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Outcomes of Patients with Clinical T1 Grade 3 Urothelial Cell Bladder Carcinoma Treated with Radical Cystectomy
Oncology Outcomes of Patients with Clinical T1 Grade 3 Urothelial Cell Bladder Carcinoma Treated with Radical Cystectomy Amit Gupta, Yair Lotan, Patrick J. Bastian, Ganesh S. Palapattu, Pierre I. Karakiewicz, Ganesh V. Raj, Mark P. Schoenberg, Seth P. Lerner, Arthur I. Sagalowsky, and Shahrokh F. Shariat OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
Urothelial tumors that invade the lamina propria but not the muscularis propria are a particularly problematic clinical entity. The aim of the present study was to assess the pathologic features and clinical outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma (UCBC) treated with radical cystectomy. We reviewed the records of 958 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer at three U.S. academic centers. Of these patients, 167 (median age, 66.7 years) underwent radical cystectomy for clinical stage T1 grade 3 UCBC. The median follow-up was 33.8 months (mean ⫾ standard deviation: 45.9 ⫾ 39.2 months, range, 0.4 to 177.1) for patients alive at last follow-up. Disease recurred in 48 of 167 of patients (29.4%) and 30 of 162 patients (18.5%) died from bladder cancer. A total of 29 of 166 patients (17.5%) had lymph nodal metastases. Of 167 patients, 84 (50%) were pathologically upstaged and 167 (27.5%) had extravesical disease. Patients with disease upstaging had poorer survival (P ⬍0.001). A greater than 3-month delay between cystectomy and last transurethral resection showed a trend toward upstaging (P ⫽ 0.06). Presence of carcinoma in situ (CIS) was the only precystecomy factor that predicted disease recurrence (hazard ratio [HR]: 2.13, 95% confidence interval [CI]: 1.14 to 3.98) and mortality (HR: 2.75, 95% CI: 1.17 to 6.46). A large proportion of patients undergoing cystectomy for clinical T1 grade 3 disease have adverse pathological features. The recurrence and survival outcomes in this group are suboptimal. Presence of CIS precystectomy predicts outcomes. Better markers are needed to identify patients at high risk for adverse outcomes. UROLOGY 71: 302–307, 2008. © 2008 Elsevier Inc.
O
ptimal management of clinical T1 grade 3 urothelial cell bladder cancer (UCBC) lesions is controversial. Understaging of disease is common1– 8 and residual disease is present up to 78% of the times on reresection.9 Although some patients have good long-term outcomes with transurethral resection (TUR) and intravesical therapy, others develop disease progression and metastases, and die despite radical cystectomy.10 Early cystectomy offers definitive therapy but must be balanced with the morbidity related to treatment.11 Furthermore, the optimal timing of cystectomy and the factors that predict outcomes in patients undergoing radFrom the Bladder Cancer Research Consortium (BCRC). From the Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland; the Cancer Prognostics and Health Outcomes Unit, University of Montreal, Montreal, Quebec, Canada; and the Scott Department of Urology, Baylor College of Medicine, Houston, Texas Reprint requests: Shahrokh F. Shariat, M.D., Department of Urology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9110. E-mail: [email protected] Submitted: May 17, 2007, accepted (with revisions): October 22, 2007
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© 2008 Elsevier Inc. All Rights Reserved
ical cystectomy are unclear. In this large, multi-institutional, retrospective study we describe the outcomes of patients who underwent cystectomy for clinical T1 grade 3 disease, and investigate the precystectomy factors that predicted outcomes for these patients.
MATERIAL AND METHODS Patient Population All studies were undertaken with the approval of the institutional review board at each institution. A total of 958 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy with curative intent by select surgeons at three academic medical centers during the period March 11, 1984 through January 24, 2003, and who had data available, were candidates for this analysis. Indications for radical cystectomy were tumor invasion into the muscularis propria or prostatic stroma or Ta, T1, or carcinoma in situ (CIS) refractory to TUR with intravesical chemotherapy and/or immunotherapy. Clinical stage was assigned according to the 1997 Tumor, Nodes, and Metastases (TNM) system. A total of 202 two patients had clinical tumor stage T1. We excluded 17 patients 0090-4295/08/$34.00 doi:10.1016/j.urology.2007.10.041
with grade 2 disease and 18 patients with nonurothelial histology, which left 167 patients for analysis. A total of 73 patients (43.7%) had received intravesical chemotherapy or immunotherapy. Adjuvant chemotherapy was administered to 34 patients (20.4%). Adjuvant external beam radiotherapy was administered to 5 patients (3%). Second TUR was not standard practice during the time these patients were treated.
Pathology Staff pathologists from each institution with expertise in genitourinary pathology examined all specimens. We used the 1997 TNM classification for pathologic staging and the 1973 World Health Organization classification for pathologic grading. Patients were categorized into pathologically downstaged (lower pathologic than clinical stage and negative lymph nodes), same stage (same clinical and pathologic stage and negative lymph nodes), and pathologically upstaged (higher pathologic than clinical stage or positive lymph nodes). We determined cause of death by chart review corroborated by death certificates, or by death certificates alone. Perioperative mortality (death within 30 days of surgery) was censored at time of death for bladder cancer–specific survival analyses.
Statistical Analysis We calculated time to radical cystectomy as the time from the last TUR or bladder biopsy before cystectomy. We used Fisher’s exact and Chi-square tests to evaluate the association among categorical variables. We assessed differences for continuous variables using the Mann-Whitney U-test. We used the Kaplan-Meier method to calculate survival functions and assessed differences with the log-rank test. We performed survival analyses with the Cox proportional hazard regression model. Statistical significance was set as a two-sided P ⬍0.05. Analyses were performed with SPSS Inc, Chicago, IL (version 13.0).
