title: Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy.
abstract: BACKGROUND
  A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≥5 yr after initial nephrectomy.
  
  
  OBJECTIVE
  To characterize the clinical outcome of patients with late recurrence beyond 5 yr.
  
  
  METHODS
  Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr.
  
  
  METHODS
  Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses.
  
  
  CONCLUSIONS
  Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p<0.0001), fewer with sarcomatoid features (p<0.0001), more clear cell histology (p=0.001), and lower Fuhrman grade (p<0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p=0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p=0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p=0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols.
  
  
  CONCLUSIONS
  A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.
authors.affiliation: University of Calgary, Tom Baker Cancer Center, Calgary, AB, Canada; University Medicine Greifswald, Department of Urology, Greifswald, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Kroeger
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: University of Ulsan College of Medicine, Asan, South Korea.
authors.forename: Jae-Lyn
authors.initials: JL
authors.lastname: Lee
authors.affiliation: Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Bjarnason
authors.affiliation: Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Knox
authors.affiliation: London Health Sciences Center, London, ON, Canada.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: MacKenzie
authors.affiliation: Queen Elizabeth II Health Sciences Center, Halifax, NS, Canada.
authors.forename: Lori
authors.initials: L
authors.lastname: Wood
authors.affiliation: Stanford Cancer Institute, Stanford University, School of Medicine, Stanford, CA, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ulka N
authors.initials: UN
authors.lastname: Vaishamayan
authors.affiliation: Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.affiliation: Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Frede
authors.initials: F
authors.lastname: Donskov
authors.affiliation: University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: Department of Medical Oncology, National Cancer Centre and Institute of Bioengineering and Nanotechnology, Singapore.
authors.forename: Min-Han
authors.initials: MH
authors.lastname: Tan
authors.affiliation: Department of Clinical Therapeutics, University of Athens, Athens, Greece.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Bamias
authors.affiliation: Vancouver Cancer Center, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Kollmannsberger
authors.affiliation: Cross Cancer Center, University of Alberta, Edmonton, AB, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: North
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: University of Calgary, Tom Baker Cancer Center, Calgary, AB, Canada. Electronic address: daniel.heng@albertahealthservices.ca.
authors.forename: Daniel Y C
authors.initials: DY
authors.lastname: Heng
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D009392:Nephrectomy; D012189:Retrospective Studies; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Late recurrence; Renal cell carcinoma; Survival outcome; Targeted therapies; Treatment response