Second Line Chemotherapy for Advanced and Metastatic Urothelial Carcinoma: Vinflunine and Beyond-A Comprehensive Review of the Current Literature.
PURPOSE
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.


MATERIALS AND 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.
['Oing|Christoph|C|', 'Rink|Michael|M|', 'Oechsle|Karin|K|', 'Seidel|Christoph|C|', 'von Amsberg|Gunhild|G|', 'Bokemeyer|Carsten|C|']
D000971:Antineoplastic Combined Chemotherapy Protocols D001685:Biological Factors D016190:Carboplatin D002295:Carcinoma, Transitional Cell D002945:Cisplatin D003841:Deoxycytidine D006801:Humans D007191:Indazoles D009364:Neoplasm Recurrence, Local D017239:Paclitaxel D000068437:Pemetrexed D011743:Pyrimidines D016879:Salvage Therapy D013449:Sulfonamides D001749:Urinary Bladder Neoplasms D014747:Vinblastine
carcinoma drug therapy salvage therapy urinary bladder urothelium