Clinical Outcomes of Patients with pt0 Bladder Cancer after Radical Cystectomy: A Single-institute Experience Fumimasa Fukuta, Naoya Masumori *, Ichiya Honma, Masatoshi Muto, Koji Ichihara, Hiroshi Kitamura and Taiji Tsukamoto Department of Urology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan *For reprints and all correspondence: Naoya Masumori, Department of Urology, School of Medicine, Sapporo Medical University, S1W16, Sapporo, Hokkaido, Japan. E-mail: masumori@sapmed.ac.jp Received March 26, 2010; accepted July 8, 2010 Jpn J Clin Oncol 2011;41(1)115 120 doi:10.1093/jjco/hyq148 Advance Access Publication 9 August 2010 Objective: To investigate the clinical outcomes of patients who underwent radical cystectomy for bladder cancer at a single institution and compare those who had pt0 specimens with those who had residual cancer. Methods: From January 1990 to December 2006, 186 patients underwent radical cystectomy with or without neoadjuvant chemotherapy for ct2 or higher stage urothelial carcinoma in the bladder in our hospital. We estimated the 5-year disease-free survival, cancer-specific survival and overall survival by the pathological stage. Results: The median follow-up of the 186 patients was 38.5 months (0 194). Of these, 51 received neoadjuvant chemotherapy. For all subjects, the 5-year disease-free survival was 54.9%, cancer-specific survival 61.0% and overall survival 57.1%. Of the 186 patients, 24 (12.9%) had no residual cancer in the bladder specimen at radical cystectomy. Of the 24 patients with pt0, only 1 (4.2%) died of bladder cancer. The 5-year disease-free survival, cancer-specific survival and overall survival rates in patients with pt0 were 96.0%. We found pt0 histology in 11 of the 51 patients (21.6%) with neoadjuvant chemotherapy and in 13 of the 135 patients (9.6%) with radical cystectomy alone (P ¼ 0.047). Conclusions: We demonstrated that the outcomes of patients who underwent radical cystectomy were similar to those in previous reports. Patients with pt0 showed favorable outcomes for disease-free survival, cancer-specific survival and overall survival in our study. However, they should be periodically followed up because pt0 does not always mean cure. Key words: bladder cancer urothelial carcinoma cystectomy chemotherapy pt0 INTRODUCTION Indications for radical cystectomy are muscle-invasive or high-risk non-muscle-invasive bladder cancer. It is reported that 10% of patients who undergo radical cystectomy have no histologically proven residual cancer ( pt0) in the bladder specimen (1,2). Patients have favorable outcomes when they achieve pt0 histology in radical cystectomy specimens. However, there is some controversy over the clinical meaning of pt0 because it was reported that even patients with pt0 had recurrence and their survival did not differ from those with non-muscle-invasive bladder cancer who had radical cystectomy (2). In this context, we tried to determine the clinical outcomes of patients with pt0 who received radical cystectomy, comparing them with those having persistent cancer with the other pathological stages. PATIENTS AND METHODS We retrospectively investigated the clinical outcomes of patients who had radical cystectomy in our institute from January 1990 through December 2006. This study included 299 patients who had bladder cancer without distant metastasis at the initial presentation and underwent radical cystectomy with or without neoadjuvant chemotherapy. We excluded 99 patients from the current study, including 36 with a history of or concomitant upper urinary tract urothelial cancer, 29 with positive surgical margins in specimens obtained at radical cystectomy, 32 with non-urothelial carcinoma specimens and 2 with other malignant diseases that were likely to influence their survival. Of the remaining 200 patients, 186 were ct2 or higher and they were subject for this study. # The Author (2010). Published by Oxford University Press. All rights reserved.
116 pt0 bladder cancer after radical cystectomy Two cycles of chemotherapy consisting of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) were basically used as neoadjuvant chemotherapy for patients with clinical stage of T2 or higher. We performed radical cystectomy with the standard technique (3) and pelvic lymph node dissection (PLND). The boundaries of PLND were the circumflex iliac vein inferiorly, the genitofemoral nerve laterally, the internal iliac vein or artery medially, and the iliac bifurcation superiorly before August 2003. After that time, we extended the dissection area superiorly to the aortic bifurcation. We determined the tumor stage according to the 1997 TNM classification (4). The histopathological evaluation was performed by several pathologists at our hospital. We performed physical examination and studied the hemogram, serum chemistry profiles, chest X-ray or computed tomography (CT) of the lung, and CT of the abdomen and pelvis after radical cystectomy. The follow-up interval was 6 12 months in patients with pt2 or lower without lymph node involvement, and 3 6 months in those with pt3 or higher and/or lymph node involvement. We estimated disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) by the pathological stage using the Kaplan Meier method. The survival time was calculated from the date of radical cystectomy. The log-rank test was used for evaluating the statistical significance in survival. Fisher s exact test was used for comparing the pt0 incidence rate between the two groups. We analyzed the risk ratios for pt0 incidence according to the extent of the disease before radical cystectomy using logistic regression analysis. A P value of,0.05 was regarded as a statistically significant difference. All statistical analyses were performed using SPSS 15.0 (SPSS Inc., Chicago, IL, USA). RESULTS In 90% of the 186 eligible patients, the histopathology of the specimen at transurethral resection of the bladder tumor was pure urothelial carcinoma (Table 1). Only about 10% of radical cystectomy specimens were not pure urothelial carcinoma. Of the 186 patients, 151 were confirmed to have ct2 or higher disease by pathological examination, which demonstrated microscopic invasion of the bladder muscle or prostatic urethra in specimens from transurethral resection of bladder tumors. The others were diagnosed as having ct2 or higher disease by CT and/or magnetic resonance images. Of the 186 patients, 24 (12.9%) had no residual cancer in their radical cystectomy specimens. There was one patient (0.5%) who did not have a residual tumor in the bladder specimen but had lymph node involvement. We categorized this patient into the pnþ group. The incidences of pt0 histology were 25.0% in those with ct2, 1.8% in those with ct3 and 6.5% in those with ct4. Neoadjuvant chemotherapy was done for 51 patients (27.4%) (Table 2). Of the 135 patients who did not have neoadjuvant chemotherapy, the clinical stage corresponded to the pathological stage in 40.7% and understaging of the clinical stage was found in 25.9%. Of the 51 patients with neoadjuvant chemotherapy, 2 received 1 cycle of chemotherapy, 43 two cycles, 4 three cycles and 2 four cycles. We found pt0 histology in 11 of the 51 patients (21.6%) with neoadjuvant chemotherapy and in 13 of the 135 patients (9.6%) without it (Table 2). There was a significant difference (P ¼ 0.047) in the pt0 incidence between patients with and without neoadjuvant chemotherapy. Table 3 shows risk ratios for pt0 incidence according to the disease extent before radical cystectomy. The clinical stage and presence of neoadjuvant chemotherapy were significant factors for pt0 incidence in univariate analysis. However, in multivariate analysis, the clinical stage was the only independent pre-operative factor that was associated with pt0 incidence. Some patients whose pathological stages were higher than pt2 preferred to receive adjuvant chemotherapy. Nineteen patients underwent MVAC adjuvant chemotherapy ( pt3: 5, pt4: 1 and pnþ: 12). The median follow-up time of the 186 patients was 38.5 (0 194) months with pathologically non-muscle invasive disease having a follow-up period of nearly 6 years (Table 1). Of these patients, 68 died of bladder cancer and 13 died of other causes. Of the 24 patients with pt0, only 1patienthadlocalrecurrence,at11monthsfromradical cystectomy. This patient died of bladder cancer at 24 months. The clinical stage of the patient was ct2 and tumor size was.5 cm in diameter. He underwent 4 cycles of MVAC neoadjuvant chemotherapy and the tumor reduction rate was 80% by bidirectional evaluation. For all patients, the 5-year DFS was 54.9%, CSS 61.0% and OS 57.1%. Patients with pt0 histology had significantly higher DFS than those with pt1, pta or ptis, or pt2 histology (Fig. 1). Similar findings were confirmed for CSS and OS. For 186 patients, there were no significant differences in DFS (P ¼ 0.181), CSS (P ¼ 0.722) and OS (P ¼ 0.713) between those with MVAC neoadjuvant chemotherapy and those without it. DISCUSSION It was reported that the understaging rate in patients with ct2 or higher was about 20 50% (5 8). When comparing clinical stage with the pathological stage among patients without neoadjuvant chemotherapy, our understaging rate was similar to other reports. Therefore, we thought our staging was validated. It was reported that the incidences of pt0 were 40% (9,10) inpatientswithmvacneoadjuvantchemotherapy and 6.3 20.1% in those with radical cystectomy alone (11,12). In the current study, the former incidence was 21.6% and the latter 9.6%. The incidence of pt0 in our patients with radical cystectomy alone was similar to
Jpn J Clin Oncol 2011;41(1) 117 Table 1. Patients characteristics Pathological stage Total pt0 pt1 pt2 pt3 pt4 pnþ N 186 24 30 36 34 22 40 Median follow-up Months 38.5 79.5 60.5 46 29.5 37 20 Range (0 194) (18 192) (2 187) (0 180) (5 194) (2 138) (4 151) Median age Sex Years old 66 64 66.5 62 68.5 67.5 65.5 Male 158 21 28 32 25 21 31 Female 28 3 2 4 9 1 9 Histopathology at TURBT UC 161 20 26 33 30 20 33 UC. SCC 16 2 1 3 4 1 5 UC. AC 9 2 3 0 0 0 4 Histopathology at cystectomy UC 138 0 30 29 26 20 33 UC. SCC 20 0 0 6 7 2 5 UC. AC 3 0 0 0 3 0 0 UC. SCC. AC 1 0 0 1 0 0 0 No residual ca 24 24 0 0 0 0 0 Clinical stage ct2 72 18 16 21 9 1 7 ct3 55 1 6 10 21 3 14 ct4 46 3 8 3 3 17 12 cnþ 13 2 0 2 1 1 7 TURBT, transurethral resection of bladder tumor; UC, urothelial carcinoma; SCC, squamous cell carcinoma; AC, adenocarcinoma; No residual ca, no residual cancer. Table 2. Clinical stage vs. pathological stage and pt0 rate by treatment arm Pathological stage (n) Total (186) pt0 (24) pt1 (30) pt2 (36) pt3 (34) pt4 (22) pnþ (40) pt0 rate (%) Cystectomy alone (135) ct2 52 12 11 13 8 1 6 23.1 ct3 38 1 4 3 19 2 9 2.6 ct4 36 0 6 2 3 16 9 0 cnþ 9 0 0 1 1 0 7 0 Neoadjuvant MVAC (51) ct2 20 6 5 8 0 0 1 30.0 ct3 17 0 2 7 2 1 5 0 ct4 10 3 2 1 0 1 3 30.0 cnþ 4 2 0 1 0 1 0 50.0 MVAC, methotrexate, vinblastine, doxorubicin and cisplatin.
118 pt0 bladder cancer after radical cystectomy Table 3. Risk ratios for pt0 incidence according to disease extent before radical cystectomy N Univariate analysis Multivariate analysis Risk ratio 95% CI P value Risk ratio 95% CI P value Tumor size (cm),3 98 1 1 3 88 0.93 0.40 2.21 0.88 0.94 0.35 2.54 0.90 Tumor number 1 86 1 1 2 100 0.70 0.29 1.64 0.41 0.60 0.22 1.66 0.32 Tumor grade G1/2 50 1 1 G3 136 0.71 0.25 2.02 0.52 0.77 0.26 2.26 0.64 Primary or recurrent tumor Primary 140 1 1 Recurrent 46 0.40 0.11 1.40 0.15 0.32 0.08 1.23 0.10 Concomitant CIS Absent 168 1 1 Present 18 2.11 0.63 7.06 0.22 1.88 0.45 7.78 0.39 Clinical stage T2 72 1 1 T3 55 0.06 0.01 0.43,0.01 0.05 0.01 0.37,0.01 T4 46 0.21 0.06 0.76 0.02 0.20 0.05 0.78 0.02 Nþ 13 0.55 0.11 2.70 0.46 0.56 0.10 3.01 0.50 Neoadjuvant chemotherapy Absent 135 1 1 Present 51 2.58 1.07 6.21 0.03 2.52 0.95 6.71 0.06 CI, confidence interval; CIS, carcinoma in situ. previous reports. In the Southwest Oncology (SWOG) trial (9), 50% of patients who initially staged ct2 and 30% of those who staged ct3 or ct4 achieved pt0 by neoadjuvant chemotherapy. Although there was a significant difference in the pt0 incidence between patients with neoadjuvant chemotherapy and those without it in our study, the pt0 incidence in patients staged ct3 seemed to be somewhat lower than that in SWOG. The cycle of MVAC, extension of transurethral resection of bladder cancer and other factors may have been involved in the difference. There have been few reports that discussed the association between tumor status before radical cystectomy and pt0 incidence. We found that the pt0 incidence rate was significantly higher in patients with ct2 than in those with ct3 or ct4. Although neoadjuvant chemotherapy was significantly associated with pt0 incidence in univariate analysis, it was not in multivariate analysis. We considered that this result was related to the low pt0 incidence rate in ct3 in this study. There are some reports that the prognosis of pt0 bladder cancer is favorable. In SWOG, 85% of the patients with pt0 were alive at 5 years after randomization. Although 1 of the 24 patients with pt0 had recurrence and died of bladder cancer in our study, the others had good outcomes: the 5-year DFS and CSS rates were 96%. Volkmer et al. (12) andchoetal.(13) reported that they did not experience local recurrence in patients with pt0. Meanwhile, Kassouf et al. (14) experiencedthreecases (2.5%) of local recurrence in their large volume study. It was local recurrence that we experienced in the one patient with pt0 who died in our series. The original tumor size of the patient seemed to be related to the recurrence because it was.5 cm in diameter. Cheng et al. (15) found,fort2 bladder cancer, that patients with a tumor diameter of,3 cm had a favorable prognosis. In Japan, there are few reports about the prognosis of patients with pt0 bladder cancer from a single institute. There was a limitation because our study design was
Jpn J Clin Oncol 2011;41(1) 119 Figure 1. Kaplan Meier curves show disease-free survival (A), cancer-specific survival (B) and overall survival (C) by the pathological stage. retrospective. However, we found favorable outcomes in patients with pt0 bladder cancer that were similar to those in previous reports. Although the clinical outcome of patients with pt0 was better than that of patients with other stages, they should be periodically followed because pt0 does not always mean cure. CONCLUSIONS The outcomes of patients who underwent radical cystectomy in this study were similar to those in previous reports. DFS, CSS and OS in patients with pt0 bladder cancer were better than those with non-pt0. Funding This work was supported by Gohtaro Sugawara-Memorial Research Fund for Urologic diseases. The sponsor of the study had no role in the study design, collection, analysis and interpretation of data.
120 pt0 bladder cancer after radical cystectomy Conflict of interest statement None declared. References 1. Dalbagni G, Genega E, Hashibe M, Zhang ZF, Russo P, Herr H, et al. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165:1111 6. 2. Thrasher JB, Frazier HA, Robertson JE, Paulson DF. Does a stage pt0 cystectomy specimen confer a survival advantage in patients with minimally invasive bladder cancer? J Urol 1994;152:393 6. 3. Whitmore WF, Jr. Management of invasive bladder neoplasms. Semin Urol 1983;1:34 41. 4. Sobin LH, Wittekind CH. TNM Classification of Malignant Tumors. 5th edn. New York: Wiley, 1997. 5. Pagano F, Bassi P, Galetti TP, Meneghini A, Milani C, Artibani W, et al. Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol 1991;145:45 50. 6. Ghoneim MA, el-mekresh MM, el-baz MA, el-attar IA, Ashamallah A. Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1,026 cases. J Urol 1997;158:393 9. 7. Shariat SF, Palapattu GS, Karakiewicz PI, Rogers CG, Vazina A, Bastian PJ, et al. Discrepancy between clinical and pathologic stage: impact on prognosis after radical cystectomy. Eur Urol 2007;51:137 49; discussion 49 51. 8. Ficarra V, Dalpiaz O, Alrabi N, Novara G, Galfano A, Artibani W. Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. BJU Int 2005;95: 786 90. 9. 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. NEnglJ Med 2003;349:859 66. 10. Millikan R, Dinney C, Swanson D, Sweeney P, Ro JY, Smith TL, et al. Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC. JClin Oncol 2001;19:4005 13. 11. 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;19:666 75. 12. Volkmer BG, Kuefer R, Bartsch G, Jr, Straub M, de Petriconi R, Gschwend JE, et al. Effect of a pt0 cystectomy specimen without neoadjuvant therapy on survival. Cancer 2005;104:2384 91. 13. Cho KS, Seo JW, Park SY, Cho NH, Choi YD, Yang SC, et al. The prognostic significance of pathologic stage T0 on organ-confined bladder transitional cell carcinoma following radical cystectomy. Urol Int 2008;81:394 8. 14. Kassouf W, Spiess PE, Brown GA, Munsell MF, Grossman HB, Siefker-Radtke A, et al. P0 stage at radical cystectomy for bladder cancer is associated with improved outcome independent of traditional clinical risk factors. Eur Urol 2007;52:769 74. 15. Cheng L, Weaver AL, Leibovich BC, Ramnani DM, Neumann RM, Scherer BG, et al. Predicting the survival of bladder carcinoma patients treated with radical cystectomy. Cancer 2000;88:2326 32.