Systemic Chemotherapy for Upper Tract Urothelial Cancer

  • Surena F. MatinEmail author


Radical nephroureterectomy (RNU) with bladder cuff removal is considered the standard of care for most UTUC, but can be insufficient treatment for locally advanced cases, where recurrences are high and survival is short. Multimodality treatment with neoadjuvant and adjuvant chemotherapy has been an area of interest. Neoadjuvant chemotherapy (NAC) takes advantage of a patient’s maximal renal function, allowing optimal delivery of cisplatin-based regimens. Available single center retrospective series suggest a higher rate of pathological complete response with NAC as well as significantly improved 5 year overall and cancer-specific survival. A current trial evaluating NAC for both renally sufficient and renally impaired patients is currently underway. Adjuvant chemotherapy has primarily been analyzed in small retrospective uncontrolled series without consistent or convincing evidence of benefit. This is largely contributed by the high incidence of renal insufficiency after nephroureterectomy, as well as patient intolerance. A European prospective phase 3 study of adjuvant chemotherapy is underway.


Upper tract urothelial cancer Chemotherapy Neoadjuvant Adjuvant 



The author would like to recognize the Monteleone Family Professorship for Research in Kidney and Bladder Cancer and the Eleanor and Scott Petty Fund for UTUC Research for their support.


