World Journal of Urology

, Volume 37, Issue 9, pp 1759–1765 | Cite as

Forty years of cisplatin-based chemotherapy in muscle-invasive bladder cancer: are we understanding how, who and when?

  • Julian Schardt
  • Beat Roth
  • Roland SeilerEmail author
Topic Paper



For 40 years cisplatin-based chemotherapy has been administered to patients with muscle-invasive bladder cancer (MIBC). The best evidence of its efficacy is found in the context of neoadjuvant chemotherapy (NAC). However, the benefit to the patient is modest, with an improvement in 5-year overall survival of only 5–8%. Approximately 60% of patients still have muscle-invasive disease at cystectomy despite NAC. Selecting patients based on the likelihood of response appears to be a promising strategy to improve on this modest benefit. To realize this promise, researchers are investigating biomarkers for identifying responders and non-responders prior to NAC.


In this review, we discuss a number of tissue- and liquid-based biomarkers associated with the response to NAC.

Results and conclusions

We elaborate biomarkers at the methylation, DNA, RNA and protein levels and give their current status in clinical trials and/or their implementation in daily clinical practice. In particular, detection of alterations in DNA damage repair pathways as well as molecular subtypes seems to be a promising method for identifying responders to NAC. Furthermore, we illustrate liquid-based biomarkers. Circulating tumor DNA (ctDNA) in patient blood and urine appear to offer an elegant way for biological characterization of MIBC. Recent data show that the presence of ctDNA is limited in patients with localized MIBC being considered for NAC. At this disease stage, ctDNA in patient urine may be more promising for the genomic characterization of MIBC. However, ctDNA in blood or urine has not yet been rigorously investigated in this clinical context.


Muscle-invasive bladder cancer Neoadjuvant chemotherapy Cisplatin resistance Second-line treatment Molecular subtypes Gene expression analysis 


Author contributions

Protocol/project development: RS, JS. Data collection or management: RS, JS. Data analysis: NA. Manuscript writing/editing: RS, JS, BR.

Compliance with ethical standards

Conflict of interest

The authors have no direct or indirect commercial financial incentive associated with publishing this review article.

Experimental protocol and ethics

For this review, no tissue was analyzed or patient data collected. Therefore, no ethical approval was obtained.


