title: Characterizing the impact of lymph node metastases on the survival outcome for metastatic renal cell carcinoma patients treated with targeted therapies.
abstract: BACKGROUND
  It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients.
  
  
  OBJECTIVE
  To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT).
  
  
  METHODS
  Patients (n=2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n=1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively.
  
  
  METHODS
  The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS).
  
  
  CONCLUSIONS
  All patients with LNM had worse PFS (p=0.001) and OS (p<0.001) compared to those without LNM. Compared to patients without LNM (PFS 8.8 mo; OS 25.1 mo), any SBD LNM involvement was associated with worse PFS (SBD, 6.8 mo; p=0.003; SPD+/SBD+, 5.5 mo; p<0.001) and OS (SBD, 16.2 mo; p<0.001; SPD+/SBD+, 11.5 mo; p<0.001). Both SBD and SPD+/SBD+ LNM were retained as independent prognostic factors in multivariate analyses (MVA) for PFS (p=0.006 and p=0.022, respectively) and OS (both p<0.001), while SPD LNM was not an independent risk factor. Likewise, in ccRCC, SBD LNM (19.8 mo) and SPD+/SBD+ LNM (12.85 mo) patients had the worst OS. SPD+/SBD+ LNM (p=0.006) and SBD LNM (p=0.028) were independent prognostic factors for OS in MVA, while SPD LNM was not significant (p=0.301). The study is limited by its retrospective design and the lack of pathologic evaluation of LNM in all cases.
  
  
  CONCLUSIONS
  The metastatic spread of RCC to SBD lymph nodes is associated with poor prognosis in mRCC patients treated with TT.
  
  
  RESULTS
  The presence of lymph node metastases below the diaphragm is associated with shorter survival outcome when metastatic renal cell carcinoma (mRCC) patients are treated with targeted therapies. Clinical trials should evaluate whether surgical removal of regional lymph nodes at the time of nephrectomy may improve outcomes in high-risk RCC patients.
authors.affiliation: Department of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada; Department of Urology, University Medicine, Greifswald, Germany; Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at the University of California Los Angeles, CA, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Kroeger
authors.affiliation: Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at the University of California Los Angeles, CA, USA.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
authors.affiliation: Department of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.
authors.forename: J Connor
authors.initials: JC
authors.lastname: Wells
authors.affiliation: Auckland City Hospital, Auckland, New Zealand, Auckland, New Zealand.
authors.forename: Nicola
authors.initials: N
authors.lastname: Lawrence
authors.affiliation: Auckland City Hospital, Auckland, New Zealand, Auckland, New Zealand.
authors.forename: Reuben
authors.initials: R
authors.lastname: Broom
authors.affiliation: Department of Medical Oncology Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Division of Oncology, Stanford Medical Center, Stanford, CA, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Yim
authors.affiliation: Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Arnoud
authors.initials: A
authors.lastname: Templeton
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Knox
authors.affiliation: Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at the University of California Los Angeles, CA, USA.
authors.forename: Ezra
authors.initials: E
authors.lastname: Bernstein
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Smoragiewicz
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishampayan
authors.affiliation: Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, NS, Canada.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Wood
authors.affiliation: Department of General Medical Oncology and Laboratory for Experimental Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Beuselinck
authors.affiliation: Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Frede
authors.initials: F
authors.lastname: Donskov
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada. Electronic address: daniel.heng@albertahealthservices.ca.
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Heng
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D016208:Databases, Factual; D003964:Diaphragm; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D012187:Retroperitoneal Space; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D058570:TOR Serine-Threonine Kinases
keywords: Lymph node metastases; Lymph nodes; Renal cell carcinoma; Survival outcome; Targeted therapies; Treatment response