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Targeted Oncology

, Volume 14, Issue 1, pp 15–32 | Cite as

The Challenge of Managing Bladder Cancer and Upper Tract Urothelial Carcinoma: A Review with Treatment Recommendations from the Spanish Oncology Genitourinary Group (SOGUG)

  • Albert FontEmail author
  • Raquel Luque
  • José Carlos Villa
  • Montse Domenech
  • Sergio Vázquez
  • Enrique Gallardo
  • Juan Antonio Virizuela
  • Carmen Beato
  • Rafael Morales-Barrera
  • Antoni Gelabert
  • Sonia Maciá
  • Javier Puente
  • Gustavo Rubio
  • Xavier Maldonado
  • Begoña Perez-Valderrama
  • Alvaro Pinto
  • Ovidio Fernández Calvo
  • Enrique Grande
  • Javier Garde-Noguera
  • Eva Fernández-Parra
  • José Ángel Arranz
Review Article

Abstract

Bladder cancer is the fourth most common cancer in men and the ninth most common in women in the Western world. The management of bladder carcinoma requires a multidisciplinary approach. Optimal treatment depends on several factors, including histology, stage, patient status, and possible comorbidities. Here we review recent findings on the treatment of muscle-invasive bladder carcinoma, advanced urothelial carcinoma, upper tract urothelial carcinoma, non-urothelial carcinoma, and urologic complications arising from the disease or treatment. In addition, we present the recommendations of the Spanish Oncology Genitourinary Group for the treatment of these diseases, based on a focused analysis of clinical management and the potential of current research, including recent findings on the potential benefit of immunotherapy. In recent years, whole-genome approaches have provided new predictive biomarkers and promising molecular targets that could lead to precision medicine in bladder cancer. Moreover, the involvement of other specialists in addition to urologists will ensure not only appropriate therapeutic decisions but also adequate follow-up for response evaluation and management of complications. It is crucial, however, to apply recent molecular findings and implement clinical guidelines as soon as possible in order to maximize therapeutic gains and improve patient prognosis.

Notes

Acknowledgements

The authors thank Dr. Joaquin Bellmunt (Bladder Cancer Center, Gelb Center, Dana-Farber/Brigham and Women’s Cancer Center and Harvard Medical School) for his invaluable guidance and comments on previous versions of this article and Ms. Renée Grupp for her assistance in drafting the manuscript.

Compliance with Ethical Standards

Funding

This study was financed by the Spanish Oncology Genitourinary Group (SOGUG) and received no outside funding.

Conflict of interest

Albert Font reports personal fees and non-financial support from Roche, Sanofi, Janssen, and Bayer and grants from Astra-Zeneca, Pierre-Fabre, and Astellas. Enrique Gallardo has received consulting fees from Roche, BMS and Pfizer. Javier Puente has received honoraria as a consultant on advisory boards from Pfizer, Astellas, Janssen, MSD, Bayer, Roche, BMS, Boehringer, Astra Zeneca, Ipsen, Novartis, Eusa Pharma, Eisai, and Sanofi; and as speaker from Kyowa, Celgene, Lilly, Pierre-Fabre, and Merck. Begoña Perez-Valderrama has received consulting fees or honoraria from BMS, Astellas, Novartis, Pierre-Fabre, Bayer, Roche, Ipsen, and Sanofi. Ovidio Fernandez-Calvo has received consulting fees or honoraria from Astellas, Pfizer, Novartis, and Roche. Enrique Grande has received honoraria for advisory boards, meetings, and/or lectures from Pfizer, BMS, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Sanofi-Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon, and Celgene; he has also received unrestricted research grants from Pfizer, Astra Zeneca, MTEM/Threshold, Roche, Ipsen, and Lexicon.  José Ángel Arranz has received consulting fees or honoraria from MSD, Jaansen, and BMS and has participated in local advisory boards for MSD, BMS, and Roche. These authors declare that none of these potential conflicts of interest influenced their contribution to this manuscript or the decision to publish. Raquel Luque, José Carlos Villa, Montse Domenech, Sergio Vazquez-Estevez, Juan Antonio Virizuela, Carmen Beato, Rafael Morales-Barrera, Antoni Gelabert, Sonia Maciá-Escalante, Gustavo Rubio, Xavier Maldonado, Alvaro Pinto, Javier Garde-Noguera, and Eva Fernández-Parra declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