RESULTS The median age was 66.7 years (interquartile range [IQR]: 59.1 to 72.7 years; range, 37.7 to 89.2). Table 1 provides detailed descriptive characteristics. The descriptive characteristics of patients treated with radical cystectomy for clinical stage T1 grade 3 disease is shown in table 1. Eighty-six percent of patients were of male gender; 51.5% were operated between 2001 and 2003; 45.6% had concomitant CIS on their clinical specimen; 49.7% had muscle-invasive pathologic stage; 27.5% had nonorgan confined pathologic stage’ 31.1% had lymphovascular invasion; and 17.1% had metastases to lymph nodes. Twenty-three percent of the patients were pathologically downstaged, 26% had the same stage, and 50% were pathologically upstaged. More than half of those who were upstaged did not have organ-confined disease. The median number of lymph nodes removed at time of radical cystectomy was 18 (inter-quartile range: 11). The median time from TUR to RC was 1.9 months (interquartile range: 2.3). Overall, 29 patients (17.5%) had metastases to regional lymph nodes. The median number of positive lymph nodes and mean percent positive lymph nodes were 2 (IQR: 1 to 9) and 8.7% (IQR: UROLOGY 71 (2), 2008
Table 1. Descriptive characteristics of 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical stage T1 grade 3 disease Characteristic Gender (%) Female Male Year of surgery 1984–1989 1990–1994 1995–2000 2001–2003 Precystecomy carcinoma in situ Present Absent Pathologic stage (%) pT0 (no tumor) pTa pTis pT1 pT2 pT3 pT4 Pathologic grade (%) 0 (no tumor) 1 2 3 Postcystectomy carcinoma in situ Present Absent Lymphovascular invasion (%) Present Absent Metastases to lymph nodes (%) Present Absent Discrepancy between clinical and pathologic stage Pathologic downstaging Same stage Pathologic upstaging
No. Patients (%) 23 (13.8) 144 (86.2) 4 (2.4) 20 (12.0) 58 (34.7) 85 (50.9) 92 (55.1) 75 (44.9) 16 (9.6) 4 (2.4) 19 (11.4) 46 (27.5) 36 (21.6) 31 (18.6) 15 (9.0) 16 (9.6) 3 (1.8) 6 (3.6) 142 (85.0) 109 (65.3) 58 (34.7) 50 (31.3) 110 (68.8) 29 (17.5) 137 (82.5) 39 (23.4) 44 (26.3) 84 (50.3)
Lymphovascular invasion was missing in 7 patients. Lymph node status was missing in 1 patient.
6.7% to 46.1%), respectively. The median number of lymph nodes sampled was 18 (IQR: 14 to 25). Lymph node metastases were found in 4.3% (2 of 46) of patients with T1, 13.9% (5 of 36) of patients with T2, 46.7% (14 of 30) of patients with T3, and 53.3% (8 of 15) of patients with T4 disease, respectively. Cancer recurred in 48 of 167 patients (29.4%) and 51 of 166 patients (30.7%) were dead at the time of analysis. Cause of death was missing in 4 patients. Overall, 30 of 162 patients (18.5%) died from bladder cancer and 17 of 162 (10.4%) died from other causes without evidence of disease recurrence. The median follow-up was 33.8 months (mean ⫾ standard deviation: 45.9 ⫾ 39.2 months; range, 0.4 to 177.1) for patients alive at last follow-up. Actuarial recurrence-free estimates were 70.6% (standard error [SE]: 4.0%) at 3 years, 68.1% (SE: 4.2%) at 5 years, and 59.9% (SE: 5.4%) at 7 years after 303
Figure 1. Kaplan-Meier estimates of recurrence-free (A) and bladder cancer–specific survival (B) probabilities for 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical T1 grade 3 UCBC.
cystectomy (Fig. 1a). Actuarial bladder cancer–specific survival estimates were 82.1% (SE: 3.5%) at 3 years, 79.0% (SE: 4.0%) at 5 years, and 71.0% (SE: 5.7%) at 7 years (Fig. 1b). Patients who were upstaged had decreased recurrencefree survival and bladder cancer–specific survival compared with patients who were downstaged or had the same stage (log rank, P ⬍0.001).
Association of Clinical Characteristics with Upstaging and Clinical Outcomes Patients with precystectomy CIS were more likely to have disease recurrence and die from bladder cancer than those without CIS (P ⫽ 0.016 for both) (Table 2 and Fig. 2a and b). Gender, intravesical therapy, and presence of precystectomy CIS were not associated with pathological upstaging (Table 2). Precystectomy CIS was not associated with nodal metastases or lymphovascular invasion (P ⫽ 0.83 and 0.19, respectively) or with a longer delay between last TUR and cystectomy (P ⫽ 0.14).
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Table 2. Association of clinical characteristics with pathologic upstaging, disease recurrence, and disease-specific survival in 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical stage T1 grade 3 disease Pathologic Upstaging Downstaged or Same Stage Upstaged
UROLOGY 71 (2), 2008
Gender (No. patients [%]) Female Male Intravesical therapy No Yes Precystectomy concomitant CIS (No. patients [%]) Absent Present Time from TUR to radical cystectomy (No. patients [%]) ⬍3 mo ⱖ3 mo
P
Bladder Cancer Recurrence (%) 3-Year 7-Year Probability ⫾ SE Probability ⫾ SE
P
Bladder Cancer–Specific Survival (%) 3-Year 7-Year Probability ⫾ SE Probability ⫾ SE P
14 (60.9%) 69 (47.9%)
9 (39.1%) 75 (52.1%)
0.25
62.4 ⫾ 12.7 71.74 ⫾ 4.2
62.44 ⫾ 12.7 60.44 ⫾ 5.7
0.61
88.94 ⫾ 7.4 81.24 ⫾ 3.8
59.34 ⫾ 24.7 71.54 ⫾ 5.9
0.86
43 (46.2%) 39 (53.4%)
50 (53.8%) 34 (46.6%)
0.36
69.54 ⫾ 5.3 71.54 ⫾ 6.4
59.74 ⫾ 7.2 59.04 ⫾ 8.5
0.84
85.54 ⫾ 4.1 76.94 ⫾ 6.1
76.94 ⫾ 7.5 61.94 ⫾ 9.3
0.34
32 (42.7%) 51 (55.4%)
43 (57.3%) 41 (44.6%)
0.10
79.44 ⫾ 5.5 63.74 ⫾ 5.6
71.04 ⫾ 7.7 52.14 ⫾ 7.1
0.016
86.84 ⫾ 4.8 78.24 ⫾ 5.0
86.84 ⫾ 4.8 58.14 ⫾ 9.3
0.016
43 (48.3%) 10 (29.4%)
46 (51.7%) 24 (70.6%)
0.06
68.34 ⫾ 5.4 56.74 ⫾ 10.6
59.84 ⫾ 7.0 28.44 ⫾ 20.8
0.25
80.84 ⫾ 4.7 67.64 ⫾ 10.9
75.34 ⫾ 5.9 45.14 ⫾ 19.8
0.21
CIS ⫽ carcinoma in situ; TUR ⫽ transurethral resection.
