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Clinical and therapeutic factors associated with adverse pathological outcomes in clinically node-negative patients treated with neoadjuvant cisplatin-based chemotherapy and radical cystectomy

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Abstract

Purpose

Several disease characteristics have been identified as potential predictors for pathological node involvement (pN+) following radical cystectomy (RC). However, these have not been assessed in patients treated with neoadjuvant chemotherapy (NAC). We endeavored to assess factors predicting adverse pathology in clinically node-negative patients treated with NAC and RC.

Methods

Patients from four North American institutions with cT2-4aN0M0 UC who received three or four cycles of NAC followed by RC were selected. Logistic regression was used to predict pN+, <pT2 and pT4 disease.

Results

One hundred and ninety-six patients were included. The clinical stage was cT2 in 115 (61 %), cT3 in 62 (33 %) and cT4 in 12 (6 %) cases. NAC regiments were gemcitabine–cisplatin (GC)-4 cycles 57 (29 %), GC-3 cycles 77 (39 %), methotrexate, vinblastine, adriamycin, cisplatin (MVAC)-3 cycle 22 (11 %) and MVAC-4 cycles 40 (21 %). pN+ was seen in 35 (18 %) patients. In the logistic regression analysis, cT4 stage (OR 7.50; 95 % CI 1.58–33.3) and three compared to four cycles of GC (OR 3.44; 95 % CI 1.09–10.9) were significant predictors of pN+ status. Additionally, when controlling for clinical stage, three cycles of GC, compared to four, were significantly associated with higher rates of pT4 disease and lower rates of downstaging to non-muscle-invasive disease.

Conclusions

The results suggest that four cycles of neoadjuvant GC may be superior to three cycles, and the latter regimen may be associated with adverse pathological findings. Although this would require validation in a prospective trial, it does encourage the completion of the conventional four cycles GC whenever possible.

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References

  1. Karakiewicz PI, Shariat SF, Palapattu GS, Gilad AE, Lotan Y, Rogers CG, Vazina A, Gupta A, Bastian PJ, Perrotte P, Sagalowsky AI, Schoenberg M, Lerner SP (2006) Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 176(4 Pt 1):1354–1361. doi:10.1016/j.juro.2006.06.025 (discussion 1361–1352)

    Article  PubMed  Google Scholar 

  2. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG (2001) Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19(3):666–675

    CAS  PubMed  Google Scholar 

  3. Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE (2003) Radical cystectomy for bladder cancer today—a homogeneous series without neoadjuvant therapy. J Clin Oncol 21(4):690–696

    Article  PubMed  Google Scholar 

  4. Fairey AS, Daneshmand S, Quinn D, Dorff T, Dorin R, Lieskovsky G, Schuckman A, Cai J, Miranda G, Skinner EC (2013) Neoadjuvant chemotherapy with gemcitabine/cisplatin vs. methotrexate/vinblastine/doxorubicin/cisplatin for muscle-invasive urothelial carcinoma of the bladder: a retrospective analysis from the University of Southern California. Urol Oncol 31(8):1737–1743. doi:10.1016/j.urolonc.2012.07.005

    Article  CAS  PubMed  Google Scholar 

  5. Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Vavassori I, Barni S (2014) Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol 65(2):350–357. doi:10.1016/j.eururo.2013.06.049

    Article  PubMed  Google Scholar 

  6. Rosenblatt R, Sherif A, Rintala E, Wahlqvist R, Ullen A, Nilsson S, Malmstrom PU (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):1229–1238. doi:10.1016/j.eururo.2011.12.010

    Article  PubMed  Google Scholar 

  7. Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, Ribal MJ, Sherif A, Witjes JA, European Association of U (2011) Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol 59(6):1009–1018. doi:10.1016/j.eururo.2011.03.023

    Article  CAS  PubMed  Google Scholar 

  8. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349(9):859–866. doi:10.1056/NEJMoa022148

    Article  CAS  PubMed  Google Scholar 

  9. Vale C, Advanced Bladder Cancer (ABC) Meta-analysis Collaboration (2003) Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361(9373):1927–1934

    Article  CAS  Google Scholar 

  10. Vale CL (2005) 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 48(2):202–205. doi:10.1016/j.eururo.2005.04.006 (discussion 205–206)

    Article  Google Scholar 

  11. International Collaboration of T, Medical Research Council Advanced Bladder Cancer Working P, European Organisation for R, Treatment of Cancer Genito-Urinary Tract Cancer G, Australian Bladder Cancer Study G, National Cancer Institute of Canada Clinical Trials G, Finnbladder, Norwegian Bladder Cancer Study G, Club Urologico Espanol de Tratamiento Oncologico G, Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK (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):2171–2177. doi:10.1200/JCO.2010.32.3139

