title: The impact of low serum sodium on treatment outcome of targeted therapy in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Cancer Database Consortium.
abstract: BACKGROUND
  Hyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy.
  
  
  OBJECTIVE
  To investigate the influence of baseline hyponatremia in mRCC patients treated with targeted therapy in the International Metastatic Renal Cell Carcinoma Database Consortium.
  
  
  METHODS
  Data on 1661 patients treated with first-line vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) targeted therapy for mRCC were available from 18 cancer centers to study the impact of hyponatremia (serum sodium level <135 mmol/l) on clinical outcomes.
  
  
  METHODS
  The primary objective was overall survival (OS) and secondary end points included time to treatment failure (TTF) and the disease control rate (DCR). The chi-square test was used to compare the DCR in patients with and without hyponatremia. OS and TTF were estimated with the Kaplan-Meier method and differences between groups were examined by the log-rank test. Multivariable logistic regression (for DCR) and Cox regression (for OS and TTF) were undertaken adjusted for prognostic risk factors.
  
  
  CONCLUSIONS
  Median OS after treatment initiation was 18.5 mo (95% confidence interval [CI], 17.5-19.8 mo), with 552 (33.2%) of patients remaining alive on a median follow-up of 22.1 mo. Median baseline serum sodium was 138 mmol/l (range: 122-159 mmol/l), and hyponatremia was found in 14.6% of patients. On univariate analysis, hyponatremia was associated with shorter OS (7.0 vs 20.9 mo), shorter TTF (2.9 vs 7.4 mo), and lower DCR rate (54.9% vs 78.8%) (p<0.0001 for all comparisons). In multivariate analysis, these effects remain significant (hazard ratios: 1.51 [95% CI, 1.26-1.80] for OS, and 1.57 [95% CI, 1.34-1.83] for TTF; odds ratio: 0.50 [95% CI, 34-0.72] for DCR; adjusted p<0.001). Results were similar if sodium was analyzed as a continuous variable (adjusted p<0.0001 for OS, TTF, and DCR).
  
  
  CONCLUSIONS
  This is the largest multi-institutional report to show that hyponatremia is independently associated with a worse outcome in mRCC patients treated with VEGF- and mTOR-targeted agents.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Fabio A B
authors.initials: FA
authors.lastname: Schutz
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Wanling
authors.initials: W
authors.lastname: Xie
authors.affiliation: Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Frede
authors.initials: F
authors.lastname: Donskov
authors.affiliation: Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Sircar
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Sumanta Kumar
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Stanford Medical Center, Stanford, CA, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Kollmannsberger
authors.affiliation: Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: North
authors.affiliation: Dalhousie University, Halifax, NS, Canada.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Wood
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ulka
authors.initials: U
authors.lastname: Vaishampayan
authors.affiliation: National Cancer Centre Singapore, Singapore.
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Tan
authors.affiliation: London Regional Cancer Program, London, ON, Canada.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Mackenzie
authors.affiliation: Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jae Lyun
authors.initials: JL
authors.lastname: Lee
authors.affiliation: Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.affiliation: Tom Baker Cancer Center, Calgary, AB, Canada.
authors.forename: Daniel Y C
authors.initials: DY
authors.lastname: Heng
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: toni_choueiri@dfci.harvard.edu.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D002292:Carcinoma, Renal Cell / Q000150:complications* / Q000188:drug therapy* / Q000556:secondary; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007010:Hyponatremia / Q000150:complications*; D007680:Kidney Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011379:Prognosis; D012189:Retrospective Studies; D012964:Sodium / Q000097:blood*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
chemical_list: D012964:Sodium; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Anti-VEGF; Hyponatremia; Prognostic factors; Renal cell cancer