pathologic stage (P values ⬍0.001; Figure 2). The association of select clinical characteristics with pathologic up-staging and bladder cancer recurrence and survival is shown in table 2. None of the three variables was associated with pathologic up-staging. Concomitant CIS was significantly associated with an increased risk for disease recurrence and death (Table 2 and Figure 3). There was no statistical difference between patients who were upstaged and those who were not (median (IQR): 68.8 (12.9) versus 64.6 (13.6), respectively, P ⫽ 0.060). In univariable Cox Regression analyses, age was not associated with disease recurrence (hazard ratio ⫽ 1.005, P ⫽ 0.740) or death (hazard ratio ⫽ 1.024, P ⫽ 0.258). In multivariate analyses that adjusted for the effects of age, gender, and time from TUR to RC stratified by three months, clinical concomitant CIS was associated with both disease recurrence or bladder cancer-specific mortality (P ⫽ 0.014 and P ⫽ 0.023, respectively, Table 3).
DISCUSSION
Figure 2. Kaplan-Meier estimates of recurrence-free (A) and bladder cancer–specific survival (B) probabilities according to clinical concomitant CIS for 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical T1 grade 3 UCBC.
Patients with more than 3 months’ delay between the last TUR and radical cystectomy were upstaged 71% of the time compared with 52% for those for whom cystectomy was performed within 3 months (P ⫽ 0.06) (Table 2). Longer time to cystectomy was also associated with earlier disease recurrence and shorter cancer-specific survival, but these differences did not reach statistical significance (Table 2). On univariate Cox regression analysis, presence of precystectomy CIS was the only statistically significant precystectomy factor that predicted disease recurrence (hazard ratio [HR]: 2.13) and cancer-specific mortality (HR: 2.75) (Table 3). On multivariate analysis, precystectomy remained the only statistically significant predictor of disease recurrence and cancer-specific mortality. Patients who were up-staged were at a significantly higher risk of disease recurrence and death than patents who were down-staged or had the same clinical and UROLOGY 71 (2), 2008
In this retrospective study, of the 167 patients who underwent cystectomy for clinical T1 grade 3 UCBC, 29% had disease recurrence and 18.5% died from bladder cancer. Pathological upstaging was seen in half of the patients and almost a fifth of the patients had nodal metastases. Presence of CIS precystectomy was the only clinical factor found to predict postoperative outcomes. This study reiterates the difficulties associated with accurately staging T1 grade 3 tumors. Other studies of clinical stage T1 bladder cancer have found 26% to 78% prevalence of understaging1– 8 and 6% to 19% prevalence of nodal metastases.5,7,12 Understaging may occur as the result of an inadequate TUR, error and variation in pathological interpretation, or disease progression from time of TUR to radical cystectomy. Presence of detrusor muscle on the TUR specimen is essential for the precise diagnosis of T1 grade 3 tumors. Because TUR is guided by macroscopic visualization of the tumor, microscopic tumor can easily be missed, as evidenced by the 78% prevalence of residual tumor and 29% upstaging on reTUR.9 Errors and variation in pathological interpretation can also lead to understaging. Pathological staging is subjective and large interpathologist variation can occur. In a study of over 1400 patients, slides were read by the local pathologists and reviewed by a central uropathologist. Upstaging from T1 to T2 or greater occurred in 4.7% of the samples, and of the 88 samples classified as T1Gr3 by local pathologists, central review classified only 44 (50%) as T1Gr3.13 Disease progression during the interval between TUR and cystectomy may also cause upstaging. Studies suggest that delay in cystectomy results in advanced pathological stage, earlier recurrence, and decreased survival in patients with muscle-invasive disease.14,15 In this study there was a trend toward more upstaging with a longer time to cystectomy. It is likely that statistical significance 305
Table 3. Univariate Cox regression analyses of pre-operative clinical characteristics including for prediction of disease recurrence and disease-specific survival of 167 patients treated with radical cystectomy and bilateral lymphadenectomy for T1 grade 3 UCBC Bladder Cancer Recurrence Hazard Ratio 95% CI P Age Gender* Intravesical therapy Time from TUR to radical cystectomy (⬎3 months) Pre-cystectomy concomitant CIS (cT1 G3 CIS)
Bladder Cancer-specific Mortality Hazard Ratio 95% CI P
1.01 0.80 0.94 1.50
0.98–1.05 0.34–1.90 0.53–1.69 0.75–2.98
0.42 0.61 0.84 0.25
1.02 1.11 1.43 1.73
0.98–1.07 0.34–3.70 0.69–2.96 0.73–4.08
0.24 0.86 0.34 0.21
2.13
1.14–3.98
0.02
2.75
1.17–6.46
0.02
* Female is the reference category.
was not reached because only 34 patients had more than a 3-month period between TUR and cystectomy. Larger studies are needed to establish whether a longer time to cystectomy influences outcomes in T1Gr3 disease. We found no predictors of pathological upstaging other than a trend toward more upstaging in patients with longer time to cystectomy. Other studies have found that prostatic urethral involvement,7 presence of multiple tumors and/or CIS,4 absence of muscle in the biopsy specimen, and suspicious radiological findings (extravesical extension or hydronephrosis)6 predict upstaging. In this study, 29% of patients had disease recurrence and 18.5% died from bladder cancer. It is possible that performing cystectomy earlier might have cured or delayed progression in some of these patients. The biggest challenge with this disease is being able to identify patients who will benefit from an early cystectomy. We found that concomitant CIS was the only precystectomy factor independently associated with poorer postoperative outcomes. The risk of recurrence increased twofold and the risk of cancer specific mortality increased almost threefold when CIS was identified precystectomy. To our knowledge, ours is the only study that has found that precystectomy CIS to be a statistically significant predictor of outcomes in patients with clinical T1G3 cancer after radical cystectomy. Other studies that have investigated precystectomy CIS did not report an independent and/or statistically significant association between CIS and outcomes. Masood et al., for example, studied 30 patients and found that patients with multiple tumors (with or without concomitant CIS) or a single tumor with concomitant CIS had better survival than patients with a single tumor without CIS.4 Thus, they did not differentiate adequately between patients with and without CIS. Bianco et al., in their study of 66 patients, reported that patients with CIS had worse survival, but this difference was not statistically significant (P ⫽ 0.34).16 Interestingly, in a series involving 182 patients (128 with T1 with or without CIS), Freeman et al. found that patients with CIS in either the pre- or postcystectomy specimen had better cancer-specific survival than patients without CIS (P ⫽ 0.03).3 They attributed this difference to their aggressive approach toward early cystectomy in patients with CIS. Studies have also shown 306
CIS to be an independent predictor of progression to muscle-invasive disease.17,18 Thus, patients with non– muscle-invasive disease but with CIS are at a high risk of progression to muscle invasion, disease recurrence, and mortality after cystectomy. Thus, these patients should be followed up closely and be considered strongly for an early cystectomy. Second TUR for T1 cancer is associated with upstaging to T2 or more in up to 29% of cases.9 Thus, routine re-resections for T1 lesions may lead to earlier identification of patients with muscle invasion and earlier cystectomy.19 Other factors such as early recurrence, recurrence of T1 after intravesical BCG therapy, prostatic involvement, multifocal tumors, and depth of invasion into the lamina propria can be considered in decision making about early cystectomy for patients with non– muscle-invasive disease.7,17,20 –22 Better markers of progression and outcomes are needed to predict which patients will progress faster and may benefit from an earlier cystectomy. Only a prospective trial randomizing patients to conservative therapy including re-TUR and BCG versus early cystectomy will be able to identify the optimal therapy for T1 grade tumors. The strengths of our study are that it involved multiple centers and had a larger number of patients than previous series. This improves the generalizability of the findings. We performed multivariate analysis to look for precystectomy predictors of outcomes. Most other studies have evaluated postcystectomy factors as predictors of outcomes. However, what is more relevant for decision making and patient counseling are the precystectomy factors that predict postcystectomy outcomes. The study is limited by the fact that we were unable to study other precystectomy factors such as number of recurrences of non–muscle-invasive tumors, early recurrence, type of intravesical therapy, tumor size and multifocality, and prostatic involvement. Second TUR was not standard practice during the time when most of these patients were treated.
CONCLUSIONS Pathological upstaging to muscle-invasive disease or beyond was present in more than half of patients who UROLOGY 71 (2), 2008
underwent radical cystectomy for clinical non–muscleinvasive disease. These patients also experienced poor recurrence-free and cancer-specific survival. Presence of CIS in the precystectomy sample was the only precystectomy factor that predicted recurrence and survival. Patient with clinical T1 disease should be closely monitored for factors associated with poorer prognosis, and cystectomy should be performed earlier when such factors are present. Better markers of disease progression and outcomes are needed to improve outcomes in this group of patients. References 1. Amling CL, Thrasher JB, Frazier HA, et al: Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 151: 31–35; discussion 35–36, 1994. 2. Cheng L, Neumann RM, Weaver AL, et al: Grading and staging of bladder carcinoma in transurethral resection specimens: correlation with 105 matched cystectomy specimens. Am J Clin Pathol 113: 275–279, 2000. 3. Freeman JA, Esrig D, Stein JP, et al: Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 76: 833– 839, 1995. 4. Masood S, Sriprasad S, Palmer JH, et al: T1G3 bladder cancer: indications for early cystectomy. Int Urol Nephrol 36: 41– 44, 2004. 5. Wiesner C, Pfitzenmaier J, Faldum A, et al: Lymph node metastases in non-muscle invasive bladder cancer are correlated with the number of transurethral resections and tumour upstaging at radical cystectomy. BJU Int 95: 301–305, 2005. 6. Dutta SC, Smith JA Jr, Shappell SB, et al: Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol 166: 490 – 493, 2001. 7. Huguet J, Crego M, Sabate S, et al: Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 48: 53–59; discussion 59, 2005. 8. Ficarra V, Dalpiaz O, Alrabi N, et al: Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. BJU Int 95: 786 –790, 2005. 9. Herr HW: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 162: 74 –76, 1999.
UROLOGY 71 (2), 2008
10. Cookson MS, Herr HW, Zhang ZF, et al: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 158: 62– 67, 1997. 11. Stein JP: Indications for early cystectomy. Urology 62: 591–595, 2003. 12. Thalmann GN, Markwalder R, Shahin O, et al: Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? J Urol 172: 70 –75, 2004. 13. Van Der Meijden A, Sylvester R, Collette L, et al: The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer Trials. J Urol 164: 1533–1537, 2000. 14. Lee CT, Madii R, Daignault S, et al: Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol 175: 1262–1267; discussion 1267, 2006. 15. Sanchez-Ortiz RF, Huang WC, Mick R, et al: An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 169: 110 –115; discussion 115, 2003. 16. Bianco FJ Jr, Justa D, Grignon DJ, et al: Management of clinical T1 bladder transitional cell carcinoma by radical cystectomy. Urol Oncol 22: 290 –294, 2004. 17. Orsola A, Trias I, Raventos CX, et al: Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCGnon-treated patients. Eur Urol 48: 231–238; discussion 238, 2005. 18. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49: 466 – 465; discussion 475– 477, 2006. 19. Grimm MO, Steinhoff C, Simon X, et al: Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 170: 433– 437, 2003. 20. Raj GV, Herr H, Serio AM, et al: Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol 177: 1283–1286; discussion 1286, 2007. 21. Cheng L, Neumann RM, Weaver AL, et al: Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol 17: 3182–3187, 1999. 22. Gattegno B: T1G3 bladder cancer: conservative management or cystectomy? Eur Urol 45: 399 – 400, 2004.
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METHODS
RESULTS
CONCLUSIONS
Urothelial tumors that invade the lamina propria but not the muscularis propria are a particularly problematic clinical entity. The aim of the present study was to assess the pathologic features and clinical outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma (UCBC) treated with radical cystectomy. We reviewed the records of 958 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer at three U.S. academic centers. Of these patients, 167 (median age, 66.7 years) underwent radical cystectomy for clinical stage T1 grade 3 UCBC. The median follow-up was 33.8 months (mean ⫾ standard deviation: 45.9 ⫾ 39.2 months, range, 0.4 to 177.1) for patients alive at last follow-up. Disease recurred in 48 of 167 of patients (29.4%) and 30 of 162 patients (18.5%) died from bladder cancer. A total of 29 of 166 patients (17.5%) had lymph nodal metastases. Of 167 patients, 84 (50%) were pathologically upstaged and 167 (27.5%) had extravesical disease. Patients with disease upstaging had poorer survival (P ⬍0.001). A greater than 3-month delay between cystectomy and last transurethral resection showed a trend toward upstaging (P ⫽ 0.06). Presence of carcinoma in situ (CIS) was the only precystecomy factor that predicted disease recurrence (hazard ratio [HR]: 2.13, 95% confidence interval [CI]: 1.14 to 3.98) and mortality (HR: 2.75, 95% CI: 1.17 to 6.46). A large proportion of patients undergoing cystectomy for clinical T1 grade 3 disease have adverse pathological features. The recurrence and survival outcomes in this group are suboptimal. Presence of CIS precystectomy predicts outcomes. Better markers are needed to identify patients at high risk for adverse outcomes. UROLOGY 71: 302–307, 2008. © 2008 Elsevier Inc.
O
ptimal management of clinical T1 grade 3 urothelial cell bladder cancer (UCBC) lesions is controversial. Understaging of disease is common1– 8 and residual disease is present up to 78% of the times on reresection.9 Although some patients have good long-term outcomes with transurethral resection (TUR) and intravesical therapy, others develop disease progression and metastases, and die despite radical cystectomy.10 Early cystectomy offers definitive therapy but must be balanced with the morbidity related to treatment.11 Furthermore, the optimal timing of cystectomy and the factors that predict outcomes in patients undergoing radFrom the Bladder Cancer Research Consortium (BCRC). From the Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas; the James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland; the Cancer Prognostics and Health Outcomes Unit, University of Montreal, Montreal, Quebec, Canada; and the Scott Department of Urology, Baylor College of Medicine, Houston, Texas Reprint requests: Shahrokh F. Shariat, M.D., Department of Urology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9110. E-mail: [email protected] Submitted: May 17, 2007, accepted (with revisions): October 22, 2007
302
© 2008 Elsevier Inc. All Rights Reserved
ical cystectomy are unclear. In this large, multi-institutional, retrospective study we describe the outcomes of patients who underwent cystectomy for clinical T1 grade 3 disease, and investigate the precystectomy factors that predicted outcomes for these patients.
MATERIAL AND METHODS Patient Population All studies were undertaken with the approval of the institutional review board at each institution. A total of 958 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy with curative intent by select surgeons at three academic medical centers during the period March 11, 1984 through January 24, 2003, and who had data available, were candidates for this analysis. Indications for radical cystectomy were tumor invasion into the muscularis propria or prostatic stroma or Ta, T1, or carcinoma in situ (CIS) refractory to TUR with intravesical chemotherapy and/or immunotherapy. Clinical stage was assigned according to the 1997 Tumor, Nodes, and Metastases (TNM) system. A total of 202 two patients had clinical tumor stage T1. We excluded 17 patients 0090-4295/08/$34.00 doi:10.1016/j.urology.2007.10.041
with grade 2 disease and 18 patients with nonurothelial histology, which left 167 patients for analysis. A total of 73 patients (43.7%) had received intravesical chemotherapy or immunotherapy. Adjuvant chemotherapy was administered to 34 patients (20.4%). Adjuvant external beam radiotherapy was administered to 5 patients (3%). Second TUR was not standard practice during the time these patients were treated.
Pathology Staff pathologists from each institution with expertise in genitourinary pathology examined all specimens. We used the 1997 TNM classification for pathologic staging and the 1973 World Health Organization classification for pathologic grading. Patients were categorized into pathologically downstaged (lower pathologic than clinical stage and negative lymph nodes), same stage (same clinical and pathologic stage and negative lymph nodes), and pathologically upstaged (higher pathologic than clinical stage or positive lymph nodes). We determined cause of death by chart review corroborated by death certificates, or by death certificates alone. Perioperative mortality (death within 30 days of surgery) was censored at time of death for bladder cancer–specific survival analyses.
Statistical Analysis We calculated time to radical cystectomy as the time from the last TUR or bladder biopsy before cystectomy. We used Fisher’s exact and Chi-square tests to evaluate the association among categorical variables. We assessed differences for continuous variables using the Mann-Whitney U-test. We used the Kaplan-Meier method to calculate survival functions and assessed differences with the log-rank test. We performed survival analyses with the Cox proportional hazard regression model. Statistical significance was set as a two-sided P ⬍0.05. Analyses were performed with SPSS Inc, Chicago, IL (version 13.0).