    Article  Google Scholar 

  12. Zargar H, Espiritu PN, Fairey AS, Mertens LS, Dinney CP, Mir MC, Krabbe LM, Cookson MS, Jacobsen NE, Gandhi NM, Griffin J, Montgomery JS, Vasdev N, Yu EY, Youssef D, Xylinas E, Campain NJ, Kassouf W, Dall’Era MA, Seah JA, Ercole CE, Horenblas S, Sridhar SS, McGrath JS, Aning J, Shariat SF, Wright JL, Thorpe AC, Morgan TM, Holzbeierlein JM, Bivalacqua TJ, North S, Barocas DA, Lotan Y, Garcia JA, Stephenson AJ, Shah JB, van Rhijn BW, Daneshmand S, Spiess PE, Black PC (2014) Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. doi:10.1016/j.eururo.2014.09.007

    Google Scholar 

  13. Xie HY, Zhu Y, Yao XD, Zhang SL, Dai B, Zhang HL, Shen YJ, Wang CF, Zhang HZ, Ye DW (2012) Development of a nomogram to predict non-organ-confined bladder urothelial cancer before radical cystectomy. Int Urol Nephrol 44(6):1711–1719. doi:10.1007/s11255-012-0273-2

    Article  PubMed  Google Scholar 

  14. Mitra AP, Skinner EC, Miranda G, Daneshmand S (2013) A precystectomy decision model to predict pathological upstaging and oncological outcomes in clinical stage T2 bladder cancer. BJU Int 111(2):240–248. doi:10.1111/j.1464-410X.2012.11424.x

    Article  PubMed  Google Scholar 

  15. Karakiewicz PI, Shariat SF, Palapattu GS, Perrotte P, Lotan Y, Rogers CG, Amiel GE, Vazina A, Gupta A, Bastian PJ, Sagalowsky AI, Schoenberg M, Lerner SP (2006) Precystectomy nomogram for prediction of advanced bladder cancer stage. Eur Urol 50(6):1254–1260. doi:10.1016/j.eururo.2006.06.010 (discussion 1261–1252)

    Article  PubMed  Google Scholar 

  16. Herr HW, Faulkner JR, Grossman HB, Natale RB, deVere White R, Sarosdy MF, Crawford ED (2004) Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol 22(14):2781–2789. doi:10.1200/JCO.2004.11.024

    Article  PubMed  Google Scholar 

  17. Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17(6):1471–1474. doi:10.1245/s10434-010-0985-4

    Article  PubMed  Google Scholar 

  18. Clark PE, Agarwal N, Biagioli MC, Eisenberger MA, Greenberg RE, Herr HW, Inman BA, Kuban DA, Kuzel TM, Lele SM, Michalski J, Pagliaro LC, Pal SK, Patterson A, Plimack ER, Pohar KS, Porter MP, Richie JP, Sexton WJ, Shipley WU, Small EJ, Spiess PE, Trump DL, Wile G, Wilson TG, Dwyer M, Ho M, National Comprehensive Cancer N (2013) Bladder cancer. J Natl Compr Cancer Netw 11(4):446–475

    CAS  Google Scholar 

  19. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF (2000) 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 18(17):3068–3077

    PubMed  Google Scholar 

  20. Dash A, Pettus JAt, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF (2008) A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer 113(9):2471–2477. doi:10.1002/cncr.23848

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kunju LP, You L, Zhang Y, Daignault S, Montie JE, Lee CT (2008) Lymphovascular invasion of urothelial cancer in matched transurethral bladder tumor resection and radical cystectomy specimens. J Urol 180(5):1928–1932. doi:10.1016/j.juro.2008.07.056 (discussion 1932)

    Article  PubMed  Google Scholar 

  22. Tilki D, Shariat SF, Lotan Y, Rink M, Karakiewicz PI, Schoenberg MP, Lerner SP, Sonpavde G, Sagalowsky AI, Gupta A (2013) Lymphovascular invasion is independently associated with bladder cancer recurrence and survival in patients with final stage T1 disease and negative lymph nodes after radical cystectomy. BJU Int 111(8):1215–1221. doi:10.1111/j.1464-410X.2012.11455.x

    Article  PubMed  Google Scholar 

  23. Gondo T, Nakashima J, Ozu C, Ohno Y, Horiguchi Y, Namiki K, Yoshioka K, Ohori M, Hatano T, Tachibana M (2012) Risk stratification of survival by lymphovascular invasion, pathological stage, and surgical margin in patients with bladder cancer treated with radical cystectomy. Int J Clin Oncol 17(5):456–461. doi:10.1007/s10147-011-0310-7