References

  1. 1.
    Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. International variations in bladder cancer incidence and mortality. Eur Urol. 2014;66(1):59–73.  https://doi.org/10.1016/j.eururo.2013.10.001.PubMedGoogle Scholar
  2. 2.
    Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41.  https://doi.org/10.1016/j.eururo.2012.07.033.PubMedGoogle Scholar
  3. 3.
    Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. BMJ. 2008;336(7652):1049–51.  https://doi.org/10.1136/bmj.39493.646875.AE.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Tekes A, Kamel I, Imam K, Szarf G, Schoenberg M, Nasir K, et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J Roentgenol. 2005;184(1):121–7.  https://doi.org/10.2214/ajr.184.1.01840121.PubMedGoogle Scholar
  5. 5.
    Barentsz JO, Ruijs SH, Strijk SP. The role of MR imaging in carcinoma of the urinary bladder. AJR Am J Roentgenol. 1993;160(5):937–47.  https://doi.org/10.2214/ajr.160.5.8470608.PubMedGoogle Scholar
  6. 6.
    Kamat AM, Hegarty PK, Gee JR, Clark PE, Svatek RS, Hegarty N, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: screening, diagnosis, and molecular markers. Eur Urol. 2013;63(1):4–15.  https://doi.org/10.1016/j.eururo.2012.09.057.PubMedGoogle Scholar
  7. 7.
    Amin MB, McKenney JK, Paner GP, Hansel DE, Grignon DJ, Montironi R, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: pathology. Eur Urol. 2013;63(1):16–35.  https://doi.org/10.1016/j.eururo.2012.09.063.PubMedGoogle Scholar
  8. 8.
    Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. J Urol. 1982;128(1):34–6.PubMedGoogle Scholar
  9. 9.
    Park J, Ahn H. Radical cystectomy and orthotopic bladder substitution using ileum. Korean J Urol. 2011;52(4):233–40.  https://doi.org/10.4111/kju.2011.52.4.233.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Somani BK, Nabi G, Wong S, Lyttle M, Atiemo K, McPherson G, et al. How close are we to knowing whether orthotopic bladder replacement surgery is the new gold standard?—evidence from a systematic review update. Urology. 2009;74(6):1331–9.  https://doi.org/10.1016/j.urology.2009.06.086.PubMedGoogle Scholar
  11. 11.
    Shariat SF, Karakiewicz PI, Godoy G, Lerner SP. Use of nomograms for predictions of outcome in patients with advanced bladder cancer. Ther Adv Urol. 2009;1(1):13–26.  https://doi.org/10.1177/1756287209103923.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Ku JH. Role of pelvic lymphadenectomy in the treatment of bladder cancer: a mini review. Korean J Urol. 2010;51(6):371–8.  https://doi.org/10.4111/kju.2010.51.6.371.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Simone G, Papalia R, Ferriero M, Guaglianone S, Castelli E, Collura D, et al. Stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy. Int J Urol. 2013;20(4):390–7.  https://doi.org/10.1111/j.1442-2042.2012.03148.x.PubMedGoogle Scholar
  14. 14.
    Gschwend JE, Heck MM, Lehmann J, Rubben H, Albers P, Wolff JM, et al. Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial. Eur Urol. 2018.  https://doi.org/10.1016/j.eururo.2018.09.047.PubMedGoogle Scholar
  15. 15.
    Mmeje CO, Benson CR, Nogueras-Gonzalez GM, Jayaratna IS, Gao J, Siefker-Radtke AO, et al. Determining the optimal time for radical cystectomy after neoadjuvant chemotherapy. BJU Int. 2018;122(1):89–98.  https://doi.org/10.1111/bju.14211.PubMedGoogle Scholar
  16. 16.
    Park JC, Gandhi NM, Carducci MA, Eisenberger MA, Baras AS, Netto GJ, et al. A retrospective analysis of the effect on survival of time from diagnosis to neoadjuvant chemotherapy to cystectomy for muscle invasive bladder cancer. J Urol. 2016;195(4 Pt 1):880–5.  https://doi.org/10.1016/j.juro.2015.11.024.PubMedGoogle Scholar
  17. 17.
    International collaboration of trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet. 1999;354(9178):533–40.Google Scholar
  18. 18.
    Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. 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. 2011;29(16):2171–7.  https://doi.org/10.1200/JCO.2010.32.3139.PubMedGoogle Scholar