RESULTS The median age was 66.7 years (interquartile range [IQR]: 59.1 to 72.7 years; range, 37.7 to 89.2). Table 1 provides detailed descriptive characteristics. The descriptive characteristics of patients treated with radical cystectomy for clinical stage T1 grade 3 disease is shown in table 1. Eighty-six percent of patients were of male gender; 51.5% were operated between 2001 and 2003; 45.6% had concomitant CIS on their clinical specimen; 49.7% had muscle-invasive pathologic stage; 27.5% had nonorgan confined pathologic stage’ 31.1% had lymphovascular invasion; and 17.1% had metastases to lymph nodes. Twenty-three percent of the patients were pathologically downstaged, 26% had the same stage, and 50% were pathologically upstaged. More than half of those who were upstaged did not have organ-confined disease. The median number of lymph nodes removed at time of radical cystectomy was 18 (inter-quartile range: 11). The median time from TUR to RC was 1.9 months (interquartile range: 2.3). Overall, 29 patients (17.5%) had metastases to regional lymph nodes. The median number of positive lymph nodes and mean percent positive lymph nodes were 2 (IQR: 1 to 9) and 8.7% (IQR: UROLOGY 71 (2), 2008
Table 1. Descriptive characteristics of 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical stage T1 grade 3 disease Characteristic Gender (%) Female Male Year of surgery 1984–1989 1990–1994 1995–2000 2001–2003 Precystecomy carcinoma in situ Present Absent Pathologic stage (%) pT0 (no tumor) pTa pTis pT1 pT2 pT3 pT4 Pathologic grade (%) 0 (no tumor) 1 2 3 Postcystectomy carcinoma in situ Present Absent Lymphovascular invasion (%) Present Absent Metastases to lymph nodes (%) Present Absent Discrepancy between clinical and pathologic stage Pathologic downstaging Same stage Pathologic upstaging
No. Patients (%) 23 (13.8) 144 (86.2) 4 (2.4) 20 (12.0) 58 (34.7) 85 (50.9) 92 (55.1) 75 (44.9) 16 (9.6) 4 (2.4) 19 (11.4) 46 (27.5) 36 (21.6) 31 (18.6) 15 (9.0) 16 (9.6) 3 (1.8) 6 (3.6) 142 (85.0) 109 (65.3) 58 (34.7) 50 (31.3) 110 (68.8) 29 (17.5) 137 (82.5) 39 (23.4) 44 (26.3) 84 (50.3)
Lymphovascular invasion was missing in 7 patients. Lymph node status was missing in 1 patient.
6.7% to 46.1%), respectively. The median number of lymph nodes sampled was 18 (IQR: 14 to 25). Lymph node metastases were found in 4.3% (2 of 46) of patients with T1, 13.9% (5 of 36) of patients with T2, 46.7% (14 of 30) of patients with T3, and 53.3% (8 of 15) of patients with T4 disease, respectively. Cancer recurred in 48 of 167 patients (29.4%) and 51 of 166 patients (30.7%) were dead at the time of analysis. Cause of death was missing in 4 patients. Overall, 30 of 162 patients (18.5%) died from bladder cancer and 17 of 162 (10.4%) died from other causes without evidence of disease recurrence. The median follow-up was 33.8 months (mean ⫾ standard deviation: 45.9 ⫾ 39.2 months; range, 0.4 to 177.1) for patients alive at last follow-up. Actuarial recurrence-free estimates were 70.6% (standard error [SE]: 4.0%) at 3 years, 68.1% (SE: 4.2%) at 5 years, and 59.9% (SE: 5.4%) at 7 years after 303
Figure 1. Kaplan-Meier estimates of recurrence-free (A) and bladder cancer–specific survival (B) probabilities for 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical T1 grade 3 UCBC.
cystectomy (Fig. 1a). Actuarial bladder cancer–specific survival estimates were 82.1% (SE: 3.5%) at 3 years, 79.0% (SE: 4.0%) at 5 years, and 71.0% (SE: 5.7%) at 7 years (Fig. 1b). Patients who were upstaged had decreased recurrencefree survival and bladder cancer–specific survival compared with patients who were downstaged or had the same stage (log rank, P ⬍0.001).
Association of Clinical Characteristics with Upstaging and Clinical Outcomes Patients with precystectomy CIS were more likely to have disease recurrence and die from bladder cancer than those without CIS (P ⫽ 0.016 for both) (Table 2 and Fig. 2a and b). Gender, intravesical therapy, and presence of precystectomy CIS were not associated with pathological upstaging (Table 2). Precystectomy CIS was not associated with nodal metastases or lymphovascular invasion (P ⫽ 0.83 and 0.19, respectively) or with a longer delay between last TUR and cystectomy (P ⫽ 0.14).
304
Table 2. Association of clinical characteristics with pathologic upstaging, disease recurrence, and disease-specific survival in 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical stage T1 grade 3 disease Pathologic Upstaging Downstaged or Same Stage Upstaged
UROLOGY 71 (2), 2008
Gender (No. patients [%]) Female Male Intravesical therapy No Yes Precystectomy concomitant CIS (No. patients [%]) Absent Present Time from TUR to radical cystectomy (No. patients [%]) ⬍3 mo ⱖ3 mo
P
Bladder Cancer Recurrence (%) 3-Year 7-Year Probability ⫾ SE Probability ⫾ SE
P
Bladder Cancer–Specific Survival (%) 3-Year 7-Year Probability ⫾ SE Probability ⫾ SE P
14 (60.9%) 69 (47.9%)
9 (39.1%) 75 (52.1%)
0.25
62.4 ⫾ 12.7 71.74 ⫾ 4.2
62.44 ⫾ 12.7 60.44 ⫾ 5.7
0.61
88.94 ⫾ 7.4 81.24 ⫾ 3.8
59.34 ⫾ 24.7 71.54 ⫾ 5.9
0.86
43 (46.2%) 39 (53.4%)
50 (53.8%) 34 (46.6%)
0.36
69.54 ⫾ 5.3 71.54 ⫾ 6.4
59.74 ⫾ 7.2 59.04 ⫾ 8.5
0.84
85.54 ⫾ 4.1 76.94 ⫾ 6.1
76.94 ⫾ 7.5 61.94 ⫾ 9.3
0.34
32 (42.7%) 51 (55.4%)
43 (57.3%) 41 (44.6%)
0.10
79.44 ⫾ 5.5 63.74 ⫾ 5.6
71.04 ⫾ 7.7 52.14 ⫾ 7.1
0.016
86.84 ⫾ 4.8 78.24 ⫾ 5.0
86.84 ⫾ 4.8 58.14 ⫾ 9.3
0.016
43 (48.3%) 10 (29.4%)
46 (51.7%) 24 (70.6%)
0.06
68.34 ⫾ 5.4 56.74 ⫾ 10.6
59.84 ⫾ 7.0 28.44 ⫾ 20.8
0.25
80.84 ⫾ 4.7 67.64 ⫾ 10.9
75.34 ⫾ 5.9 45.14 ⫾ 19.8
0.21
CIS ⫽ carcinoma in situ; TUR ⫽ transurethral resection.