    Article  PubMed  Google Scholar 

  24. Lotan Y, Gupta A, Shariat SF, Palapattu GS, Vazina A, Karakiewicz PI, Bastian PJ, Rogers CG, Amiel G, Perotte P, Schoenberg MP, Lerner SP, Sagalowsky AI (2005) Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 23(27):6533–6539. doi:10.1200/JCO.2005.05.516

    Article  PubMed  Google Scholar 

  25. Branchereau J, Larue S, Vayleux B, Karam G, Bouchot O, Rigaud J (2013) Prognostic value of the lymphovascular invasion in high-grade stage pT1 bladder cancer. Clin Genitourin Cancer 11(2):182–188. doi:10.1016/j.clgc.2012.10.002

    Article  PubMed  Google Scholar 

  26. Xylinas E, Rink M, Novara G, Green DA, Clozel T, Fritsche HM, Guillonneau B, Lotan Y, Kassouf W, Tilki D, Babjuk M, Karakiewicz PI, Montorsi F, Abdennabi J, Trinh QD, Svatek RS, Scherr DS, Zerbib M, Shariat SF (2013) Predictors of survival in patients with soft tissue surgical margin involvement at radical cystectomy. Ann Surg Oncol 20(3):1027–1034. doi:10.1245/s10434-012-2708-5

    Article  PubMed  Google Scholar 

  27. Smith SC, Baras AS, Dancik G, Ru Y, Ding KF, Moskaluk CA, Fradet Y, Lehmann J, Stockle M, Hartmann A, Lee JK, Theodorescu D (2011) A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. Lancet Oncol 12(2):137–143. doi:10.1016/S1470-2045(10)70296-5

    Article  PubMed  PubMed Central  Google Scholar 

  28. Takata R, Katagiri T, Kanehira M, Shuin T, Miki T, Namiki M, Kohri K, Tsunoda T, Fujioka T, Nakamura Y (2007) Validation study of the prediction system for clinical response of M-VAC neoadjuvant chemotherapy. Cancer Sci 98(1):113–117. doi:10.1111/j.1349-7006.2006.00366.x

    Article  CAS  PubMed  Google Scholar 

  29. Takata R, Katagiri T, Kanehira M, Tsunoda T, Shuin T, Miki T, Namiki M, Kohri K, Matsushita Y, Fujioka T, Nakamura Y (2005) Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling. Clin Cancer Res 11(7):2625–2636. doi:10.1158/1078-0432.CCR-04-1988

    Article  CAS  PubMed  Google Scholar 

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Authors contributions

Kamran Zargar-Shoshtari: Project development, Data collection, Data analysis, Manuscript writing. Homayoun Zargar: Project development, Data collection, Data analysis, Manuscript editing. Colin P Dinney: Manuscript review and editing. Cesar E Ercole: Data collection, Manuscript review and editing. Pranav Sharma: Data analysis. Evan Kovac: Data collection, Manuscript review and editing. Petros D. Grivas: Data collection, Manuscript review and editing. Andrew J Stephenson: Manuscript review and editing. Jay B Shah: Manuscript review and editing. Peter C. Black: Data management, Manuscript review and editing. Philippe E Spiess: Manuscript review and editing.

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Authors and Affiliations

  1. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive Office 12538, Tampa, FL, 33612, USA

    Kamran Zargar-Shoshtari, Pranav Sharma & Philippe E. Spiess

  2. Vancouver Prostate Centre, Vancouver, BC, Canada

    Homayoun Zargar & Peter C. Black

  3. Department of Urology, MD Anderson Cancer Center, Houston, TX, USA

    Colin P. Dinney & Jay B. Shah

  4. Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

    Cesar E. Ercole, Evan Kovac & Andrew J. Stephenson

  5. Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Petros D. Grivas

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  1. Kamran Zargar-Shoshtari
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Corresponding author

Correspondence to Philippe E. Spiess.

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Conflict of interest

Dr. Black has the following declarations: Advisory board involvement with Novartis, AbbVie, Astellas, Janssen, Amgen, Biocancell, Cubist, and Sitka; Speaker’s bureau Janssen Ferring, Astellas and Amgen; Honorarium/Consulting: Pendopharm, Cubist; Clinical Trial Design: Roche/Genentech. Dr. Grivas reports personal fees from Genentech, outside the submitted work.

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Zargar-Shoshtari, K., Zargar, H., Dinney, C.P. et al. Clinical and therapeutic factors associated with adverse pathological outcomes in clinically node-negative patients treated with neoadjuvant cisplatin-based chemotherapy and radical cystectomy. World J Urol 34, 695–701 (2016). https://doi.org/10.1007/s00345-015-1667-4

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  • DOI: https://doi.org/10.1007/s00345-015-1667-4

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