Objectives: To prospectively evaluate the prognostic utility of the traditional prognostic factors and molecular markers p53 and Ki-67 in a homogeneous series of patients with non-muscle-invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG). Patients and Methods: 192 intermediate- and high-risk NMIBC cases were enrolled. The variables in study were age, stage, grade, focality, tumour size, presence of associated carcinoma in situ, recurrence rate before BCG, maintenance for BCG, Ki-67 and p53. The endpoints considered were recurrence-free survival, progression-free survival, cancer-specific survival (CSS) and overall survival (OS). Results: T stage resulted in being associated with CSS, whereas age with OS. BCG maintenance was a significantly favourable independent predictor of OS, CSS, recurrence and progression. In univariate analysis, the labelling index of Ki-67 was significantly associated with OS, CSS and progression. Multivariate analysis, however, confirmed this association only for OS. On the contrary, the labelling index of p53 was a significant predictor of recurrence, both in uni- and multivariate analyses, but with a HR inferior to 1. Conclusions: Ki-67 was an independent predictor of survival. p53 overexpression showed a significant yet inverse correlation with recurrence, thus showing little clinical utility. Age, stage and maintenance were confirmed as independent predictors of BCG response.

Keywords:
Non-muscle-invasive bladder cancer, Prognostic factors, Bacillus Calmette-Guérin, Ki-67, p53
1.
Hall MC, Chang S, Dalbagni G, et al: Guideline for the management of non-muscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007;178:2314-2330.
2.
Babjuk M, Oosterlinck W, Sylvester R, Kaa-sinen E, Bohle A, Palou-Redorta J: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008;54:303-314.
3.
Gontero P, Bohle A, Malmstrom P, O'Donnell MA, Oderda M, Sylvester R, Witjes F: The role of Bacillus Calmette-Guérin in the treatment of non-muscle-invasive bladder cancer. Eur Urol 2010;57:410-429.
4.
Sylvester R, Van der Meijden A, Lamm D: Intravesical Bacillus Calmette-Guérin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964-1970.
5.
Saint F, Salomon L, Quintela R, Cicco A, Hoznek A, Abbou CC, Chopin DK: Do prognostic parameters of remission versus relapse after Bacillus Calmette-Guérin immunotherapy exist? Analysis of a quarter century of literature. Eur Urol 2003;43:351-361.
6.
Herr HW, Dalbagni G: Defining Bacillus Calmette-Guérin refractory superficial bladder tumors. J Urol 2003;169:1706-1708.
7.
Sylvester RJ, van der Meijden A, Witjes JA, Jakse G, Nonomura N, Cheng C, Torres A, Watson R, Kurth KH: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005:66(suppl 1):90-107.
8.
Denzinger S, Fritsche H-M, Otto W, Blana A, Wieland W-F, Burger M: Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53:146-152.
9.
Thalmann GN, Markwalder R, Shahin O, Burkhard FC, Hochreiter WW, Studer UE: Primary T1G3 bladder cancer: organ-preserving approach or immediate cystectomy? J Urol 2004;172:70-75.
10.
Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, Palou J, Vicente-Rodriguez J: Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol 2000;163:73-78.
11.
Martinez-Pineiro JA, Martinez-Pineiro L, Solsona E, et al; Club Urológico Español de Tratamiento Oncológico (CUETO): Has a three-fold decreased dose of Bacillus Calmette-Guérin the same efficacy against the recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005;174:1242-1247.
12.
Lamm DL, Blumenstein BA, Crissman JD, et al: Maintenance Bacillus Calmette-Guérin immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:1124-1129.
13.
Sarkis AS, Dalbagni G, Cordon-Cardo C, Zhang ZF, Sheinfeld J, Fair WR, Herr HW, Reuter VE: Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 1993;85:53-59.
14.
Limas C, Bigler A, Bair R, Bernhart P, Reddy P: Proliferative activity of urothelial neoplasms: comparison of BrdU in corporation, Ki-67 expression, and nucleolar organiser regions. J Clin Pathol 1993;46:159-165.
15.
Lacombe L, Dalbagni G, Zhang ZF, Cordon-Cardo C, Fair WR, Herr HW: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after Bacillus Calmette-Guérin therapy: correlation to clinical outcome. J Clin Oncol 1996;14:2646-2652.
16.
Fernandez-Gomez J, Solsona E, Unda M, Martinez-Pineiro L, Gonzalez M, Hernandez R, Madero R, Ojea A, Pertusa C, Rodriguez-Molina J, Camacho JE, Isorna S, Rabadan M, Astobieta A, Montesinos M, Muntanola P, Gimeno A, Blas M, Martinez-Pineiro JA: Prognostic factors in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin: multivariate analysis of data from four randomized CUETO trials. Eur Urol 2008;53:992-1002.
17.
Takashi M, Wakai K, Hattori T, Furuhashi K, Ono Y, Ohshima S, Ohno Y: Multivariate evaluation of factors affecting recurrence, progression and survival in patients with superficial bladder cancer treated with intravesical Bacillus Calmette-Guérin (Tokyo 172 strain) therapy: significance of concomitant carcinoma in situ. Int Urol Nephrol 2002; 33:41-47.
18.
Andius P, Damm O, Holmang S: Prognostic factors in patients with carcinoma in situ treated with intravescical bacilli Calmette-Guérin. Scand J Urol Nephrol 2004;38:285-290.
19.
