title: Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma.
abstract: BACKGROUND
  Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.
  
  
  OBJECTIVE
  The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.
  
  
  METHODS
  We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials.
  
  
  METHODS
  Statistical analyses were performed using Cox regression and the Kaplan-Meier method.
  
  
  CONCLUSIONS
  We identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively.
  
  
  CONCLUSIONS
  We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity.
  
  
  RESULTS
  In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Rana R
authors.initials: RR
authors.lastname: McKay
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Lin
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Julia J
authors.initials: JJ
authors.lastname: Perkins
authors.affiliation: Tom Baker Cancer Center, Calgary, Alberta, Canada.
authors.forename: Daniel Y C
authors.initials: DY
authors.lastname: Heng
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: toni_choueiri@DFCI.harvard.edu.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077784:Axitinib; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D016898:Interferon-alpha / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077268:Pamidronate; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000139:chemically induced; D012189:Retrospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077157:Sorafenib; D000077210:Sunitinib; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D016898:Interferon-alpha; D010671:Phenylurea Compounds; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; C401859:temsirolimus; D000077211:Zoledronic Acid; D000077157:Sorafenib; D000077784:Axitinib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077268:Pamidronate; D000077210:Sunitinib; D020123:Sirolimus
keywords: Bisphosphonates; Bone metastases; Renal cell carcinoma; VEGF-targeted therapy; mTOR inhibitors