pathologic stage (P values ⬍0.001; Figure 2). The association of select clinical characteristics with pathologic up-staging and bladder cancer recurrence and survival is shown in table 2. None of the three variables was associated with pathologic up-staging. Concomitant CIS was significantly associated with an increased risk for disease recurrence and death (Table 2 and Figure 3). There was no statistical difference between patients who were upstaged and those who were not (median (IQR): 68.8 (12.9) versus 64.6 (13.6), respectively, P ⫽ 0.060). In univariable Cox Regression analyses, age was not associated with disease recurrence (hazard ratio ⫽ 1.005, P ⫽ 0.740) or death (hazard ratio ⫽ 1.024, P ⫽ 0.258). In multivariate analyses that adjusted for the effects of age, gender, and time from TUR to RC stratified by three months, clinical concomitant CIS was associated with both disease recurrence or bladder cancer-specific mortality (P ⫽ 0.014 and P ⫽ 0.023, respectively, Table 3).
DISCUSSION
Figure 2. Kaplan-Meier estimates of recurrence-free (A) and bladder cancer–specific survival (B) probabilities according to clinical concomitant CIS for 167 patients treated with radical cystectomy and bilateral lymphadenectomy for clinical T1 grade 3 UCBC.
Patients with more than 3 months’ delay between the last TUR and radical cystectomy were upstaged 71% of the time compared with 52% for those for whom cystectomy was performed within 3 months (P ⫽ 0.06) (Table 2). Longer time to cystectomy was also associated with earlier disease recurrence and shorter cancer-specific survival, but these differences did not reach statistical significance (Table 2). On univariate Cox regression analysis, presence of precystectomy CIS was the only statistically significant precystectomy factor that predicted disease recurrence (hazard ratio [HR]: 2.13) and cancer-specific mortality (HR: 2.75) (Table 3). On multivariate analysis, precystectomy remained the only statistically significant predictor of disease recurrence and cancer-specific mortality. Patients who were up-staged were at a significantly higher risk of disease recurrence and death than patents who were down-staged or had the same clinical and UROLOGY 71 (2), 2008
In this retrospective study, of the 167 patients who underwent cystectomy for clinical T1 grade 3 UCBC, 29% had disease recurrence and 18.5% died from bladder cancer. Pathological upstaging was seen in half of the patients and almost a fifth of the patients had nodal metastases. Presence of CIS precystectomy was the only clinical factor found to predict postoperative outcomes. This study reiterates the difficulties associated with accurately staging T1 grade 3 tumors. Other studies of clinical stage T1 bladder cancer have found 26% to 78% prevalence of understaging1– 8 and 6% to 19% prevalence of nodal metastases.5,7,12 Understaging may occur as the result of an inadequate TUR, error and variation in pathological interpretation, or disease progression from time of TUR to radical cystectomy. Presence of detrusor muscle on the TUR specimen is essential for the precise diagnosis of T1 grade 3 tumors. Because TUR is guided by macroscopic visualization of the tumor, microscopic tumor can easily be missed, as evidenced by the 78% prevalence of residual tumor and 29% upstaging on reTUR.9 Errors and variation in pathological interpretation can also lead to understaging. Pathological staging is subjective and large interpathologist variation can occur. In a study of over 1400 patients, slides were read by the local pathologists and reviewed by a central uropathologist. Upstaging from T1 to T2 or greater occurred in 4.7% of the samples, and of the 88 samples classified as T1Gr3 by local pathologists, central review classified only 44 (50%) as T1Gr3.13 Disease progression during the interval between TUR and cystectomy may also cause upstaging. Studies suggest that delay in cystectomy results in advanced pathological stage, earlier recurrence, and decreased survival in patients with muscle-invasive disease.14,15 In this study there was a trend toward more upstaging with a longer time to cystectomy. It is likely that statistical significance 305
Table 3. Univariate Cox regression analyses of pre-operative clinical characteristics including for prediction of disease recurrence and disease-specific survival of 167 patients treated with radical cystectomy and bilateral lymphadenectomy for T1 grade 3 UCBC Bladder Cancer Recurrence Hazard Ratio 95% CI P Age Gender* Intravesical therapy Time from TUR to radical cystectomy (⬎3 months) Pre-cystectomy concomitant CIS (cT1 G3 CIS)
Bladder Cancer-specific Mortality Hazard Ratio 95% CI P
1.01 0.80 0.94 1.50
0.98–1.05 0.34–1.90 0.53–1.69 0.75–2.98
0.42 0.61 0.84 0.25
1.02 1.11 1.43 1.73
0.98–1.07 0.34–3.70 0.69–2.96 0.73–4.08
0.24 0.86 0.34 0.21
2.13
1.14–3.98
0.02
2.75
1.17–6.46
0.02
* Female is the reference category.
was not reached because only 34 patients had more than a 3-month period between TUR and cystectomy. Larger studies are needed to establish whether a longer time to cystectomy influences outcomes in T1Gr3 disease. We found no predictors of pathological upstaging other than a trend toward more upstaging in patients with longer time to cystectomy. Other studies have found that prostatic urethral involvement,7 presence of multiple tumors and/or CIS,4 absence of muscle in the biopsy specimen, and suspicious radiological findings (extravesical extension or hydronephrosis)6 predict upstaging. In this study, 29% of patients had disease recurrence and 18.5% died from bladder cancer. It is possible that performing cystectomy earlier might have cured or delayed progression in some of these patients. The biggest challenge with this disease is being able to identify patients who will benefit from an early cystectomy. We found that concomitant CIS was the only precystectomy factor independently associated with poorer postoperative outcomes. The risk of recurrence increased twofold and the risk of cancer specific mortality increased almost threefold when CIS was identified precystectomy. To our knowledge, ours is the only study that has found that precystectomy CIS to be a statistically significant predictor of outcomes in patients with clinical T1G3 cancer after radical cystectomy. Other studies that have investigated precystectomy CIS did not report an independent and/or statistically significant association between CIS and outcomes. Masood et al., for example, studied 30 patients and found that patients with multiple tumors (with or without concomitant CIS) or a single tumor with concomitant CIS had better survival than patients with a single tumor without CIS.4 Thus, they did not differentiate adequately between patients with and without CIS. Bianco et al., in their study of 66 patients, reported that patients with CIS had worse survival, but this difference was not statistically significant (P ⫽ 0.34).16 Interestingly, in a series involving 182 patients (128 with T1 with or without CIS), Freeman et al. found that patients with CIS in either the pre- or postcystectomy specimen had better cancer-specific survival than patients without CIS (P ⫽ 0.03).3 They attributed this difference to their aggressive approach toward early cystectomy in patients with CIS. Studies have also shown 306
CIS to be an independent predictor of progression to muscle-invasive disease.17,18 Thus, patients with non– muscle-invasive disease but with CIS are at a high risk of progression to muscle invasion, disease recurrence, and mortality after cystectomy. Thus, these patients should be followed up closely and be considered strongly for an early cystectomy. Second TUR for T1 cancer is associated with upstaging to T2 or more in up to 29% of cases.9 Thus, routine re-resections for T1 lesions may lead to earlier identification of patients with muscle invasion and earlier cystectomy.19 Other factors such as early recurrence, recurrence of T1 after intravesical BCG therapy, prostatic involvement, multifocal tumors, and depth of invasion into the lamina propria can be considered in decision making about early cystectomy for patients with non– muscle-invasive disease.7,17,20 –22 Better markers of progression and outcomes are needed to predict which patients will progress faster and may benefit from an earlier cystectomy. Only a prospective trial randomizing patients to conservative therapy including re-TUR and BCG versus early cystectomy will be able to identify the optimal therapy for T1 grade tumors. The strengths of our study are that it involved multiple centers and had a larger number of patients than previous series. This improves the generalizability of the findings. We performed multivariate analysis to look for precystectomy predictors of outcomes. Most other studies have evaluated postcystectomy factors as predictors of outcomes. However, what is more relevant for decision making and patient counseling are the precystectomy factors that predict postcystectomy outcomes. The study is limited by the fact that we were unable to study other precystectomy factors such as number of recurrences of non–muscle-invasive tumors, early recurrence, type of intravesical therapy, tumor size and multifocality, and prostatic involvement. Second TUR was not standard practice during the time when most of these patients were treated.
CONCLUSIONS Pathological upstaging to muscle-invasive disease or beyond was present in more than half of patients who UROLOGY 71 (2), 2008
underwent radical cystectomy for clinical non–muscleinvasive disease. These patients also experienced poor recurrence-free and cancer-specific survival. Presence of CIS in the precystectomy sample was the only precystectomy factor that predicted recurrence and survival. Patient with clinical T1 disease should be closely monitored for factors associated with poorer prognosis, and cystectomy should be performed earlier when such factors are present. Better markers of disease progression and outcomes are needed to improve outcomes in this group of patients. References 1. Amling CL, Thrasher JB, Frazier HA, et al: Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 151: 31–35; discussion 35–36, 1994. 2. Cheng L, Neumann RM, Weaver AL, et al: Grading and staging of bladder carcinoma in transurethral resection specimens: correlation with 105 matched cystectomy specimens. Am J Clin Pathol 113: 275–279, 2000. 3. Freeman JA, Esrig D, Stein JP, et al: Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 76: 833– 839, 1995. 4. Masood S, Sriprasad S, Palmer JH, et al: T1G3 bladder cancer: indications for early cystectomy. Int Urol Nephrol 36: 41– 44, 2004. 5. Wiesner C, Pfitzenmaier J, Faldum A, et al: Lymph node metastases in non-muscle invasive bladder cancer are correlated with the number of transurethral resections and tumour upstaging at radical cystectomy. BJU Int 95: 301–305, 2005. 6. Dutta SC, Smith JA Jr, Shappell SB, et al: Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol 166: 490 – 493, 2001. 7. Huguet J, Crego M, Sabate S, et al: Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 48: 53–59; discussion 59, 2005. 8. Ficarra V, Dalpiaz O, Alrabi N, et al: Correlation between clinical and pathological staging in a series of radical cystectomies for bladder carcinoma. BJU Int 95: 786 –790, 2005. 9. Herr HW: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 162: 74 –76, 1999.
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10. Cookson MS, Herr HW, Zhang ZF, et al: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 158: 62– 67, 1997. 11. Stein JP: Indications for early cystectomy. Urology 62: 591–595, 2003. 12. Thalmann GN, Markwalder R, Shahin O, et al: Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? J Urol 172: 70 –75, 2004. 13. Van Der Meijden A, Sylvester R, Collette L, et al: The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer Trials. J Urol 164: 1533–1537, 2000. 14. Lee CT, Madii R, Daignault S, et al: Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol 175: 1262–1267; discussion 1267, 2006. 15. Sanchez-Ortiz RF, Huang WC, Mick R, et al: An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 169: 110 –115; discussion 115, 2003. 16. Bianco FJ Jr, Justa D, Grignon DJ, et al: Management of clinical T1 bladder transitional cell carcinoma by radical cystectomy. Urol Oncol 22: 290 –294, 2004. 17. Orsola A, Trias I, Raventos CX, et al: Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCGnon-treated patients. Eur Urol 48: 231–238; discussion 238, 2005. 18. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49: 466 – 465; discussion 475– 477, 2006. 19. Grimm MO, Steinhoff C, Simon X, et al: Effect of routine repeat transurethral resection for superficial bladder cancer: a long-term observational study. J Urol 170: 433– 437, 2003. 20. Raj GV, Herr H, Serio AM, et al: Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol 177: 1283–1286; discussion 1286, 2007. 21. Cheng L, Neumann RM, Weaver AL, et al: Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol 17: 3182–3187, 1999. 22. Gattegno B: T1G3 bladder cancer: conservative management or cystectomy? Eur Urol 45: 399 – 400, 2004.
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