  1. 1.
    Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL et al (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349(9):859–866CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party, European Organisation for Research, Treatment of Cancer Genito-Urinary Tract Cancer Group, Australian Bladder Cancer Study Group, National Cancer Institute of Canada Clinical Trials Group et al (2011) International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 29(16):2171–2177CrossRefPubMedCentralGoogle Scholar
  3. 3.
    Zargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC et al (2015) Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 67(2):241–249CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bajorin DF, Herr HW (2011) Kuhn’s paradigms: are those closest to treating bladder cancer the last to appreciate the paradigm shift? J Clin Oncol 29(16):2135–2137CrossRefPubMedGoogle Scholar
  5. 5.
    Wifjes A, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, Hernández V, Espinós EL, Dunn J, Rouanne M, Neuzillet Y, Veskimäe E, van der Heijden AG, Gakis G, Ribal MJ (2017) Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol 71(3):462–475CrossRefGoogle Scholar
  6. 6.
    Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, Ullen A, Nilsson S et al (2012) Pathologic downstaging is a surrogate marker for efficacy and increased survival following neoadjuvant chemotherapy and radical cystectomy for muscle-invasive urothelial bladder cancer. Eur Urol 61(6):1229–1238CrossRefPubMedGoogle Scholar
  7. 7.
    Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334(2):115–124CrossRefPubMedGoogle Scholar
  9. 9.
    Miller RP, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of cisplatin nephrotoxicity. Toxins (Basel) 2(11):2490–2518CrossRefGoogle Scholar
  10. 10.
    Marshak T, Steiner M, Kaminer M, Levy L, Shupak A (2014) Prevention of cisplatin-induced hearing loss by intratympanic dexamethasone: a randomized controlled study. Otolaryngol Head Neck Surg 150(6):983–990CrossRefPubMedGoogle Scholar
  11. 11.
    Marina N, Chang KW, Malogolowkin M, London WB, Frazier AL, Womer RB et al (2005) Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children’s Oncology Group study. Cancer 104(4):841–847CrossRefPubMedGoogle Scholar
  12. 12.
    Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V (1995) Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22(4 Suppl 11):3–10PubMedGoogle Scholar
  13. 13.
    Chen GK, Duran GE, Mangili A, Beketic-Oreskovic L, Sikic BI (2000) MDR 1 activation is the predominant resistance mechanism selected by vinblastine in MES-SA cells. Br J Cancer 83(7):892–898CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wang Z, Liang S, Lian X, Liu L, Zhao S, Xuan Q et al (2015) Identification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis. Sci Rep 5:9301CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Xylinas E, Hassler MR, Zhuang D, Krzywinski M, Erdem Z, Robinson BD et al (2016) An epigenomic approach to improving response to neoadjuvant cisplatin chemotherapy in bladder cancer. Biomolecules 6(3):37CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Shindo T, Niinuma T, Nishiyama N, Shinkai N, Kitajima H, Kai M et al (2018) Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer. Oncotarget 9(36):24457–24469CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601CrossRefPubMedGoogle Scholar
  18. 18.
    Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H et al (2014) Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 4(10):1140–1153CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liu D, Plimack ER, Hoffman-Censits J, Garraway LA, Bellmunt J, Van Allen E et al (2016) Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol 2(8):1094–1096CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Groenendijk FH, de Jong J, Fransen van de Putte EE, Michaut M, Schlicker A, Peters D et al (2015) ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur Urol 69(3):384–388CrossRefPubMedGoogle Scholar
  21. 21.
    Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG et al (2015) Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 68(6):959–967CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kiss B, Wyatt AW, Douglas J, Skuginna V, Mo F, Anderson S et al (2017) Her2 alterations in muscle-invasive bladder cancer: patient selection beyond protein expression for targeted therapy. Sci Rep 7:42713CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD et al (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171(3):540–556e25CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Iyer G, Balar AV, Milowsky MI, Bochner BH, Dalbagni G, Donat SM et al (2018) Multicenter prospective phase II trial of neoadjuvant dose-dense gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer. J Clin Oncol 36(19):1949–1956CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J et al (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25(2):152–165CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    McConkey DJ, Choi W, Shen Y, Lee IL, Porten S, Matin SF et al (2016) A prognostic gene expression signature in the molecular classification of chemotherapy-naive urothelial cancer is predictive of clinical outcomes from neoadjuvant chemotherapy: a phase 2 trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with bevacizumab in urothelial cancer. Eur Urol 69(5):855–862CrossRefPubMedGoogle Scholar
  27. 27.
    Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S et al (2012) A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 18(12):3377–3386CrossRefPubMedGoogle Scholar
  28. 28.
    Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE et al (2014) Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 111(8):3110–3115CrossRefPubMedGoogle Scholar
  29. 29.
    Seiler R, Ashab HAD, Erho N, van Rhijn BWG, Winters B, Douglas J et al (2017) Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur Urol 72(4):544–554CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kiss B, Skuginna V, Fleischmann A, Bell RH, Collins C, Thalmann GN et al (2015) Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder. Urol Oncol 33(4):166e1–8CrossRefGoogle Scholar
  31. 31.
    Hemdan T, Malmstrom PU, Jahnson S, Segersten U (2015) Emmprin expression predicts response and survival following cisplatin containing chemotherapy for bladder cancer: a validation study. J Urol 194(6):1575–1581CrossRefPubMedGoogle Scholar
  32. 32.
    Baras AS, Gandhi N, Munari E, Faraj S, Shultz L, Marchionni L et al (2015) Identification and validation of protein biomarkers of response to neoadjuvant platinum chemotherapy in muscle invasive urothelial carcinoma. PLoS ONE 10(7):e0131245CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Baras AS, Drake C, Liu JJ, Gandhi N, Kates M, Hoque MO et al (2016) The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. Oncoimmunology 5(5):e1134412CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Sjodahl G, Eriksson P, Liedberg F, Hoglund M (2017) Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J Pathol 242(1):113–125CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Sjodahl G (2018) Molecular subtype profiling of urothelial carcinoma using a subtype-specific immunohistochemistry panel. Methods Mol Biol 1655:53–64CrossRefPubMedGoogle Scholar
  36. 36.
    Fleischmann A, Thalmann GN, Perren A, Seiler R (2014) Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival. Am J Surg Pathol 38(3):325–332CrossRefPubMedGoogle Scholar
  37. 37.
    Shen HM, D’Souza AM, Green IF, Pohar KS, Mortazavi A, Zynger DL (2015) Do amount of variant differentiation and mitotic rate in bladder cancer change with neoadjuvant chemotherapy? Hum Pathol 46(9):1367–1375CrossRefPubMedGoogle Scholar
  38. 38.
    Scosyrev E, Ely BW, Messing EM, Speights VO, Grossman HB, Wood DP et al (2011) Do mixed histological features affect survival benefit from neoadjuvant platinum-based combination chemotherapy in patients with locally advanced bladder cancer? A secondary analysis of Southwest Oncology Group-Directed Intergroup Study (S8710). BJU Int 108(5):693–699CrossRefPubMedGoogle Scholar
  39. 39.
    Ghoneim IA, Miocinovic R, Stephenson AJ, Garcia JA, Gong MC, Campbell SC et al (2011) Neoadjuvant systemic therapy or early cystectomy? Single-center analysis of outcomes after therapy for patients with clinically localized micropapillary urothelial carcinoma of the bladder. Urology 77(4):867–870CrossRefPubMedGoogle Scholar
  40. 40.
    Culp SH, Dickstein RJ, Grossman HB, Pretzsch SM, Porten S, Daneshmand S et al (2014) Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 191(1):40–47CrossRefPubMedGoogle Scholar
  41. 41.
    Vetterlein MW, Wankowicz SAM, Seisen T, Lander R, Loppenberg B, Chun FK et al (2017) Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology. Cancer 123(22):4346–4355CrossRefPubMedGoogle Scholar
  42. 42.
    Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M et al (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338(6104):221CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH et al (2015) Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med 7(8):1034–1047CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Goodall J, Mateo J, Yuan W, Mossop H, Porta N, Miranda S et al (2017) Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov 7(9):1006–1017CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Vandekerkhove G, Todenhofer T, Annala M, Struss WJ, Wong A, Beja K et al (2017) Circulating tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer. Clin Cancer Res 23(21):6487–6497CrossRefPubMedGoogle Scholar
  46. 46.
    Patel KM, van der Vos KE, Smith CG, Mouliere F, Tsui D, Morris J et al (2017) Association of plasma and urinary mutant DNA with clinical outcomes in muscle invasive bladder cancer. Sci Rep 7(1):5554CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zargar H, Zargar-Shoshtari K, Lotan Y, Shah JB, van Rhijn BW, Daneshmand S et al (2016) Final pathological stage after neoadjuvant chemotherapy and radical cystectomy for bladder cancer-does pT0 predict better survival than pTa/Tis/T1? J Urol 195(4P1):886–893CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical OncologyUniversity of BernBernSwitzerland
  2. 2.Department of UrologyUniversity of BernBernSwitzerland

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