Skip to main content

Advertisement

SpringerLink
Log in

Overview of Current and Future Adjuvant Therapy for Muscle-Invasive Urothelial Carcinoma

  • Genitourinary Cancers (N Agarwal, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Muscle-invasive bladder cancer (MIBC) has high metastatic potential at diagnosis but is still often curable with aggressive management, which may give patients the best odds for a favorable clinical outcome. The standard-of-care management of MIBC includes a radical cystectomy and pelvic lymph node dissection. If the patient is cisplatin-eligible, neoadjuvant cisplatin-based combination chemotherapy should also be given. Post-surgery adjuvant treatments include observation, chemotherapy, radiation, or enrollment in a clinical trial. Several adjuvant immunotherapy trials with checkpoint inhibitors, which block the interaction between PD-1 and PD-L1, as monotherapy or in combinations with chemotherapy, radiation, or other immunotherapy agents are currently ongoing. Given the lack of level 1 evidence for the survival benefit of adjuvant therapies post-cystectomy, the standard of care remains observation with radiologic and clinical surveillance. However, in patients who did not receive neoadjuvant cisplatin-based combination chemotherapy and are cisplatin-eligible, adjuvant cisplatin-based chemotherapy should be considered and discussed. Genomic alterations and gene expression profiles may eventually help to identify patient subgroups for more effective adjuvant therapy. Genetic abnormalities in the DNA repair genes and basal intrinsic tumor subtype appear to predict response to neoadjuvant cisplatin-based chemotherapy in MIBC. In the coming years, validating these genetic markers will be key to individualizing perioperative chemotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References and Recommended Reading

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

  1. World Health Organization. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Default.aspx. Accessed April 2018.

  2. Kirkali Z, Chan T, Manoharan M, Algaba F, Busch C, Cheng L, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66(6 Suppl 1):4–34.

    Article  PubMed  Google Scholar 

  3. Raghavan D. Chemotherapy and cystectomy for invasive transitional cell carcinoma of bladder. Urol Oncol. 2003;21(6):468–74.

    Article  PubMed  CAS  Google Scholar 

  4. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol. 2001;19(3):666–75.

    Article  PubMed  CAS  Google Scholar 

  5. Bergland R, Herr H. Surgery for bladder cancer. In: McDougal W, Wein A, Kavoussi L, Novick A, Partin A, Peters C, editors. Campbell-Walsh Urology. 10th ed. Philadelphia: Elsevier Saunders; 2011. p. 448–51.

    Google Scholar 

  6. Stenzl A, Nagele U, Kuczyk M, Sievert K, Anastasiadis A. Cystectomy: technical considerations in male and female patients. EAU Updat Ser. 2005;3:138–46.

    Article  Google Scholar 

  7. Lee RK, Abol-Enein H, Artibani W, Bochner B, Dalbagni G, Daneshmand S, et al. Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. BJU Int. 2014;113(1):11–23.

    Article  PubMed  Google Scholar 

  8. Abdollah F, Gandaglia G, Thuret R, Schmitges J, Tian Z, Jeldres C, et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. 2013;37(3):219–25.

    Article  PubMed  Google Scholar 

  9. Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, et al. Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy. J Clin Oncol. 2003;21(4):690–6.

    Article  PubMed  Google Scholar 

  10. Dotan ZA, Kavanagh K, Yossepowitch O, Kaag M, Olgac S, Donat M, et al. Positive surgical margins in soft tissue following radical cystectomy for bladder cancer and cancer specific survival. J Urol. 2007;178(6):2308–12. discussion 13.

    Article  PubMed  Google Scholar 

  11. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy for invasive bladder cancer (individual patient data). Cochrane Database Syst Rev. 2006;(2):Cd006018.

  12. Leow JJ, Martin-Doyle W, Rajagopal PS, Patel CG, Anderson EM, Rothman AT, et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol. 2014;66(1):42–54.

    Article  PubMed  CAS  Google Scholar 

  13. •• Galsky MD, Stensland KD, Moshier E, Sfakianos JP, McBride RB, Tsao CK, et al. Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J Clin Oncol. 2016;34(8):825–32. In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer.

    Article  PubMed  CAS  Google Scholar 

  14. Alfred Witjes J, Lebret T, Comperat EM, Cowan NC, De Santis M, Bruins HM, et al. Updated 2016 EAU Guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2017;71(3):462–75.

