title: Cytotoxic chemotherapy in the treatment of advanced renal cell carcinoma in the era of targeted therapy.
abstract: BACKGROUND
  Renal cell carcinoma (RCC) is a heterogeneous disease with regards to histology, progression, and response to treatment. Cytotoxic chemotherapy has been extensively studied in metastatic RCC (mRCC). Responses in most studies are modest and the mechanisms of resistance remain poorly understood. Targeted therapies have significantly improved outcomes in mRCC; however, most patients eventually relapse and die of their disease. Early clinical data suggest that combinations of chemotherapy and targeted agents are clinically active and are well tolerated.
  
  
  METHODS
  We reviewed the available literature for published clinical trials incorporating traditional chemotherapeutic agents in the treatment of mRCC. These papers were identified through a Medline search and were included if they employed at least one chemotherapeutic agent in the treatment of mRCC. The literature was also reviewed for information regarding mechanisms of chemotherapy resistance.
  
  
  RESULTS
  The data regarding the use of cytotoxic chemotherapy in mRCC consist of small, non-randomized phase I and II studies. The major response proportions with single agent chemotherapies are low but combination regimens either with other cytotoxic agents, cytokines, or targeted agents have demonstrated moderate activity. Disparate trial designs and lack of head to head clinical trials make it difficult to compare the efficacy of chemotherapy with that of immunotherapy or targeted agents. Chemotherapy is particularly useful in patients with collecting duct histology and predominantly sarcomatoid differentiation. Chemotherapy resistance may be mediated by overexpression of p-glycoprotein efflux pumps and the dysregulation of the microtubule-hypoxia inducible factor signaling axis.
  
  
  CONCLUSIONS
  The role of cytotoxic chemotherapy in the treatment for clear cell RCC remains poorly defined. Cytotoxic chemotherapy is considered a standard of care in patients with mRCC with predominantly sarcomatoid differentiation and collecting duct RCC variants (Motzer et al., 2014). Early trials combining chemotherapy with targeted therapies are generally well tolerated and show clinical activity. A better understanding of the biology of aggressive subsets of RCC and mechanisms of resistance will help elucidate the role of cytotoxic agents in the current treatment paradigm of RCC.
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: E
authors: E
authors: Diamond
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: A M
authors: AM
authors: Molina
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: M
authors: M
authors: Carbonaro
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: N H
authors: NH
authors: Akhtar
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: P
authors: P
authors: Giannakakou
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors: S T
authors: ST
authors: Tagawa
authors: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: dnanus@med.cornell.edu.
authors: D M
authors: DM
authors: Nanus
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D058990:Molecular Targeted Therapy
chemical_list: D000970:Antineoplastic Agents
keywords: Chemotherapy; Chemotherapy resistance; Immunotherapy; Renal cell carcinoma; Targeted therapy