  19. 19.
    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.  https://doi.org/10.1056/NEJMoa022148.Google Scholar
  20. 20.
    Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet. 2003;361(9373):1927–34.Google Scholar
  21. 21.
    Winquist E, Kirchner TS, Segal R, Chin J, Lukka H. Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder: a systematic review and meta-analysis. J Urol. 2004;171(2 Pt 1):561–9.  https://doi.org/10.1097/01.ju.0000090967.08622.33.PubMedGoogle Scholar
  22. 22.
    Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48(2):202–5.  https://doi.org/10.1016/j.eururo.2005.04.006.Google Scholar
  23. 23.
    Zargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015;67(2):241–9.  https://doi.org/10.1016/j.eururo.2014.09.007.PubMedGoogle Scholar
  24. 24.
    Galsky MD, Pal SK, Chowdhury S, Harshman LC, Crabb SJ, Wong YN, et al. Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer. 2015;121(15):2586–93.  https://doi.org/10.1002/cncr.29387.PubMedGoogle Scholar
  25. 25.
    Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, et al. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol. 2014;32(18):1895–901.  https://doi.org/10.1200/JCO.2013.53.2465.PubMedPubMedCentralGoogle Scholar
  26. 26.
    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.  https://doi.org/10.1200/JCO.2013.52.4785.PubMedGoogle Scholar
  27. 27.
    Powles T, Rodriguez-Vida A, Duran I, Crabb SJ, Heijden MSVD, Pous AF, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). J Clin Oncol. 2018;36(15 suppl):4506.  https://doi.org/10.1200/jco.2018.36.15_suppl.4506.Google Scholar
  28. 28.
    Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J Clin Oncol. 2018;36(34):3353–60.  https://doi.org/10.1200/jco.18.01148.Google Scholar
  29. 29.
    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. 2001;19(3):666–75.Google Scholar
  30. 30.
    Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol. 2005;48(2):189–99.Google Scholar
  31. 31.
    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.  https://doi.org/10.1093/annonc/mdr354.PubMedGoogle Scholar
  32. 32.
    Paz-Ares L, Solsona E, Esteban E, Saez A, Gonzalez-Larriba J, Anton A, et al. 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(18 suppl):abstr LBA4518.  https://doi.org/10.1200/jco.2010.28.18_suppl.lba4518.Google Scholar
  33. 33.
    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.  https://doi.org/10.1016/S1470-2045(14)71160-X.PubMedGoogle Scholar
  34. 34.
    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.  https://doi.org/10.1016/j.eururo.2013.08.033.PubMedGoogle Scholar
  35. 35.
    Rodel C, Weiss C, Sauer R. Trimodality treatment and selective organ preservation for bladder cancer. J Clin Oncol. 2006;24(35):5536–44.  https://doi.org/10.1200/JCO.2006.07.6729.PubMedGoogle Scholar
  36. 36.
    Morales R, Font A, Carles J, Isla D. SEOM clinical guidelines for the treatment of invasive bladder cancer. Clin Transl Oncol. 2011;13(8):552–9.  https://doi.org/10.1007/s12094-011-0696-8.PubMedGoogle Scholar
  37. 37.
    Leibovici D, Kassouf W, Pisters LL, Pettaway CA, Wu X, Dinney CP, et al. Organ preservation for muscle-invasive bladder cancer by transurethral resection. Urology. 2007;70(3):473–6.  https://doi.org/10.1016/j.urology.2007.05.007.PubMedGoogle Scholar
  38. 38.
    Solsona E, Iborra I, Collado A, Rubio-Briones J, Casanova J, Calatrava A. Feasibility of radical transurethral resection as monotherapy for selected patients with muscle invasive bladder cancer. J Urol. 2010;184(2):475–80.  https://doi.org/10.1016/j.juro.2010.04.008.PubMedGoogle Scholar
  39. 39.
    Sweeney P, Kursh ED, Resnick MI. Partial cystectomy. Urol Clin North Am. 1992;19(4):701–11.PubMedGoogle Scholar
  40. 40.