    Article  PubMed  CAS  Google Scholar 

  15. Paz-Ares L, Solsona E, Saez E, Gonzalez-Larriba J, Anton A, Hevia M. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabine/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study. J Clin Oncol. 2010;28(18S):abstr LBA4518.

    Article  Google Scholar 

  16. Stadler WM, Lerner SP, Groshen S, Stein JP, Shi SR, Raghavan D, et al. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol. 2011;29(25):3443–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Cognetti F, Ruggeri EM, Felici A, Gallucci M, Muto G, Pollera CF, et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol. 2012;23(3):695–700.

    Article  PubMed  CAS  Google Scholar 

  18. •• Sternberg CN, Skoneczna I, Kerst JM, Albers P, Fossa SD, Agerbaek M, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(1):76–86. EORTC 30994 evaluated immediate vs. deferred chemotherapy after radical cystectomy in patients with pT3/T4 or N-positive M0 urothelial carcinoma of the bladder. This study failed to demonstrate improved OS with immediate chemotherapy.

    Article  PubMed  Google Scholar 

  19. Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Nichols P, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol. 1991;145(3):459–64. discussion 64–7.

    Article  PubMed  CAS  Google Scholar 

  20. Stockle M, Meyenburg W, Wellek S, Voges GE, Rossmann M, Gertenbach U, et al. Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience. J Urol. 1995;153(1):47–52.

    Article  PubMed  CAS  Google Scholar 

  21. Lehmann J, Franzaring L, Thuroff J, Wellek S, Stockle M. Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer. BJU Int. 2006;97(1):42–7.

    Article  PubMed  Google Scholar 

  22. Freiha F, Reese J, Torti FM. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol. 1996;155(2):495–9. discussion 9–500.

    Article  PubMed  CAS  Google Scholar 

  23. Studer UE, Bacchi M, Biedermann C, Jaeger P, Kraft R, Mazzucchelli L, et al. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol. 1994;152(1):81–4.

    Article  PubMed  CAS  Google Scholar 

  24. Pianezza O, Meneguelo M, Merlo F. Adjuvant chemotherapy in locally advanced bladder cancer: long term follow up of a multicenter study. J Urol. 2003;169:337.

    Google Scholar 

  25. Otto T, Borgemann C, Krege S, Rubben H. Adjuvant chemotherapy in locally advanced bladder cancer [pT3/pT4a,pN1–2,M0]: a phase III study. Eur Urol. 2001;39(supp 2):147.

    Google Scholar 

  26. Otto T, Goebell PJ, Rubben H. Perioperative chemotherapy in advanced bladder cancer—part II: adjuvant treatment. Onkologie. 2003;26(5):484–8.

    PubMed  CAS  Google Scholar 

  27. • Bono A, Benvenuti C, Gibba A, Guazzeri S, Cosciani-Cunico S, Anselmo G. Adjuvant chemotherapy in locally advancedbladder cancer. Final analysis of a controlled multicentre study. Acta Urologica Italica. 1997;11:5–8. This retrospective study found that adjuvant chemotherapy may decrease overall and bladder cancer-specific mortality after radical cystectomy.

    Google Scholar 

  28. Froehner M, Koch R, Heberling U, Novotny V, Oehlschlaeger S, Hubler M, et al. Decreased overall and bladder cancer-specific mortality with adjuvant chemotherapy after radical cystectomy: multivariable competing risk analysis. Eur Urol. 2016;69(6):984–7.

    Article  PubMed  Google Scholar 

  29. Vetterlein MW, Seisen T, May M, Nuhn P, Gierth M, Mayr R et al. Effectiveness of adjuvant chemotherapy after radical cystectomy for locally advanced and/or pelvic lymph node-positive muscle-invasive urothelial carcinoma of the bladder: a propensity score-weighted competing risks analysis. Eur Urol Focus. 2016.

  30. •• Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data. Eur Urol. 2005;48(2):189–99. discussion 99–201. This observational study found that adjuvant chemotherapy after neoadjuvant chemotherapy and radical cystectomy may be associated with an OS benefit for patients with pT3/T4 and/or pN-positive urothelial carcinoma of the bladder.

    Article  Google Scholar 

  31. Kassouf W, Agarwal PK, Grossman HB, Leibovici D, Munsell MF, Siefker-Radtke A, et al. Outcome of patients with bladder cancer with pN+ disease after preoperative chemotherapy and radical cystectomy. Urology. 2009;73(1):147–52.

    Article  PubMed  Google Scholar 

  32. Seisen T, Jamzadeh A, Leow JJ, Roupret M, Cole AP, Lipsitz SR, et al. Adjuvant chemotherapy vs observation for patients with adverse pathologic features at radical cystectomy previously treated with neoadjuvant chemotherapy. JAMA Oncol. 2018;4(2):225–9.

    Article  PubMed  Google Scholar 

  33. Shariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol. 2007;51(1):137–49. discussion 49–51.

    Article  PubMed  Google Scholar 

  34. Dalbagni G, Genega E, Hashibe M, Zhang ZF, Russo P, Herr H, et al. Cystectomy for bladder cancer: a contemporary series. J Urol. 2001;165(4):1111–6.

    Article  PubMed  CAS  Google Scholar 

  35. Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G, et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer. 2006;107(3):506–13.

    Article  PubMed  CAS  Google Scholar 

  36. Donat SM, Shabsigh A, Savage C, Cronin AM, Bochner BH, Dalbagni G, et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol. 2009;55(1):177–85.

    Article  PubMed  Google Scholar 

  37. Dorff TB, Tsao-Wei D, Miranda G, Skinner DG, Stein JP, Quinn DI. Adjuvant chemotherapy for locally advanced urothelial carcinoma: an overview of the USC experience. World J Urol. 2009;27(1):39–44.

    Article  PubMed  CAS  Google Scholar 

  38. Lee CT, Madii R, Daignault S, Dunn RL, Zhang Y, Montie JE, et al. Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol. 2006;175(4):1262–7. discussion 7.

    Article  PubMed  Google Scholar 

  39. Sanchez-Ortiz RF, Huang WC, Mick R, Van Arsdalen KN, Wein AJ, Malkowicz SB. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol. 2003;169(1):110–5. discussion 5.

    Article  PubMed  Google Scholar 

  40. Nielsen ME, Palapattu GS, Karakiewicz PI, Lotan Y, Bastian PJ, Lerner SP, et al. A delay in radical cystectomy of >3 months is not associated with a worse clinical outcome. BJU Int. 2007;100(5):1015–20.

    Article  PubMed  Google Scholar 

  41. Haas CR, Barlow LJ, Badalato GM, DeCastro GJ, Benson MC, McKiernan JM. The timing of radical cystectomy for bacillus Calmette-Guerin Failure: comparison of outcomes and risk factors for prognosis. J Urol. 2016;195(6):1704–9.

    Article  PubMed  Google Scholar 

  42. Reardon ZD, Patel SG, Zaid HB, Stimson CJ, Resnick MJ, Keegan KA, et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol. 2015;67(1):165–70.

    Article  PubMed  Google Scholar 

  43. Apolo AB, Kim JW, Bochner BH, Steinberg SM, Bajorin DF, Kelly WK, et al. Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States. Urol Oncol. 2014;32(5):637–44.

    Article  PubMed  Google Scholar 

  44. Lerner SP, Tangen C, Svatek R, Koppie T, Alva A, La Rosa F. A phase III surgical trial to evaluate the benefit of a standard versus an extended pelvic lymphadenectomy performed at time of radical cystectomy for muscle invasive urothelial cancer: SWOG S1011 (NCT #01224665). J Urol. 2015;193(4S):e807.

    Article  Google Scholar 

  45. Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014;32(18):1889–94.

    Article  PubMed  CAS  Google Scholar 

  46. Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol. 2012;61(5):1039–47.

    Article  PubMed  Google Scholar 

  47. Millikan R, Dinney C, Swanson D, Sweeney P, Ro JY, Smith TL, et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. J Clin Oncol. 2001;19(20):4005–13.

    Article  PubMed  CAS  Google Scholar 

  48. Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, et al. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol. 1999;161(5):1494–7.

    Article  PubMed  CAS  Google Scholar 

  49. Stockle M, Wellek S, Meyenburg W, Voges GE, Fischer U, Gertenbach U, et al. Radical cystectomy with or without adjuvant polychemotherapy for non-organ-confined transitional cell carcinoma of the urinary bladder: prognostic impact of lymph node involvement. Urology. 1996;48(6):868–75.

    Article  PubMed  CAS  Google Scholar 

  50. Skinner DG, Stein JP, Lieskovsky G, Skinner EC, Boyd SD, Figueroa A, et al. 25-year experience in the management of invasive bladder cancer by radical cystectomy. Eur Urol. 1998;33(Suppl 4):25–6.

    Article  PubMed  Google Scholar 

  51. Bochner BH, Kattan MW, Vora KC. Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer. J Clin Oncol. 2006;24(24):3967–72.

    Article  PubMed  Google Scholar 

  52. Zaak D, Burger M, Otto W, Bastian PJ, Denzinger S, Stief CG, et al. Predicting individual outcomes after radical cystectomy: an external validation of current nomograms. BJU Int. 2010;106(3):342–8.

    Article  PubMed  Google Scholar 

  53. Cancer Genome Atlas Research. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22.

    Article  Google Scholar 

  54. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18(12):3377–86.

    Article  PubMed  Google Scholar 

  56. McConkey DJ, Choi W, Ochoa A, Siefker-Radtke A, Czerniak B, Dinney CP. Therapeutic opportunities in the intrinsic subtypes of muscle-invasive bladder cancer. Hematol Oncol Clin North Am. 2015;29(2):377–94. x-xi.

    Article  PubMed  Google Scholar 

  57. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 2014;4(10):1140–53.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Groenendijk FH, de Jong J, Fransen van de Putte EE, Michaut M, Schlicker A, Peters D, et al. ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur Urol. 2016;69(3):384–8.

    Article  PubMed  CAS  Google Scholar 

  59. Plimack ER, Dunbrack RL, Brennan TA, Andrake MD, Zhou Y, Serebriiskii IG, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol. 2015;68(6):959–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Zaghloul MS, Awwad HK, Akoush HH, Omar S, Soliman O, el Attar I. Postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local control. Int J Radiat Oncol Biol Phys. 1992;23(3):511–7.

    Article  PubMed  CAS  Google Scholar 

  61. Zaghloul MS. Distant metastasis from bilharzial bladder cancer. Cancer. 1996;77(4):743–9.

    Article  PubMed  CAS  Google Scholar 

  62. •• Huncharek M, Muscat J, Geschwind JF. Planned preoperative radiation therapy in muscle invasive bladder cancer: results of a meta-analysis. Anticancer Res. 1998;18(3b):1931–4. First randomized controlled trial comparing adjuvant radiation therapy (± chemotherapy) vs. adjuvant chemotherapy post-cystectomy for bladder cancer. Radiation therapy was associated with significantly improved local control compared to chemotherapy alone.

    PubMed  CAS  Google Scholar 

  63. Shariat SF, Karakiewicz PI, Palapattu GS, Lotan Y, Rogers CG, Amiel GE, et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol. 2006;176(6 Pt 1):2414–22. discussion 22.

    Article  PubMed  Google Scholar 

  64. Zaghloul MS, Christodouleas J, Smith A, Abdalla A, William H, Khaled H. A randomized clinical trial comparing adjuvant radiation versus chemo-RT versus chemotherapy alone after radical cystectomy for locally advanced bladder cancer. J Clin Oncol. 2016;34(2S):abstr 356.

    Article  Google Scholar 

  65. Reisinger SA, Mohiuddin M, Mulholland SG. Combined pre- and postoperative adjuvant radiation therapy for bladder cancer—a ten year experience. Int J Radiat Oncol Biol Phys. 1992;24(3):463–8.

    Article  PubMed  CAS  Google Scholar 

  66. NRG Oncology. NRG-GU001. Randomized phase II trial of postoperative adjuvant IMRT following cystectomy for pT3/pT4 urothelial bladder cancer. nrgoncology.org/Clinical-Trials/NRG-GU001. Accessed April 2018.

Download references

Author information

Authors and Affiliations

  1. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive Room 12N226, Bethesda, MD, 20892, USA

    Rosa Nadal MD, PhD & Andrea B. Apolo MD

Authors
  1. Rosa Nadal MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea B. Apolo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea B. Apolo MD.

Ethics declarations

Conflict of Interest

The authors declare they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Genitourinary Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nadal, R., Apolo, A.B. Overview of Current and Future Adjuvant Therapy for Muscle-Invasive Urothelial Carcinoma. Curr. Treat. Options in Oncol. 19, 36 (2018). https://doi.org/10.1007/s11864-018-0551-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-018-0551-z

Keywords

Search

Navigation