Checkpoint inhibitors: the new treatment paradigm for urothelial bladder cancer
Bladder cancer is the most common malignancy involving the genitourinary system (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). In the USA, it is the fifth most common cancer and approximately 79,000 new cases will be diagnosed in 2017 (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). The mortality from bladder cancer is approximately 17,000 deaths each year (Siegel et al. in CA Cancer J Clin, 66:7–30, 2016). The incidence rate for bladder cancer is higher in men compared to women. Risk factors are predominantly related to tobacco smoking, although infection with Schistosoma haematobium is another risk factor in selected populations (Antoni et al. in Eur Urol, 71:96–108, 2017). Cisplatin-based systemic chemotherapy regimens remain the standard of care in both the neoadjuvant and metastatic setting for muscle-invasive bladder cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; De Santis et al. in J Clin Oncol, 30:191–199, 2012; Bellmunt et al. in J Clin Oncol, 27: 4454–4461, 2009). There is an estimated overall survival of 9–15 months in metastatic bladder cancer in those who receive the standard of care platinum-based chemotherapy (Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; De Santis et al. in J Clin Oncol, 30:191–199, 2012). The median survival, however, is significantly reduced after relapse in patient treated with platinum chemotherapy to less than 7 months (Bellmunt et al. in J Clin Oncol, 27: 4454–4461, 2009). Thus, this approach is preferred for patients who can tolerate this treatment as first-line chemotherapy (Gupta et al. in Cancer, 9(15):1–14, 2017). Until recently, there were few treatment options for those patients with poor performance status who are ineligible to receive cisplatin including renal insufficiency and multiple comorbidities or had disease progression after receiving platinum-based chemotherapy (Gupta et al. in Cancer, 9(15):1–14, 2017). With further understanding of tumor immune evasion, systemic immunotherapy which utilizes the patient’s own immune system directly to eradicate and target neoplastic cells, has now been approved for urothelial bladder cancer. Monoclonal antibodies that target programmed cell death protein 1 (PD-1), including Nivolumab and Pembrolizumab, and its ligand, PD-L1, including Atezolizumab, Durvalumab, Avelumab, have all been investigated and approved in the setting of metastatic refractory urothelial cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Von der Maase et al. in J Clin Oncol, 23:4602–4608, 2005; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174). Atezolizumab and Pembrolizumab have also been approved as first-line therapy in the setting of cisplatin-ineligible metastatic bladder cancer (Gupta et al. in Cancer, 9(15):1–14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174). Those that target cytotoxic T-lymphocyte-associated protein 4, including Ipilimumab and Tremelimumab, have also been investigated and further studies are being performed (Gupta et al. in Cancer, 9(15):1–14, 2017; Zilchi et al. in BioMed Res Int, 2017, 2017, doi: 10.1155/2017/5618174). This review outlines the systemic immunotherapies that have been approved or are currently being investigated.
KeywordsUrothelial bladder cancer Immune therapy Checkpoint inhibitors
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
No animal or human were involved in this study.
- 3.Rosenberg J, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Patel M, Ellerton J, Infante J, et al. Avelumab in patients with metastatic urothelial carcinoma: pooled results from two cohorts of the phase 1b JAVELIN solid tumor trial. J Clin Oncol. 2017; 35(supplement 6S), abstract 330.Google Scholar
- 11.Balar A, Castellano D, O’Donnell P, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population. J Clin Oncol. 2017; 35(supplement 6S), abstract 284.Google Scholar
- 16.Sternberg C, de Mulder P, Schornagel J, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19:2638–46.CrossRefPubMedGoogle Scholar
- 21.Gupta S, Gill D, Poole A, Agarwal N. Systemic immunotherapy for urothelial cancer: current trends and future direction. Cancer. 2017;9(15):1–14.Google Scholar
- 23.De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30:191–9.CrossRefPubMedGoogle Scholar
- 24.Bellmunt J, Theodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27:4454–61.CrossRefPubMedGoogle Scholar
- 25.Zilchi C, Tucci M, Leone G, et al. Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives. BioMed Res Int. 2017; 2017, Article ID 5618174. doi: 10.1155/2017/5618174.