    Holzbeierlein JM, Lopez-Corona E, Bochner BH, Herr HW, Donat SM, Russo P, et al. Partial cystectomy: a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendations for patient selection. J Urol. 2004;172(3):878–81.  https://doi.org/10.1097/01.ju.0000135530.59860.7d.PubMedGoogle Scholar
  41. 41.
    Shipley WU, Prout GR Jr, Einstein AB, Coombs LJ, Wajsman Z, Soloway MS, et al. Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery. JAMA. 1987;258(7):931–5.PubMedGoogle Scholar
  42. 42.
    Mak RH, Hunt D, Shipley WU, Efstathiou JA, Tester WJ, Hagan MP, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014;32(34):3801–9.  https://doi.org/10.1200/JCO.2014.57.5548.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Coppin CM, Gospodarowicz MK, James K, Tannock IF, Zee B, Carson J, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1996;14(11):2901–7.PubMedGoogle Scholar
  44. 44.
    Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol. 2010;28(33):4912–8.  https://doi.org/10.1200/JCO.2010.28.4950.PubMedGoogle Scholar
  45. 45.
    James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012;366(16):1477–88.  https://doi.org/10.1056/NEJMoa1106106.PubMedGoogle Scholar
  46. 46.
    Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol. 1998;16(11):3576–83.PubMedGoogle Scholar
  47. 47.
    Hagan MP, Winter KA, Kaufman DS, Wajsman Z, Zietman AL, Heney NM, et al. RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys. 2003;57(3):665–72.PubMedGoogle Scholar
  48. 48.
    Seisen T, Sun M, Lipsitz SR, Abdollah F, Leow JJ, Menon M, et al. Comparative effectiveness of trimodal therapy versus radical cystectomy for localized muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2017;72(4):483–7.  https://doi.org/10.1016/j.eururo.2017.03.038.PubMedGoogle Scholar
  49. 49.
    Kulkarni GS, Hermanns T, Wei Y, Bhindi B, Satkunasivam R, Athanasopoulos P, et al. propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. J Clin Oncol. 2017;35(20):2299–305.  https://doi.org/10.1200/JCO.2016.69.2327.PubMedGoogle Scholar
  50. 50.
    Abida W, Bajorin DF, Rosenberg JE. First-line treatment and prognostic factors of metastatic bladder cancer for platinum-eligible patients. Hematol Oncol Clin North Am. 2015;29(2):319–328.  https://doi.org/10.1016/j.hoc.2014.10.005.PubMedGoogle Scholar
  51. 51.
    Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. Treatment of patients with metastatic urothelial cancer “unfit” for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29(17):2432–8.  https://doi.org/10.1200/JCO.2011.34.8433.PubMedGoogle Scholar
  52. 52.
    von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18(17):3068–77.PubMedGoogle Scholar
  53. 53.
    von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–8.  https://doi.org/10.1200/JCO.2005.07.757.PubMedGoogle Scholar
  54. 54.
    Roberts J, von der Maase H, Sengelov L, Conte P, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer. Ann Oncol. 2006;17(suppl 5):118–22.Google Scholar
  55. 55.
    Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, 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(10):2638–46.PubMedGoogle Scholar
  56. 56.
    Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol. 2012;30(10):1107–13.  https://doi.org/10.1200/JCO.2011.38.6979.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol. 2001;19(9):2527–33.PubMedGoogle Scholar
  58. 58.
    Hainsworth JD, Meluch AA, Litchy S, Schnell FM, Bearden JD, Yost K, et al. Paclitaxel, carboplatin, and gemcitabine in the treatment of patients with advanced transitional cell carcinoma of the urothelium. Cancer. 2005;103(11):2298–303.  https://doi.org/10.1002/cncr.21078.PubMedGoogle Scholar
  59. 59.
    De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, 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(2):191–9.  https://doi.org/10.1200/JCO.2011.37.3571.PubMedGoogle Scholar
  60. 60.
    Li J, Juliar B, Yiannoutsos C, Ansari R, Fox E, Fisch MJ, et al. Weekly paclitaxel and gemcitabine in advanced transitional-cell carcinoma of the urothelium: a phase II Hoosier Oncology Group study. J Clin Oncol. 2005;23(6):1185–91.  https://doi.org/10.1200/JCO.2005.05.089.PubMedGoogle Scholar
  61. 61.
    Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA. Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol. 1997;15(11):3394–8.PubMedGoogle Scholar
  62. 62.
    Beer TM, Goldman B, Nichols CR, Petrylak DP, Agarwal M, Ryan CW, et al. Southwest Oncology Group phase II study of irinotecan in patients with advanced transitional cell carcinoma of the urothelium that progressed after platinum-based chemotherapy. Clin Genitourin Cancer. 2008;6(1):36–9.PubMedGoogle Scholar
  63. 63.
    Gallagher DJ, Milowsky MI, Bajorin DF. Advanced bladder cancer: status of first-line chemotherapy and the search for active agents in the second-line setting. Cancer. 2008;113(6):1284–93.  https://doi.org/10.1002/cncr.23692.PubMedGoogle Scholar
  64. 64.
    Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Investig New Drugs. 2007;25(3):265–70.  https://doi.org/10.1007/s10637-006-9020-9.Google Scholar
  65. 65.
    Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013;14(8):769–76.  https://doi.org/10.1016/S1470-2045(13)70162-1.PubMedGoogle Scholar
  66. 66.
    Lin CC, Hsu CH, Huang CY, Keng HY, Tsai YC, Huang KH, et al. Gemcitabine and ifosfamide as a second-line treatment for cisplatin-refractory metastatic urothelial carcinoma: a phase II study. Anticancer Drugs. 2007;18(4):487–91.  https://doi.org/10.1097/CAD.0b013e3280126603.PubMedGoogle Scholar
  67. 67.
    McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15(5):1853–7.PubMedGoogle Scholar
  68. 68.
    Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002;20(4):937–40.PubMedGoogle Scholar
  69. 69.
    Winquist E, Vokes E, Moore MJ, Schumm LP, Hoving K, Stadler WM. A Phase II study of oxaliplatin in urothelial cancer. Urol Oncol. 2005;23(3):150–4.  https://doi.org/10.1016/j.urolonc.2004.11.008.PubMedGoogle Scholar
  70. 70.
    Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol. 1997;15(2):589–93.PubMedGoogle Scholar
  71. 71.
    Witte RS, Manola J, Burch PA, Kuzel T, Weinshel EL, Loehrer PJ Sr. Topotecan in previously treated advanced urothelial carcinoma: an ECOG phase II trial. Investig New Drugs. 1998;16(2):191–5.Google Scholar
  72. 72.
    Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, et al. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011;22(2):288–94.  https://doi.org/10.1093/annonc/mdq398.PubMedGoogle Scholar
  73. 73.
    Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol. 2010;28(11):1850–5.  https://doi.org/10.1200/JCO.2009.25.4599.PubMedGoogle Scholar
  74. 74.
    Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, 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):4454–61.  https://doi.org/10.1200/JCO.2008.20.5534.PubMedGoogle Scholar
  75. 75.
    Necchi A, Pond GR, Giannatempo P, Di Lorenzo G, Eigl BJ, Locke J, et al. Cisplatin-based first-line therapy for advanced urothelial carcinoma after previous perioperative cisplatin-based therapy. Clin Genitourin Cancer. 2015;13(2):178–84.  https://doi.org/10.1016/j.clgc.2014.08.010.PubMedGoogle Scholar
  76. 76.
    Kattan J, Culine S, Theodore C, Droz JP. Second-line M-VAC therapy in patients previously treated with the M-VAC regimen for metastatic urothelial cancer. Ann Oncol. 1993;4(9):793–4.PubMedGoogle Scholar
  77. 77.
    Vaishampayan UN, Faulkner JR, Small EJ, Redman BG, Keiser WL, Petrylak DP, et al. Phase II trial of carboplatin and paclitaxel in cisplatin-pretreated advanced transitional cell carcinoma: a Southwest Oncology Group study. Cancer. 2005;104(8):1627–32.  https://doi.org/10.1002/cncr.21370.PubMedGoogle Scholar
  78. 78.
    Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76.  https://doi.org/10.1016/S0140-6736(16)32455-2.PubMedGoogle Scholar
  79. 79.
    Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483–92.  https://doi.org/10.1016/S1470-2045(17)30616-2.PubMedGoogle Scholar
  80. 80.
    Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, 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.  https://doi.org/10.1016/S0140-6736(16)00561-4.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391:748–57.  https://doi.org/10.1016/s0140-6736(17)33297-x.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.  https://doi.org/10.1056/NEJMoa1613683.PubMedPubMedCentralGoogle Scholar
  83. 83.
    de Wit R, Kulkarni GS, Uchio E, Singer EA, Krieger L, Grivas P, et al. 864O Pembrolizumab for high-risk (HR) non-muscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): phase II KEYNOTE-057 trial. Ann Oncol. 2018;29(suppl 8):mdy283.073.  https://doi.org/10.1093/annonc/mdy283.073.Google Scholar
  84. 84.
    Apolo AB, Infante JR, Hamid O, Patel MR, Wang D, Kelly K, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression. J Clin Oncol. 2016;34(15 suppl):4514.  https://doi.org/10.1200/jco.2016.34.15_suppl.4514.Google Scholar
  85. 85.
    Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22.  https://doi.org/10.1016/S1470-2045(17)30065-7.PubMedGoogle Scholar
  86. 86.
    Rosenberg JE, Sharma P, de Braud FGM, Basso U, Calvo E, Bono P, et al. LBA32 Nivolumab (N) alone or in combination with ipilimumab (I) in patients (pts) with platinum-pretreated metastatic urothelial carcinoma (mUC), including the nivolumab 1 mg/kg + ipilimumab 3 mg/kg expansion from CheckMate 032. Ann Oncol. 2018;29(suppl 8):mdy424.038.  https://doi.org/10.1093/annonc/mdy424.038.Google Scholar
  87. 87.
    Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25.  https://doi.org/10.1200/jco.2016.67.9761.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Chromecki TF, Bensalah K, Remzi M, Verhoest G, Cha EK, Scherr DS, et al. Prognostic factors for upper urinary tract urothelial carcinoma. Nat Rev Urol. 2011;8(8):440–7.  https://doi.org/10.1038/nrurol.2011.96.PubMedGoogle Scholar
  89. 89.
    Roupret M, Zigeuner R, Palou J, Boehle A, Kaasinen E, Sylvester R, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. 2011;59(4):584–94.  https://doi.org/10.1016/j.eururo.2010.12.042.PubMedGoogle Scholar
  90. 90.
    Latchamsetty KC, Porter CR. Treatment of upper tract urothelial carcinoma: a review of surgical and adjuvant therapy. Rev Urol. 2006;8(2):61–70.PubMedPubMedCentralGoogle Scholar
  91. 91.
    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.  https://doi.org/10.1016/j.eururo.2014.03.003.PubMedGoogle Scholar
  92. 92.
    Birtle AJ, Chester JD, Jones RJ, Johnson M, Hill M, Bryan RT, et al. Results of POUT: a phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol. 2018;36(6 suppl):407.  https://doi.org/10.1200/jco.2018.36.6_suppl.407.Google Scholar
  93. 93.
    Gupta R, Paner GP, Amin MB. Neoplasms of the upper urinary tract: a review with focus on urothelial carcinoma of the pelvicalyceal system and aspects related to its diagnosis and reporting. Adv Anat Pathol. 2008;15(3):127–39.  https://doi.org/10.1097/PAP.0b013e31817145a9.PubMedGoogle Scholar
  94. 94.
    Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol. 2003;44(6):672–81.PubMedGoogle Scholar
  95. 95.
    Kassouf W, Spiess PE, Siefker-Radtke A, Swanson D, Grossman HB, Kamat AM, et al. Outcome and patterns of recurrence of nonbilharzial pure squamous cell carcinoma of the bladder: a contemporary review of The University of Texas M D Anderson Cancer Center experience. Cancer. 2007;110(4):764–9.  https://doi.org/10.1002/cncr.22853.PubMedGoogle Scholar
  96. 96.
    Richie JP, Waisman J, Skinner DG, Dretler SP. Squamous carcinoma of the bladder: treatment by radical cystectomy. J Urol. 1976;115(6):670–2.PubMedGoogle Scholar
  97. 97.
    Jones MA, Bloom HJ, Williams G, Trott PA, Wallace DM. The management of squamous cell carcinoma of the bladder. Br J Urol. 1980;52(6):511–4.PubMedGoogle Scholar
  98. 98.
    Swanson DA, Liles A, Zagars GK. Preoperative irradiation and radical cystectomy for stages T2 and T3 squamous cell carcinoma of the bladder. J Urol. 1990;143(1):37–40.PubMedGoogle Scholar
  99. 99.
    Raghavan D. Progress in the chemotherapy of metastatic cancer of the urinary tract. Cancer. 2003;97(8 Suppl):2050–5.  https://doi.org/10.1002/cncr.11280.PubMedGoogle Scholar
  100. 100.
    Galsky MD, Iasonos A, Mironov S, Scattergood J, Donat SM, Bochner BH, et al. Prospective trial of ifosfamide, paclitaxel, and cisplatin in patients with advanced non-transitional cell carcinoma of the urothelial tract. Urology. 2007;69(2):255–9.  https://doi.org/10.1016/j.urology.2006.10.029.PubMedGoogle Scholar
  101. 101.
    Khaled HM, Hamza MR, Mansour O, Gaafar R, Zaghloul MS. A phase II study of gemcitabine plus cisplatin chemotherapy in advanced bilharzial bladder carcinoma. Eur J Cancer. 2000;36(Suppl 2):34–7.PubMedGoogle Scholar
  102. 102.
    Holmang S, Aldenborg F. Stage T1 adenocarcinoma of the urinary bladder—complete response after transurethral resection and intravesical bacillus Calmette-Guerin. Scand J Urol Nephrol. 2000;34(2):141–3.PubMedGoogle Scholar
  103. 103.
    Malek RS, Rosen JS, O’Dea MJ. Adenocarcinoma of bladder. Urology. 1983;21(4):357–9.PubMedGoogle Scholar
  104. 104.
    Abenoza P, Manivel C, Fraley EE. Primary adenocarcinoma of urinary bladder Clinicopathologic study of 16 cases. Urology. 1987;29(1):9–14.PubMedGoogle Scholar
  105. 105.
    Siefker-Radtke AO, Gee J, Shen Y, Wen S, Daliani D, Millikan RE, et al. Multimodality management of urachal carcinoma: the M. D. Anderson Cancer Center experience. J Urol. 2003;169(4):1295–8.  https://doi.org/10.1097/01.ju.0000054646.49381.01.PubMedGoogle Scholar
  106. 106.
    el-Mekresh MM, el-Baz MA, Abol-Enein H, Ghoneim MA. Primary adenocarcinoma of the urinary bladder: a report of 185 cases. Br J Urol. 1998;82(2):206–12.PubMedGoogle Scholar
  107. 107.
    Zaghloul MS, Nouh A, Nazmy M, Ramzy S, Zaghloul AS, Sedira MA, et al. Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol. 2006;24(1):13–20.  https://doi.org/10.1016/j.urolonc.2005.05.027.PubMedGoogle Scholar
  108. 108.
    Hong JY, Choi MK, Uhm JE, Park MJ, Lee J, Park SH, et al. Palliative chemotherapy for non-transitional cell carcinomas of the urothelial tract. Med Oncol. 2009;26(2):186–92.PubMedGoogle Scholar
  109. 109.
    Siefker-Radtke A. Urachal carcinoma: surgical and chemotherapeutic options. Expert Rev Anticancer Ther. 2006;6(12):1715–21.  https://doi.org/10.1586/14737140.6.12.1715.PubMedGoogle Scholar
  110. 110.
    Yanagihara Y, Tanji N, Miura N, Shirato A, Nishimura K, Fukumoto T, et al. Modified FOLFOX6 chemotherapy in patients with metastatic urachal cancer. Chemotherapy. 2013;59(6):402–6.  https://doi.org/10.1159/000362400.PubMedGoogle Scholar
  111. 111.
    Cheng L, Pan CX, Yang XJ, Lopez-Beltran A, MacLennan GT, Lin H, et al. Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer. 2004;101(5):957–62.  https://doi.org/10.1002/cncr.20456.PubMedGoogle Scholar
  112. 112.
    Mukesh M, Cook N, Hollingdale AE, Ainsworth NL, Russell SG. Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the Anglian Cancer Network. BJU Int. 2009;103(6):747–52.  https://doi.org/10.1111/j.1464-410X.2008.08241.x.PubMedGoogle Scholar
  113. 113.
    Mackey JR, Au HJ, Hugh J, Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J Urol. 1998;159(5):1624–9.  https://doi.org/10.1097/00005392-199805000-00058.PubMedGoogle Scholar
  114. 114.
    Sandler AB. Chemotherapy for small cell lung cancer. Semin Oncol. 2003;30(1):9–25.  https://doi.org/10.1053/sonc.2003.50012.PubMedGoogle Scholar
  115. 115.
    Lynch SP, Shen Y, Kamat A, Grossman HB, Shah JB, Millikan RE, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol. 2013;64(2):307–13.  https://doi.org/10.1016/j.eururo.2012.04.020.PubMedGoogle Scholar
  116. 116.
    Fairchild WV, Spence CR, Solomon HD, Gangai MP. The incidence of bladder cancer after cyclophosphamide therapy. J Urol. 1979;122(2):163–4.PubMedGoogle Scholar
  117. 117.
    Centeno C, Gonzalez C. Radiotherapy for palliation of symptoms. In: Fisch M, editor. Handbook of advanced cancer care. Cambridge: Cambridge University Press; 2003. p. 27–39.Google Scholar
  118. 118.
    Ganatra AM, Loughlin KR. The management of malignant ureteral obstruction treated with ureteral stents. J Urol. 2005;174(6):2125–8.  https://doi.org/10.1097/01.ju.0000181807.56114.b7.PubMedGoogle Scholar
  119. 119.
    Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.  https://doi.org/10.1038/nature13904.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–556 e25.  https://doi.org/10.1016/j.cell.2017.09.007.PubMedPubMedCentralGoogle Scholar
  121. 121.
    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.  https://doi.org/10.1016/j.ccr.2014.01.009.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Rintala E, Hannisdahl E, Fossa SD, Hellsten S, Sander S. Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol. 1993;27(3):355–62.PubMedGoogle Scholar
  123. 123.
    Malmstrom PU, Rintala E, Wahlqvist R, Hellstrom P, Hellsten S, Hannisdal E. Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol. 1996;155(6):1903–6.PubMedGoogle Scholar
  124. 124.
    Sherif A, Rintala E, Mestad O, Nilsson J, Holmberg L, Nilsson S, et al. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer—nordic cystectomy trial 2. Scand J Urol Nephrol. 2002;36(6):419–25.  https://doi.org/10.1080/003655902762467567.PubMedGoogle Scholar
  125. 125.
    Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50–4.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Albert Font
    • 1
    Email author
  • Raquel Luque
    • 2
  • José Carlos Villa
    • 3
  • Montse Domenech
    • 4
  • Sergio Vázquez
    • 5
  • Enrique Gallardo
    • 6
  • Juan Antonio Virizuela
    • 7
  • Carmen Beato
    • 7
  • Rafael Morales-Barrera
    • 8
  • Antoni Gelabert
    • 9
  • Sonia Maciá
    • 10
  • Javier Puente
    • 11
  • Gustavo Rubio
    • 12
  • Xavier Maldonado
    • 13
  • Begoña Perez-Valderrama
    • 14
  • Alvaro Pinto
    • 15
  • Ovidio Fernández Calvo
    • 16
  • Enrique Grande
    • 17
  • Javier Garde-Noguera
    • 18
  • Eva Fernández-Parra
    • 19
  • José Ángel Arranz
    • 20
  1. 1.Medical Oncology Service, B-ARGO GroupCatalan Institute of Oncology, Hospital Germans Trias i PujolBadalonaSpain
  2. 2.Medical Oncology ServiceH.U. Virgen de las NievesGranadaSpain
  3. 3.Medical Oncology ServiceHospital General Universitario Ciudad RealCiudad RealSpain
  4. 4.Medical Oncology ServiceHospital Fundació AlthaiaManresaSpain
  5. 5.Medical Oncology ServiceHospital Universitario Lucus Augusti, EOXI de LugoCervo e MonforteSpain
  6. 6.Oncology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PTUniversitat Autònoma de BarcelonaSabadellSpain
  7. 7.Medical Oncology ServiceHospital Virgen de la MacarenaSevilleSpain
  8. 8.Medical Oncology Service, Hospital Universitario Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO)Universitat Autònoma de BarcelonaBarcelonaSpain
  9. 9.Urology DepartmentHospital del MarBarcelonaSpain
  10. 10.Medical Oncology DepartmentCRO PivotalMadridSpain
  11. 11.Medical Oncology Department, Hospital Clínico San CarlosInstituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONCMadridSpain
  12. 12.Medical Oncology ServiceHospital Universitario Fundación Jimenez DiazMadridSpain
  13. 13.Radiation Oncology ServiceHospital Universitario Vall d’HebronBarcelonaSpain
  14. 14.Medical Oncology ServiceHospital Universitario Virgen del RocioSevilleSpain
  15. 15.Medical Oncology ServiceHospital Universitario La PazMadridSpain
  16. 16.Medical Oncology ServiceComplejo Hospitalario Universitario OurenseOrenseSpain
  17. 17.Medical OncologyMD Anderson Cancer CenterMadridSpain
  18. 18.Medical Oncology ServiceHospital Arnau de VilanovaValenciaSpain
  19. 19.Medical Oncology ServiceHospital Universitario Nuestra Señora de ValmeSevilleSpain
  20. 20.Medical Oncology ServiceHospital General Universitario Gregorio MarañonMadridSpain

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