Davies JW, Sheth SI, Doviak MJ, Schellhammer PF: Superficial bladder carcinoma treated with Bacillus Calmette-Guérin: progression-free and disease specific survival with 10-year minimum follow-up. J Urol 2002;167:494-501.
20.
Pansadoro V, Emiliozzi P, de Paula F, Scarpone P, Pansadoro A, Sternberg CN: Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intra-vesical Bacillus Calmette-Guérin: 18-year experience. Urology 2002;59:227-231.
21.
Lopez-Beltran A, Luque RJ, Alvarez-Kindelan J, Quintero A, Merlo F, Carrasco JC, Requena MJ, Montironi R: Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, cyclin D1, and cyclin D3) and proliferation index (Ki-67-MIB1). Eur Urol 2004;45:606-612.
22.
Marx J: How p53 suppresses cell growth. Science 1993;262:1644-1645.
23.
Muller PA, Vousden KH, Norman JC: p53 and its mutants in tumor cell migration and invasion. J Cell Biol 2011;192:209-218.
24.
Levine AJ, Momand J, Finlay CA: The p53 tumour suppressor gene. Nature 1991;351:453-456.
25.
Gontero P, Casetta G, Zitella A, Ballario R, Pacchioni D, Magnani C, Muir GH, Tizzani A: Evaluation of p53 protein overexpression, Ki-67 proliferative activity and mitotic index as markers of tumour recurrence in superficial transitional cell carcinoma of the bladder. Eur Urol 2000;38:287-296.
26.
Nakopoulou L, Vourlakou C, Zervas A, Tzonou A, Gakiopoulou H, Dimopoulos MA: The prevalence of bcl-2, p53, and Ki-67 immunoreactivity in transitional cell bladder carcinomas and their clinicopathologic correlates. Hum Pathol 1998;29:146-154.
27.
Ovesen H, Horn T, Steven K: Long-term efficacy of intravesical Bacillus of Calmette-Guérin for carcinoma in situ: relationship of progression to histologic response and p53 nuclear accumulation. J Urol 1997;157:1655-1659.
28.
Saint F, Le Frere Belda MA, Quintela R, Hoznek A, Patard JJ, Bellot J, Popov Z, Zafrani ES, Abbou CC, Chopin DK, Diez de -Medina SG: Pretreatment p53 nuclear over-expression as a prognostic marker in superficial bladder cancer treated with Bacillus Calmette-Guérin. Eur Urol 2004;45:475-482.
29.
Cormio L, Tolve I, Annese P, Saracino A, Zamparese R, Sanguedolce F, Bufo P, Battaglia M, Selvaggi FP, Carrieri G: Altered p53 and pRb expression is predictive of response to BCG treatment in T1G3 bladder cancer. Anticancer Res 2009;29:4201-4204.
30.
Lebret T, Becette V, Barbagelatta M, Herve JM, Gaudez F, Barre P: Correlation between p53 overexpression and response to Bacillus Calmette-Guérin therapy in a high risk select population of patients with T1G3 bladder cancer. J Urol 1998;159:788-791.
31.
Peyromaure M, Weibing S, Sebe P, Verpillat P, Toublanc M, Dauge MC, Boccon-Gibod L, Ravery V: Prognostic value of p53 overexpression in T1G3 bladder tumours treated with Bacillus Calmette-Guérin therapy. Urology 2002;59:409-413.
32.
Esuvaranathan K, Chiong E, Thamboo TP, Chan YH, Kamaraj R, Mahendran R, Teh M: Predictive value of p53 and pRb expression in superficial bladder cancer patients treated with BCG and interferon-α. Cancer 2007;109:1097-1105.
33.
Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2,596 patients from seven EORTC trials. Eur Urol 2006;49:466-475, discussion 475-477.
34.
Sylvester RJ, Van der Meijden A, Witjes JA, Jakse G, Nonomura N, Cheng C, Torres A, Watson R, Kurth KH: High-grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 2005;66:90-107.
35.
McShane LM, Aamodt R, Cordon-Cardo C, et al: Reproducibility of p53 immunohistochemistry. J Natl Cancer Inst 1996;88:173-182.
36.
Gerdes J, Lemke H, Baisch H: cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710-1715.
37.
Rodriguez-Alonso A, Pita-Fernandez S, Gonzalez-Carrero J, Nogueira-March JL: p53 and Ki-67 expression as prognostic factors for cancer-related survival in stage T1 transitional cell bladder carcinoma. Eur Urol 2002;41:182-189.
38.
Lebret T, Becette V, Hervé JM, Molinié V, Barré P, Lugagne PM, Gentille A, Baglin AC, Botto H: Prognostic value of MIB-1 antibody labeling index to predict response to Bacillus Calmette-Guérin therapy in a high-risk selected population of patients with stage T1 grade G3 bladder cancer. Eur Urol 2000;37:654-659.
39.
Zlotta AR, Noel JC, Fayt I, Drowart A, Van Vooren JP, Huygen K, Simon J, Schulman CC: Correlation and prognostic significance of p53, p21/WAF1/CIP1 and Ki-67 expression in patients with superficial bladder tumours treated with Bacillus Calmette-Guerin intravesical therapy. J Urol 1999;161:792-798.
40.
Zuiverloon TCM, Nieuweboer AJM, Vékony H, Kirkels WJ, Bangma CH, Zwarthoff EC: Markers predicting response to Bacillus Calmette-Guérin immunotherapy in high-risk bladder cancer patients: a systematic review. Eur Urol 2012;61:128-145.
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