  1. 1.
    Konety BR, Joyce GF, Wise M. Bladder and upper tract urothelial cancer. J Urol. 2007;177(5):1636–45.CrossRefPubMedGoogle Scholar
  2. 2.
    Adibi M, Youssef R, Shariat SF, Lotan Y, Wood CG, Sagalowsky AI, et al. Oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: comparison over the three decades. Int J Urol. 2012;19(12):1060–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Brown GA, Busby JE, Wood CG, Pisters LL, Dinney CP, Swanson DA, et al. Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: time to change the treatment paradigm? BJU Int. 2006;98(6):1176–80.CrossRefPubMedGoogle Scholar
  4. 4.
    Munoz JJ, Ellison LM. Upper tract urothelial neoplasms: incidence and survival during the last 2 decades. J Urol. 2000;164(5):1523–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Lughezzani G, Jeldres C, Isbarn H, Sun M, Shariat SF, Alasker A, et al. Nephroureterectomy and segmental ureterectomy in the treatment of invasive upper tract urothelial carcinoma: a population-based study of 2299 patients. Eur J Cancer. 2009;45(18):3291–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Margulis V, Shariat SF, Matin SF, Kamat AM, Zigeuner R, Kikuchi E, et al. Outcomes of radical nephroureterectomy: a series from the upper tract urothelial carcinoma collaboration. Cancer. 2009;115(6):1224–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Kaag MG, O’Malley RL, O’Malley P, Godoy G, Chen M, Smaldone MC, et al. Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. Eur Urol. 2010;58(4):581–7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Skolarikos A, Griffiths TR, Powell PH, Thomas DJ, Neal DE, Kelly JD. Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment. Urology. 2003;61(6):1146–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998;52(4):594–601.CrossRefPubMedGoogle Scholar
  10. 10.
    Fritsche HM, Novara G, Burger M, Gupta A, Matsumoto K, Kassouf W, et al. Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. Urol Oncol. 2010.Google Scholar
  11. 11.
    Remzi M, Haitel A, Margulis V, Karakiewicz P, Montorsi F, Kikuchi E, et al. Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. BJU Int. 2009;103(3):307–11.CrossRefPubMedGoogle Scholar
  12. 12.
    Brien JC, Shariat SF, Herman MP, Ng CK, Scherr DS, Scoll B, et al. Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma. J Urol. 2010;184(1):69–73.CrossRefPubMedGoogle Scholar
  13. 13.
    Cho KS, Hong SJ, Cho NH, Choi YD. Grade of hydronephrosis and tumor diameter as preoperative prognostic factors in ureteral transitional cell carcinoma. Urology. 2007;70(4):662–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Ito Y, Kikuchi E, Tanaka N, Miyajima A, Mikami S, Jinzaki M, et al. Preoperative hydronephrosis grade independently predicts worse pathological outcomes in patients undergoing nephroureterectomy for upper tract urothelial carcinoma. J Urol. 2011;185(5):1621–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Ng CK, Shariat SF, Lucas SM, Bagrodia A, Lotan Y, Scherr DS, et al. Does the presence of hydronephrosis on preoperative axial CT imaging predict worse outcomes for patients undergoing nephroureterectomy for upper-tract urothelial carcinoma? Urol Oncol. 2011;29(1):27–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Keeley FX, Kulp DA, Bibbo M, McCue PA, Bagley DH. Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol. 1997;157(1):33–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Williams SK, Denton KJ, Minervini A, Oxley J, Khastigir J, Timoney AG, et al. Correlation of upper-tract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma. J Endourol. 2008;22(1):71–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Brown GA, Matin SF, Busby JE, Dinney CP, Grossman HB, Pettaway CA, et al. Ability of clinical grade to predict final pathologic stage in upper urinary tract transitional cell carcinoma: implications for therapy. Urology. 2007;70(2):252–6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Margulis V, Youssef RF, Karakiewicz PI, Lotan Y, Wood CG, Zigeuner R, et al. Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. J Urol. 2010;184(2):453–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Favaretto RL, Shariat SF, Savage C, Godoy G, Chade DC, Kaag M, et al. Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma. BJU Int. 2012;109(1):77–82.CrossRefPubMedGoogle Scholar
  21. 21.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859–66.CrossRefPubMedGoogle Scholar
  23. 23.
    Tannock I, Gospodarowicz M, Connolly J, Jewett M. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy for transitional cell carcinoma: the Princess Margaret Hospital experience. J Urol. 1989;142(2 Pt 1):289–92.CrossRefPubMedGoogle Scholar
  24. 24.
    Lerner SE, Blute ML, Richardson RL, Zincke H. Platinum-based chemotherapy for advanced transitional cell carcinoma of the upper urinary tract. Mayo Clin Proc. 1996;71(10):945–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Sternberg CN, Yagoda A, Scher HI, Watson RC, Herr HW, Morse MJ, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol. 1988;139(3):461–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol Off J Am Soc Clin Oncol. 1992;10(7):1066–73.CrossRefGoogle Scholar
  27. 27.
    Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, et al. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(2):220–8.CrossRefGoogle Scholar
  28. 28.
