Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium

Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma.