PREDICTIVE FACTORS OF EVOLUTION OF PATIENTS AFTER pT0 RADICAL
CYSTECTOMY DUE TO BLADDER CANCER
E. Mediavilla, J.A. Portillo, D. Truán, F. Campos-Juanatey, L. Gala, J. Fuentes, C. Carrión and
J.L. Gutiérrez.
Urology Department. Hospital Universitario “Marques De Valdecilla”. (HUMV). Santander. Spain.
@
CORRESPONDENCE
Enrique Mediavilla Diez
C/ Cisneros, nº 96-C, piso 8º Izda,
39007, Santander, Cantabria (Spain)
[email protected]
Accepted for publication: May 20th, 2014
Summary.- OBJECTIVES: To analyze the influence of the different pre – cystectomy factors, both clinical and pathological, in the follow up of patients with no residual tumor ( pT0 ) in the pathological examination of the radical cystectomy specimen as predictors of tumor recurrence. Secondly we intend to compare overall survival, disease free survival and cancer-specific survival with the rest of cystectomy patients in our series.
METHODS: Between 1985 and 2010, radical cystectomy was performed in 280 patients with bladder cancer, being 41 pT0 (14.6%). We analyzed potential predictors for overall survival and disease-free survival: age, sex , number of transurethral resections of bladder tumor before cystectomy , tumor type , tumor grade, tumor stage, tumor size, number of tumors, associated Cis and previous instillations. We used univariate analysis of
Cox regression. Survival analysis was performed using Kaplan – Meier curves and log-rank test.
RESULTS: Mean age was 61.7 years and 37 patients were males (90.2%). Stages before cystectomy were pT1 in eight (19.5%) , pT2 in 31 (75.6%) and Cis in two (4.9 %) with tumor grade III in 37 (90.2%). Cystectomy specimens revealed the presence of papillary transitional cell carcinoma in 38 (92.7%) cases. The median number of pre-cistectomy-TURBT was one. Eleven patients (26.8%) received intravesical instillations. Six patients (14.63 %) had tumor recurrence and 10 (24.4 %) died from causes unrelated to the disease. None of the variables analyzed was statistically significant in the univariate analysis as a predictor of tumor recurrence. With a median follow up of 70 months (3-272) disease-free survival and overall survival at five years were 85.9% and 72.8% respectively. Compared to the non pT0 cystectomies in our series, pT0 had a statistically significant difference for better recurrence-free survival (63.4 % and 36.8%, respectively in pT0 and no-pT0 patients) (p<0,05).
CONCLUSIONS: According to the results, we have found a better outcome for pT0 patients after cystectomy compared to those with residual tumor. We have not found any pre - cystectomy predictive factor related to disease-free survival and overall survival.
Keywords: Bladder carcinoma. Cystectomy. pT0. Predictors. Overall Survival. Disease free survival. Resumen.- OBJETIVOS: Analizar la influencia de los diferentes factores pre-cistectomía tanto clínicos como anatomopatológicos, en el seguimiento de pacientes con estudio anatomopatológico de la pieza de cistecto-mía radical con ausencia de tumor residual (pT0), como
INTRODUCTION
Radical cystectomy is the preferred treatment for muscle invasive and non-muscle invasive bladder cancer with a high risk of progression (1,2), however
approximately 10% of patients have no residual tumor (pT0) in the pathological analysis of the surgical specimen.
Unlike other pathologies this finding does not imply the cure of the disease, but it does indicate a lower rate of recurrence (10%) and an increase in disease-free survival (DFS) (85,3%) and overall survival (OS) (79,7%) for patients with this condition (3,4).
The aim of this study was to analyze the influence of different clinical and pathological pre-cystectomy factors on disease progression in these patients in terms of recurrence and to compare DFS, OS and cancer-specific survival (CSS) between pT0 vs non pT0 patients.
MATERIAL AND METHODS
We analyzed the data of 280 cystectomies performed between 1985-2010 of which 41 (14.6%) presented pT0 in surgical specimen.