    Kaufman DS, Carducci MA, Kuzel TM, Todd MB, Oh WK, Smith MR, et al. A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer. Urol Oncol. 2004;22(5):393–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Lane BR, Smith AK, Larson BT, Gong MC, Campbell SC, Raghavan D, et al. Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy. Cancer. 2010;116(12):2967–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Splinter TA, Denis L, Scher HI, Schroder FH, Dalesio O. Neoadjuvant chemotherapy of invasive bladder cancer. The prognostic value of local tumor response. Prog Clin Biol Res. 1989;303:541–7.PubMedGoogle Scholar
  31. 31.
    Matin SF, Margulis V, Kamat A, Wood CG, Grossman HB, Brown GA, et al. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer. 2010;116(13):3127–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Igawa M, Urakami S, Shiina H, Kishi H, Himeno Y, Ishibe T, et al. Neoadjuvant chemotherapy for locally advanced urothelial cancer of the upper urinary tract. Urol Int. 1995;55(2):74–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Porten S, Siefker-Radtke AO, Xiao L, Margulis V, Kamat AM, Wood CG, et al. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer. 2014;120(12):1794–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Siefker-Radtke A, Millikan RE, Kamat A, Shen Y, Williams D, Grossman H, Dinney C, A phase II trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine (IAG), followed by cisplatin, gemcitabine and ifosfamide (CGI) in locally advanced urothelial cancer (UC): final results from the M.D. Anderson Cancer Center. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 5079).CrossRefGoogle Scholar
  35. 35.
    Palapattu GS, Shariat SF, Karakiewicz PI, Bastian PJ, Rogers CG, Amiel G, et al. Cancer specific outcomes in patients with pT0 disease following radical cystectomy. J Urol. 2006;175(5):1645–9; discussion 9.CrossRefPubMedGoogle Scholar
  36. 36.
    Tilki D, Svatek RS, Novara G, Seitz M, Godoy G, Karakiewicz PI, et al. Stage pT0 at radical cystectomy confers improved survival: an international study of 4,430 patients. J Urol. 2010;184(3):888–94.CrossRefPubMedGoogle Scholar
  37. 37.
    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 1,054 patients. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19(3):666–75.CrossRefGoogle Scholar
  38. 38.
    Rajput MZ, Kamat AM, Clavell-Hernandez J, Siefker-Radtke AO, Grossman HB, Dinney CP, et al. Perioperative outcomes of laparoscopic radical nephroureterectomy and regional lymphadenectomy in patients with upper urinary tract urothelial carcinoma after neoadjuvant chemotherapy. Urology. 2011.Google Scholar
  39. 39.
    Sundi D, Svatek RS, Margulis V, Wood CG, Matin SF, Dinney CP, et al. Upper tract urothelial carcinoma: impact of time to surgery. Urol Oncol. 2010.Google Scholar
  40. 40.
    Leow JJ, Martin-Doyle W, Fay AP, Choueiri TK, Chang SL, Bellmunt J. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol. 2014;66(3):529–41.CrossRefPubMedGoogle Scholar
  41. 41.
    Hellenthal NJ, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Bolenz C, et al. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the upper tract urothelial carcinoma collaboration. J Urol. 2009;182(3):900–6.CrossRefPubMedGoogle Scholar
  42. 42.
    Vassilakopoulou M, de la Motte Rouge T, Colin P, Ouzzane A, Khayat D, Dimopoulos MA, et al. Outcomes after adjuvant chemotherapy in the treatment of high-risk urothelial carcinoma of the upper urinary tract (UUT-UC): results from a large multicenter collaborative study. Cancer. 2011.Google Scholar
  43. 43.
    Bamias A, Deliveliotis C, Fountzilas G, Gika D, Anagnostopoulos A, Zorzou MP, et al. Adjuvant chemotherapy with paclitaxel and carboplatin in patients with advanced carcinoma of the upper urinary tract: a study by the Hellenic Cooperative Oncology Group. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(11):2150–4.CrossRefGoogle Scholar
  44. 44.
    Bellmunt J, Ribas A, Eres N, Albanell J, Almanza C, Bermejo B, et al. Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer. 1997;80(10):1966–72.CrossRefPubMedGoogle Scholar
  45. 45.
    Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, et al. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004;100(8):1639–45.CrossRefPubMedGoogle Scholar
  46. 46.
    Petrioli R, Frediani B, Manganelli A, Barbanti G, De Capua B, De Lauretis A, et al. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer. 1996;77(2):344–51.CrossRefPubMedGoogle Scholar
  47. 47.
    Dogliotti L, Carteni G, Siena S, Bertetto O, Martoni A, Bono A, et al. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007;52(1):134–41.CrossRefPubMedGoogle Scholar
  48. 48.
    Soga N, Arima K, Sugimura Y. Adjuvant methotrexate, vinblastine, adriamycin, and cisplatin chemotherapy has potential to prevent recurrence of bladder tumors after surgical removal of upper urinary tract transitional cell carcinoma. Int J Urol. 2008;15(9):800–3.CrossRefPubMedGoogle Scholar
  49. 49.
    Ku JH, Choi WS, Kwak C, Kim HH. Bladder cancer after nephroureterectomy in patients with urothelial carcinoma of the upper urinary tract. Urol Oncol. 2009.Google Scholar
  50. 50.
    Kwak C, Lee SE, Jeong IG, Ku JH. Adjuvant systemic chemotherapy in the treatment of patients with invasive transitional cell carcinoma of the upper urinary tract. Urology. 2006;68(1):53–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Lee KS, Kim KH, Yoon YE, Choi KH, Yang SC, Han WK. Impact of adjuvant chemotherapy in patients with upper tract urothelial carcinoma and lymphovascular invasion after radical nephroureterectomy. Korean J Urol. 2015;56(1):41–7.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of UrologyUniversity of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations