title: Integrating surgery with targeted therapies for renal cell carcinoma: current evidence and ongoing trials.
abstract: BACKGROUND
  Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.
  
  
  OBJECTIVE
  This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.
  
  
  METHODS
  A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.
  
  
  RESULTS
  Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.
  
  
  CONCLUSIONS
  For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.
authors.affiliation: Department of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. a.bex@nki.nl
authors.forename: Axel
authors.initials: A
authors.lastname: Bex
authors.forename: Eric
authors.initials: E
authors.lastname: Jonasch
authors.forename: Ziya
authors.initials: Z
authors.lastname: Kirkali
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mejean
authors.forename: Peter
authors.initials: P
authors.lastname: Mulders
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Patard
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.forename: Hendrik
authors.initials: H
authors.lastname: van Poppel
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
mesh_terms: D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D017024:Chemotherapy, Adjuvant; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D019317:Evidence-Based Medicine; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D058990:Molecular Targeted Therapy / Q000009:adverse effects / Q000401:mortality; D020360:Neoadjuvant Therapy; D009392:Nephrectomy / Q000009:adverse effects / Q000401:mortality; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome