Current Urology Reports

, Volume 13, Issue 2, pp 147–152

Recent Advances in Treatment of Advanced Urothelial Carcinoma

Bladder and Urothelial Cancer (A Sagalowsky, Section Editor)


GC (cisplatin and gemcitabine) and MVAC (methotrexate, vinblastine, Adriamycin [doxorubicin], and cisplatin) have been the standard systemic chemotherapy in advanced urothelial carcinoma. These regimens have shown significant response rates in this patient population. Nevertheless, disease does recur with most patients who unfortunately do succumb to the disease. Research efforts are focused in several different areas of therapy, targeted therapy, and immunotherapy. Further efforts include those in improving understanding of the molecular biology of urothelial carcinoma which may lead development of biomarkers that may enhance therapeutic index. This paper reviews recent advances in the treatment and ongoing study of molecular biology of urothelial carcinoma.


Urothelial carcinoma Chemotherapy Targeted therapy Immunotherapy Biomarker 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Bellmunt J, Théodore 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(27):4454. The only phase 3 trial in a second-line setting that evaluated vinflunine is reported in this paper.PubMedCrossRefGoogle Scholar
  2. 2.
    Galsky MD, Mironov S, Iasonos A, et al. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007;25:265.PubMedCrossRefGoogle Scholar
  3. 3.
    Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24:3451.PubMedCrossRefGoogle Scholar
  4. 4.
    Von der Maase H, Lehmann J, Gravis G, et al. A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium. Ann Oncol. 2006;17:1533.PubMedCrossRefGoogle Scholar
  5. 5.
    Sridhar SS, Canil CM, Mukherjee SD et al. Results of a phase II study of single agent nab-paclitaxel in platinum refractory second line metastatic urothelial carcinoma. J Clin Oncol. 2011;suppl 7, abstract 241.Google Scholar
  6. 6.
    •• Hahn NM, Stadler WM, ZOn RT et al. Phase II Trial of Cisplatin, Gemcitabine, and bevacizumab as first line therapy for metastatic urothelial carcinoma: hoosier oncology Group GU 04-75. J Clin Oncol. 2011. The authors describe a phase 2 study evaluating bevacizumab in combination with chemotherapy. An intergroup trial based on this study is ongoing. Google Scholar
  7. 7.
    National Institutes of Health Clinical Trials database. Accessed on September 2011.
  8. 8.
    • Bellmunt J, Gonzalez-Larriba JL, Maroto JP et al. First-line treatment with sunitinib monotherapy in patients with advanced urothelial cancer ineligible for cisplatin-based chemotherapy: Pretreatment levels of IL8 and Hounsfield units as predictors of clinical benefit. J Clin Oncol 28:15s, 2010 (suppl; abstr 4540). This article delineates the efficacy of VEGFR TKI in urothelial carcinoma. Google Scholar
  9. 9.
    Gallagher DJ, Millowsky MI, Gerst SR, et al. A phase II study of sunitinib on a continuous dosing schedule in patients with relapsed or refractory urothelial carcinoma (UC). J Clin Oncol. 2009;27:15s. suppl; abstr 5072.CrossRefGoogle Scholar
  10. 10.
    Galsky MD, Sonpavde G, Hellerstedt BA, et al. Phase II study of gemcitabine, cisplatin, and sunitinib in patients with advanced urothelial carcinoma. J Clin Oncol. 2010;28:15s. suppl; abstr 4573.Google Scholar
  11. 11.
    Krege S, Rexer H, vom Dorp F, et al. Gemcitabine and cisplatin with or without sorafenib in urothelial carcinoma (AUO-AB 31/05). J Clin Oncol. 2010;28:15s. suppl; abstr 4574.Google Scholar
  12. 12.
    Milowsky MI, Tickoo SK, Gallagher DJ et al. HIF and mTOR pathways in invasive urothelial carcinoma: A study with potential therapeutic implications. J Clin Oncol. 2008. Abstr 292Google Scholar
  13. 13.
    Milowsky MI, Regazzi AM, Garcia-Grossman IR et al. Final results of a phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium. J Clin Oncol. 2011;29. (suppl; abstr 4606).Google Scholar
  14. 14.
    • Milowsky MI, Carlson GL, Shi MM et al. A multicenter, open-label phase II trial of dovitinib (TKI1258) in advanced urothelial carcinoma patients with either mutated or wild-type FGFR3. J Clin Oncol. 2011;29 (suppl; abstr TPS186). This article evaluates another antiangiogenic pathway (FGFR) in treatment of urothelial carcinoma. Google Scholar
  15. 15.
    Daher A, de Boer WI, El-Marjou A, et al. Epidermal growth factor receptor regulates normal urothelial regeneration. Lab Invest. 2003;83:1333.PubMedCrossRefGoogle Scholar
  16. 16.
    Cheng J, Huang H, Zhang ZT, et al. Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Res. 2002;62:4157.PubMedGoogle Scholar
  17. 17.
    Neal DE, Marsh C, Bennett MK, et al. Epidermal growth factor receptors in human bladder cancer: comparison of invasive and superficial tumors. Lancet. 1985;1:366.PubMedCrossRefGoogle Scholar
  18. 18.
    Berger MS, Greenfield C, Gullick WJ, et al. Evaluation of epidermal growth factor receptors in bladder tumors. Br J Cancer. 1987;56:533.PubMedCrossRefGoogle Scholar
  19. 19.
    Wong Y, Litwin S, Plimack ER et al. Effect of EGFR inhibition with cetuximab on the efficacy of paclitaxel in previously treated metastatic urothelial cancer.Google Scholar
  20. 20. Study of gemcitabine and cisplatin with or without cetuximab in urothelial cancer (NCT00645593). Available at Accessed January 2012.
  21. 21.
    Petrylak DP, Tangen CM, Van Veldhuizen Jr PJ, et al. Results of the Southwest Oncology Group phase II evaluation (study S0031) of ZD1839 for advanced transitional cell carcinoma of the urothelium. BJU Int. 2010;105:317.PubMedCrossRefGoogle Scholar
  22. 22.
    Philips GK, Halabi S, Sanford BL, et al. A phase II trial of cisplatin, fixed dose-rate gemcitabine and gefitinib for advanced urothelial tract carcinoma: results of the Cancer and Leukemia Group B 90102. BJU Int. 2008;101:20.PubMedGoogle Scholar
  23. 23.
    Philips GK, Halabi S, Sanford BL, et al. A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102. Ann Oncol. 2009;20:1074.PubMedCrossRefGoogle Scholar
  24. 24. Gefitinib plus combination chemotherapy in treating patients with locally advanced or metastatic bladder cancer. Accessed on January 2012.
  25. 25.
    Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol. 2007;25:2218.PubMedCrossRefGoogle Scholar
  26. 26. Trastuzumab in treating patients with previously treated, locally advanced, or metastatic cancer of the urothelium (NCT00004856). Available at Accessed January 2012.
  27. 27. Neoadjuvant Erlotinib (Tarceva) in transitional cell carcinoma (NCT00749892). Available at Accessed January 2012.
  28. 28. Erlotinib before and after surgery in treating patients with muscle-invasive bladder cancer (NCT00380029). Available at Accessed January 2012.
  29. 29.
    Sharma P, Shen Y, Wen S, et al. Cancer-testis antigens: expression and correlation with survival in human urothelial carcinoma. Clin Cancer Res. 2006;12:5442.PubMedCrossRefGoogle Scholar
  30. 30.
    Gnjatic S, Nishikawa H, Jungbluth AA, et al. NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res. 2006;95:1.PubMedCrossRefGoogle Scholar
  31. 31.
    Sharma P, Gnjatic S, Jungbluth AA, et al. Frequency of NY-ESO-1 and LAGE-1 expression in bladder cancer and evidence of a new NY-ESO-1T cell epitope in a patient with bladder cancer. Cancer Immun. 2003;3:19.PubMedGoogle Scholar