All patients underwent cystectomy for oncological reasons (bladder tumor T2-4 N0M0, high-risk non-muscle-invasive bladder tumor or recurrent bladder tumor refractory to standard therapy, or non-muscle-invasive bladder so extensive that it was impossible to control through TUR), and with the aim to eradicate the disease. We have excluded the cystectomies for other reasons. Before radical cystectomy all patients were evaluated by an uro-oncologic multidisciplinary committee.
The criteria used to recommend an orthotopic diversion in these patients were: Absence of neurological or psychiatric disease, life expectancy greater than 10 years, absence of renal failure, absence of tumor in prostatic urethra, sphincter function preserved, and a BMI <30 . The remaining patients were referred by ileal conduit or ureterosigmoidostomy to their preference after explaining the advantages and disadvantages of each option. The cutaneous diversion was performed in cases with limited life expectancy.
Demographic, clinical and pathological study population data were taken from a data base and analyzed manteined prospectively.
Subsequently using SPSS version 15.0 for Microsoft® the following pre-cystectomy variables were analyzed: age, gender, number of bladder transurethral resection (TUR) prior to cystectomy, tumor type, grade, stage, size tumor, number of tumors,
factores predictivos de recurrencia tumoral en estos pa-cientes. En segundo lugar pretendemos comparar la su-pervivencia global, susu-pervivencia libre de enfermedad y la supervivencia cáncer específica con las del resto de pacientes cistectomizados de nuestra serie.
MÉTODOS: Entre 1985-2010 se intervinieron 280 pa-cientes de cistectomía radical por causa tumoral, de los cuales 41 fueron pT0 (14,6%). Se exploraron los poten-ciales factores predictores para supervivencia global y supervivencia libre de enfermedad: edad, sexo, número de resecciones transuretrales de vejiga previas a la cis-tectomía, tipo tumoral, grado, estadio, tamaño tumoral, número de tumores, Cis asociado e instilaciones previas usando un análisis univariado de regresión de Cox. El análisis de supervivencia se realizó mediante curvas de Kaplan-Meier y Log-Rank test.
RESULTADOS: La edad media fue 61,7 años y 37 (90,2%) de ellos fueron varones. Los estadios previos a la cistectomía fueron pT1 en ocho (19,5%), pT2 en 31 (75,6%), y Cis en dos (4,9%), con un grado tu-moral III en 37 (90,2%). La anatomía patológica (AP), reveló la presencia de carcinoma transicional papilar en 38 (92,7%) casos. La mediana de RTU-V previas fue una. Habían recibido instilaciones endovesicales 11 (26,8%) pacientes. Seis pacientes (14,63%) pre-sentaron recidiva tumoral y diez (24,4%) fallecieron por causas ajenas a la enfermedad. Ninguna de las variables analizadas resultó ser estadísticamente signi-ficativa en el estudio univariado como predictora de recurrencia tumoral. Con una mediana de seguimiento de 70 meses (3-272), la supervivencia libre de enfer-medad y supervivencia global fueron del 85,9% y del 72,8% a los cinco años respectivamente. Comparando con las cistectomías no pT0 de nuestra serie, los pT0 presentaban una diferencia estadísticamente significati-va en cuanto a mayor supervivencia libre de recurrencia (63,4% y 36,8% respectivamente en pacientes no pT0) (p<0,05).
CONCLUSIONES: En nuestra serie, al análisis encon-tramos que los resultados clínicos de los pacientes pT0 tras la cistectomía son mejores que los de los pacientes con tumor residual. No habiendo encontrado factores pronósticos pre-cistectomía predictivos para la superviv-envia libre de enfrmedad.
Palabras clave: Carcinoma vesical. Cistectomía. pT0. Factores predictivos. Supervivencia Global. Supervivencia Libre de Enfermedad.
associated Cis and prior instillations. We compared their influence regarding the recurrence rate of pT0 patients. In addition we compared the DFS, the OS and CSS with the non-pT0 cystectomies. In all cases p<0.05 value was taken as statistically significant.
Univariate analysis was performed using Cox regression. Survival analysis was performed using Kaplan-Meier curves and log-rank test.
RESULTS
The mean age of the 41 pT0 patients was 61.7 years range (58,5-64,9) and 62.3 years IC95% (61.2-63.6) in the remaining 239 cases. Only 4 (9.8%) patients were women in the pT0 group and a similar rate in the rest of the series (21 women, 8.8%). Of the patients studied, 15 (36.6%) had received neoadyuvant chemotherapy, 11 patients had
Table I. General Characteristics of The Study Population.
Patients pT0 (n) (%) Age (years) (range): Gender (%):
Female Male
Neoadyuvant Chemotherapy (%) BCG instillations (%)
TUR before cystectomy (median) (range) Pathological Stage (%) CIS T1 T2 Pathological Grade (%): Grade I Grade II
Grade III (including CIS) Tumoral Histology (%): Transitional Squamous Adenocarcinoma
Median tumoral size (cm) (range)
Number of tumors in TUR (Median) (range) Urinary Diversion (%):
Orthotopic Bladder Ileal conduit (Bricker) Ureterosigmoidostomy Cutaneous diversion
Lymph node involvement in lymphadenectomy (%) Median time between RTU-V and cystectomy (range)
41 (100) 61,7 (58,5-64,9) 4 (9,8) 37 (90,2) 15 (36,6) 11 (26,8) 1 (1-11) 2 (4,9) 8 (19,5) 31 (75,6) 1 (2,4) 3 (7,3) 37 (90,3) 38 (92,7) 1 (2,4) 2 (4,9) 3 (1-10) 1 (0-3) 29 (70,8) 6 (14,6) 5 (12,2) 1 (2,4) 1 (2,4) 109 (21-459)
received BCG instillations prior to cystectomy, and 5 of these had also received instillations with some kind of chemotherapy drug. None of the patients had metastatic disease at the time of cystectomy. Table I shows the general characteristics of the study population.
Thirteen deaths were recorded (21.7%), 3 of them (7,3%) were secondary to the cancer occurring in the first five years of follow-up. Tumor recurrence was observed in 6 out of 41 cases (14,6%), all during the first five years of follow-up, and 4 of them (9,8%) in the first two years. Recurrences were away from the urinary tract in 3 cases (7.3%) in the upper urinary tract in 2 cases (4.9%) and in the urethra in 1 case (2.4%).
We did not find any statistically significant when we compared the different clinical and tumor characteristics (age, gender, number of TUR, histology, tumoral size, prior instillations, infiltration, grade and prior CIS) between recurrent and non-recurrent pT0 tumors (Table II).
With a median follow-up of 70 months (3-272), CSS and OS was 85.9% and 72.8% at five years respectively, while for the rest of the 239 no pT0 patients, these figures dropped to 63.4% and 36.8% respectively (p<0.05). The CSS were 90.9% and in the pT0 group versus 51.8% in the no pT0 group (p<0.05) (Figure 1, 2 and 3).
Also evidenced a lower recurrence rate for patients pT0 group, which when analyzed by stage, was not statistically significant in for Cis (p = 0.21), pT1 (p = 0.53) and T2a (p = 0.11). However, from the stage pT2b it was not statistically significant (p <0,05).
DISCUSSION
Unlike other tumoral diseases when we deal with bladder cancer, a pT0 cystectomy does not mean the condition of being cured, but it could mean an improvement in the long term prognosis; the finding of this improvement in survival is one of the premises that currently supports using neoadjuvant chemotherapy in patients fitted to get it because this therapy appears to increase the number of cases with no residual tumor on histopathology cystectomy specimen (2,5).
Current available literature presents a proportion of pT0 ranging between 6-14%. (6,7,8). In our series, the percentage is 14.6%, a figure similar to that of other Spanish authors such as Loizaga or Mallén (6,7), although it is a little far from the 5.1%
obtained by Tilki (9) in a series of 4,430 cystectomies, the largest series published so far, or by other authors such as May (2). However, despite this last figure, we can state that our study results are much as expected, given the variability between the different series.
As regards the prognostic implications of this finding, all the data presented in literature seem to indicate that, although it does not imply a cure of the disease, it seems to show higher rates of OS and CSS. Results are in line with those reported in our serie, where overall survival in the not pT0 patient group was 36.8% vs. 72.8% in pT0 group at five years (p <0.05) showing a statistically significant difference, as and those reported by Palapattu et al. (10).
However, in our study we were not able to observe any factor which may indicate a poorer prognosis among these patients, as it was the case in Rodríguez Faba or Kassouf (8,11), who indicate lymphovascular invasion, prior muscle invasive disease or more than five TURs prior to the cystectomy as influential factors for a poor prognosis.
Another topic for discussion is to try to know to what extent the pT0 finding is related to an advantage for patients. Tilki (9) stated that more than
Figura 1. !"##"$ÿ%&ÿ'(")*+,-!"" #$" #"" %$" %"" $" " ./(/#0*123ÿ4/52120# %&" "&' "&( "&) "&* "&$ "&+ "&! "&# "&% "&" ,-ÿ./" ./" &67ÿ2,ÿ)"ÿ&67 839/553)93:!533ÿ4/52120#ÿ'8!4-.0"1"$ 1 234567ÿ% !"##"$ÿ%&ÿ'(")*+,-!"" #$" #"" %$" %"" $" " ./(/#0*123ÿ4/52120# %&" "&' "&( "&) "&* "&$ "&+ "&! "&# "&% "&" ,-ÿ./" ./" &67ÿ2,ÿ)"ÿ&67 839/553)93:!533ÿ4/52120#ÿ'8!4-.0"1"$ 1 234567ÿ%
the pT0 cystectomy in itself, the greater survival rate is actually caused by a reduction in the pre-cystectomy TUR stage. In the same way Kassouf (11), in a series of 1104 cystectomies highlights that the survival of pT0 is independent of the baseline clinical stage.
Independently of the mentioned above, what it does seem to be clear is the heterogeneous behavior of pT0 patients, although it looks similar to those patients with non-muscle invasive residual illness (10,12). !"ÿ#$% #$% !"#ÿ$%ÿ&'ÿ!"# ('))'*ÿ+!ÿ,-'./0%1 &%% '(% '%% )(% )%% (% % 23-3)4/5$6ÿ738$5$4) )*% %*+ %*, %*-%*. %*( %*/ %*& %*' %*) %*% 9$684))ÿ738$5$4)ÿ,971 #0%1%( 1 234567ÿ) !"ÿ#$% #$% !"#ÿ$%ÿ&'ÿ!"# ('))'*ÿ+!ÿ,-'./0%1 &%% '(% '%% )(% )%% (% % 23-3)4/5$6ÿ738$5$4) )*% %*+ %*, %*-%*. %*( %*/ %*& %*' %*) %*% 9$684))ÿ738$5$4)ÿ,971 #0%1%( 1 234567ÿ) !"##"$ÿ%&ÿ'(")*+,-!"# !## $"# $## "# # ./(/#0*123ÿ4/52120# $%# #%& #%' #%( #%) #%" #%* #%+ #%! #%$ #%# ,-ÿ./# ./# &67ÿ2,ÿ8"ÿ&67 .0)935:4&391;19ÿ4/52120#ÿ'.44-.0#1#" 1 234567ÿ$ !"##"$ÿ%&ÿ'(")*+,-!"# !## $"# $## "# # ./(/#0*123ÿ4/52120# $%# #%& #%' #%( #%) #%" #%* #%+ #%! #%$ #%# ,-ÿ./# ./# &67ÿ2,ÿ8"ÿ&67 .0)935:4&391;19ÿ4/52120#ÿ'.44-.0#1#" 1 234567ÿ$ Figura 2. Figura 3.
Table II. Analysis of the differences of the variables analyzed between pT0 patients with and without recurrence.
Age
Gender (Male/Female) Number of TUR
Histology (Transitional/ Other) Tumoral Size
Prior Instillations
Infiltration (No invasive/ Invasive) Grade (I-II/III) Prior Cis HR (IC 95%) 0,993 (0,921-1,071) 0,043 (0-7986) 1,085 (0,788-1,496 0,044 (0-31,195) 0,539 0,270-1,077 3,101 (0,624-15,418) 0,923 (0,306-2,770) 2.545 (0,918-7,042) 0,045 (0-178361) p value 0,860 0,611 0,616 0,650 0,080 0,167 0,882 0,072 0,690
A weak point in our study could be the heterogeneity of patients and indications due to the 25 year recruitment period. But on the other hand this adds a certain advantage to the study making it comparable to the reality and other published series.
CONCLUSION
We emphasize that the finding of pT0 in the cystectomy specimen provides greater SG and SCE, but nevertheless, we could not find any factor that makes us predict recurrence.
Fukuta, F. Masumori, N. Honma, I. Muto, M. IChihara, K. Kitamura, H. et Al. Clinical Outco-mes of Patients with pT0 Bladder Cancer after Radical Cystectomy: A Single-institute Experien-ce. Jpn J Clin Oncol. 2011;41:115-20.
May M, Bastian PJ, Burger M, Bolenz C, Trojan L, Herrmann E, et al. Multicenter evaluation of the prognostic value of pT0 stage after radical cystectomy due to urothelial carcinoma of the bladder. BJU Int. 2011;108:E278-83.
Rouprêt M, Drouin SJ, Larrè S, Neuzillet Y, Botto H, Hitier M, et al. Oncologic Outcomes and Sur-vival in pT0 Tumors After Radical Cystectomy in Patients Without Neoadjuvant Chemotherapy: Results from a Large Multicentre Collaborative Study. Ann Surg Oncol, 2011;18:3833-8.
Hitier M, Marconnet L, Luyckx F, Branchereau J, Braud G, Karam G, et al. Facteurs prédictifs et résultats carcinologiques à long terme des patients n’ayant plus de tumeur résiduelle (stade pT0) sur la pièce de cystectomie totale réalisée pour cancer de vessie. Prog Urol, 2010; 20 :130-7.
1. 2. 3. 4. 5. 6. *7. *8. **9. 10. *11. 12.
Kaag MG, Milowsky MI, Dalbagni G, Thompson RH, Katz D, Reuter VE, et al. Regional lymph node status in patients with bladder cancer found to be pathological stage T0 at radical cystectomy following systemic chemotherapy. BJU Int. 2011; 108: E272-7.
Loizaga Iriarte A, Senarriaga Ruiz de la Illa N, La Casa Visacsillas I, Rabade Ferreiro A, Iriarte Soldevilla I, Unda Urzaiz M. ¿Implica el pT0 en la pieza de cistectomía encontrarse libre de tumor a largo plazo?. Actas Urol Esp, 2009;33:865-8. Mallen Mateo E, Gil Martinez P, Gil Sanz MJ, Sancho Serrano C, Pascual Regueiro D, Rioja Sanz LA. Tumores de vejiga pT0 tras cistectomía radical: análisis de nuestra serie. Actas Urol Esp, 2006;30:763-71.
Rodriguez Faba O, Palou J, Rosales A, Breda A, Algaba F, Urdaneta G, et al. Clinical Predictive Factors of Poor Outcome in Patients With Sta-ge pT0 Disease at Radical Cystectomy. J Urol, 2001;186:442-7.
Tilki D, Svatek RS, Novara G, Seitz M, Godoy G, Karakiewicz PI, et al. Stage pT0 at Radical Cystec-tomy Confers Improved Survival: An International Study of 4,430 Patients. J Urol, 2010;184: 888-94. Palapattu GS, Shariat SF, Karakiewicz PI, Bastian PJ, Rogers CG, Amie G, et al. Cancer Specific Outcomes in Patients With PT0 Disease Following Radical Cystectomy. J Urol, 2006;175:1645-9. Kassouf W, Spiess PE, Brown GA, Munsell MF, Grossman HB, Siefker-Radtke A. et al. P0 Sta-ge at Radical Cystectomy for Bladder Cancer is Associated with Improved Outcome Independent of Traditional Clinical Risk Factors. Eur Urol, 2007;52:769-76.
Su K, Wan J, Yul S, Hoon N, Deuk Y, Choul S, et al. The prognostic significance of pathologic sta-ge pT0 on organed-confinated bladder transitional cell carcinoma following radical cystectomy. Urol Int, 2008; 81: 394-8.
REFERENCES AND RECOMMENDED READINGS (*of special interest, **of outstanding interest)
