title: Second Line Chemotherapy for Advanced and Metastatic Urothelial Carcinoma: Vinflunine and Beyond-A Comprehensive Review of the Current Literature.
abstract: OBJECTIVE
  We comprehensively reviewed current efforts and advances in the field of chemotherapeutic and biologically targeted treatment options after the failure of cisplatin based, first line regimens for urothelial carcinoma.
  
  
  METHODS
  We searched MEDLINE®, Central®, and meeting abstracts of ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) to identify original articles, reviews and retrospective analyses on second line treatment of urothelial carcinoma. Articles were included in analysis if they described prospective phase II/III studies or larger high quality retrospective studies of second line treatment of urothelial carcinoma.
  
  
  RESULTS
  Although considered a chemosensitive disease, most patients with advanced or metastatic urothelial carcinoma relapse after cisplatin based first line treatment. Today none of the commonly used drugs, ie paclitaxel, carboplatin and/or gemcitabine, are approved by the FDA (Food and Drug Administration) for second line systemic treatment. In Europe vinflunine plus best supportive care is the only option approved by the EMA (European Medicines Agency) with moderate clinical efficacy. Responses to combined chemotherapy approaches are often better but associated with remarkable toxicity. In patients who respond well to first line treatment and, thus, are considered cisplatin sensitive readministration of a platinum based combination regimen may be an option. To date targeted therapies do not have a role in second line treatment of urothelial cancer. Immunotherapeutic strategies to target the PD-1/PD-L1 axis are emerging. In a recent phase I trial evaluating the PD-L1 targeted monoclonal antibody MPDL3280A a promising 43% response rate with good tolerability was achieved, which led to an immediate breakthrough therapy designation by the FDA. Combining chemotherapy with targeted agents, eg weekly paclitaxel and pazopanib, also shows promising activity in this prognostically poor treatment situation.
  
  
  CONCLUSIONS
  Response rates and survival are poor after second line chemotherapy for advanced or metastatic urothelial carcinoma. To improve outcomes of salvage treatment novel biologically targeted drugs as monotherapy or as part of a combination with conventional cytostatics are urgently needed.
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Eppendorf, Hamburg, Germany; Department of Urology (MR), University Medical Center Eppendorf, Hamburg, Germany. Electronic address: c.oing@uke.uni-hamburg.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Oing
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Eppendorf, Hamburg, Germany; Department of Urology (MR), University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rink
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Eppendorf, Hamburg, Germany; Department of Urology (MR), University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Oechsle
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Eppendorf, Hamburg, Germany; Department of Urology (MR), University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Seidel
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Eppendorf, Hamburg, Germany; Department of Urology (MR), University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Gunhild
authors.initials: G
authors.lastname: von Amsberg
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Eppendorf, Hamburg, Germany; Department of Urology (MR), University Medical Center Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001685:Biological Factors / Q000008:administration & dosage; D016190:Carboplatin / Q000008:administration & dosage; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007191:Indazoles; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D000068437:Pemetrexed / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016879:Salvage Therapy; D013449:Sulfonamides / Q000008:administration & dosage; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000093542:Gemcitabine
chemical_list: D001685:Biological Factors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000068437:Pemetrexed; D003841:Deoxycytidine; C111217:vinflunine; D014747:Vinblastine; C516667:pazopanib; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine
keywords: carcinoma; drug therapy; salvage therapy; urinary bladder; urothelium