  32. 32.
    Sharma P, Shen Y, Wen S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104:3967.PubMedCrossRefGoogle Scholar
  33. 33.
    Sharma P, Bajorin DF, Jungbluth AA, et al. Immune response detected in urothelial carcinoma patients after vaccination with NY-ESO-1 protein plus BCG and GM-CSF. J Immunother. 2008;31:849.PubMedCrossRefGoogle Scholar
  34. 34.
    Sun J, Schiffman J, Raghunath A, et al. Concurrent decrease in IL-10 with development of immune-related adverse events in a patient treated with anti-CTLA 4 antibody. Cancer Immun. 2008;8:9.PubMedGoogle Scholar
  35. 35.
    Lee JK, Havaleshko DM, Cho H, et al. A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci USA. 2007;104:13086.PubMedCrossRefGoogle Scholar
  36. 36.
    Lorenzo-Romero JG, Salinas-Sánchez AS, et al. Prognostic implications of p53 gene mutations in bladder tumors. J Urol. 2003;169(2):492.PubMedCrossRefGoogle Scholar
  37. 37.
    Kuczyk MA, Bokemeyer C, Serth J, et al. p53 overexpression as a prognostic factor for advanced stage bladder cancer. Eur J Cancer. 1995;31A(13–14):2243.PubMedCrossRefGoogle Scholar
  38. 38.
    Edelman MJ, Meyers FJ, Miller TR, et al. Phase I/II study of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma: a well-tolerated regimen with activity independent of p53 mutation. Urology. 2000;55(4):521.PubMedCrossRefGoogle Scholar
  39. 39.
    Koga F, Kitahara S, Arai K, Honda M, Sumi S, Yoshida K. Negative p53/positive p21 immunostaining is a predictor of favorable response to chemotherapy in patients with locally advanced bladder cancer. Jpn J Cancer Res. 2000;91(4):416.PubMedCrossRefGoogle Scholar
  40. 40.
    Sarkis AS, Bajorin DF, Reuter VE, et al. Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol. 1995;13(6):1384.PubMedGoogle Scholar
  41. 41.
    • Stadler WM, Lerner SP, Groshen S, et al. Randomized trial of p53 targeted adjuvant therapy for patients with organ-confined node-negative urothelial bladder cancer (abstract #5017). J Clin Oncol. 2009;27:239s. This article describes p53-directed adjuvant therapy in urothelial carcinoma.CrossRefGoogle Scholar
  42. 42.
    Kim WJ, Kakehi Y, Yoshida O. Multifactorial involvement of multidrug resistance-associated [correction of resistance]protein, DNA topoisomerase II and glutathione/glutathione-S-transferase in non P-glycoprotein-mediated multidrug resistance in human bladder cancer cells. Int J Urol. 1997;4(6):583–90.Google Scholar
  43. 43.
    Kotoh S, Naito S, Yokomizo A, Kohno K, Kuwano M, Kumazawa J. Enhanced expression of gamma-glutamylcysteine synthetase and glutathione S-transferase genes in cisplatin-resistant bladder cancer cells with multidrug resistance phenotype. J Urol. 1997;157(3):1054.PubMedCrossRefGoogle Scholar
  44. 44.
    Pendyala L, Velagapudi S, Toth K, et al. Translational studies of glutathione in bladder cancer cell lines and human specimens. Clin Cancer Res. 1997;3(5):793.PubMedGoogle Scholar
  45. 45.
    Petrylak DP, Scher HI, Reuter V, O’Brien JP, Cordon-Cardo C. P-glycoprotein expression in primary and metastatic transitional cell carcinoma of the bladder. Ann Oncol. 1994;5(9):835.PubMedGoogle Scholar
  46. 46.
    Siegsmund MJ, Marx C, Seemann O, Schummer B, et al. Cisplatin-resistant bladder carcinoma cells: enhanced expression of metallothioneins. Urol Res. 1999;27(3):157.PubMedCrossRefGoogle Scholar
  47. 47.
    Bellmunt J, Paz-Ares L, Cuello M, Cecere FL, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol. 2007;18(3):522.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA

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