CYSTECTOMY FOR BLADDER CANCER: A CONTEMPORARY SERIES

0022-5347/01/1654-1111/0 THE JOURNAL OF UROLOGY® Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 165, 1111–1116, April 2001 Printed in U.S.A.

CYSTECTOMY FOR BLADDER CANCER: A CONTEMPORARY SERIES GUIDO DALBAGNI, ELIZABETH GENEGA, MIA HASHIBE, ZUO-FENG ZHANG, PAUL RUSSO, HARRY HERR AND VICTOR REUTER From the Departments of Urology and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, and Department of Epidemiology and Biostatistics, University of California Los Angeles, Los Angeles, California

ABSTRACT

Purpose: To validate the current TNM staging system, we analyzed our contemporary experience with 300 cystectomies. Materials and Methods: The pathological material and medical records of 300 patients treated with cystectomy were reviewed, and the new TNM classification was adopted. Results: The median followup of patients with no evidence of disease was 65 months, and overall survival rate was 45% with a median survival of 50 months. In a Cox regression analysis only patient age, pT stage and neoadjuvant chemotherapy were significant factors for survival. The disease specific survival was 67% with a median survival of 94 months. In a multiple proportional hazards analysis only pT stage and previous chemotherapy were significant factors of disease specific survival. A significant difference was seen in the overall and disease specific survival between patients with organ confined and nonorgan confined tumors. We did not observe a difference in the survival rate among patients with pT4a to pT3 tumors. Significant differences were not seen in survival rates between sexes or among patients of different age groups. Transitional cell carcinoma was the predominant histological type, and no significant difference was found in patient outcome among the different histological subtypes. Conclusions: Bladder cancer can be categorized into organ confined and nonorgan confined tumors. This dichotomous grouping is better suited for evaluating adjuvant clinical trials. The pT stage of the bladder and prostate should be prospectively analyzed together to better define the clinical implications of prostatic involvement. In our opinion the histological subtypes do not affect outcome. KEY WORDS: carcinoma, bladder, bladder neoplasms, cystectomy

Bladder cancer is the fifth most common cancer in the United States with an estimated 53,200 cases for the year 2000.1 Radical cystectomy has been the standard treatment for patients with muscle invasive tumors. The American Joint Committee on Cancer in collaboration with the TNM Committee of the International Union Against Cancer has recently modified the TNM staging system for bladder cancer.2 In the new TNM staging T2a and T2b correspond to the T2 and T3a of the old staging, and the T3a and T3b of the new system correspond to T3b of the old system. Briefly, in the new system T2 is organ confined and T3 is nonorgan confined. We report our experience with 300 patients who were treated with cystectomy between 1990 and 1993 to validate the current staging system in a contemporary series. The 5-year survival has increased from 73% during 1974 to 1976, to 81% during 1989 to 1995.1 This improvement in survival is multifactorial. The management of high risk superficial bladder cancer with intravesical bacillus CalmetteGuerin (BCG) and refinement of surgical techniques have a role in improving outcome. Intravesical BCG is the most effective therapy for carcinoma in situ, and several series have shown a decrease in recurrence and progression in T1 tumors.3 However, optimizing clinical staging of bladder cancer is crucial before instituting intravesical therapy. Restaging with transurethral resection has been standard practice at Memorial Sloan-Kettering Cancer Center for patients with

high risk superficial disease. We also evaluate the efficacy of this approach in decreasing the nonorgan confined rate in the patient subset that will require cystectomy after BCG. MATERIALS AND METHODS

Subjects and procedures. The pathological material from 300 patients who underwent partial or radical cystectomy between 1990 and 1993 was independently reviewed by 2 pathologists (V. R. and E. G.) who agreed on the diagnosis. The tumors were staged according to the new TNM system of the International Union Against Cancer.2 In the new classification T2a and T2b correspond to the T2 and T3a of the old staging system. The T3b from the old classification has been subdivided into T3a and T3b for microscopic and gross involvement of the perivesical fat. Restaging of transurethral resection was performed in all patients. The charts were reviewed, and demographic data, preoperative chemotherapy or radiation therapy and survival data were recorded. Statistical methods. Two end points were used in analyses, including overall and specific deaths. In the analyses of overall and specific survival cases of death of any cause or death from bladder cancer were classified as having treatment that failed,4 and those who survived, were without these end points or lost to followup were coded as censored. Survival time was defined as the time from the date of diagnosis to the end point, including death or censoring. Survival rates were evaluated using the Kaplan-Meier method and log-rank test. 5, 6 Commercial software was also used.7 Proportional hazards analysis was used to obtain maximum likelihood estimates of relative risks and the 95% confidence intervals (CI) in multivariate analysis.4, 8

Accepted for publication October 6, 2000. Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1264 and 1265. 1111

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TABLE 1. Demographics of 300 patients treated with radical cystectomy for bladder cancer between 1990 and 1993 Characteristics Transurethral resection staging: Ta, Tis T1 T2⫹ T4 Not applicable Pathological stage: pT0 pTa pTis pT1 pT2a pT2b pT3a pT3b pT4a pT4b N0 N⫹ NX Histology: Pure transitional cell Pure squamous cell Ca Pure adenocarcinoma Pure small cell Transurethral resection, squamous cell Ca, adenoca. small cell Grade: High Low Neoadjuvant chemotherapy: Yes (methotrexate, vinblastine doxorubicin, cisplatin) No Not applicable Neoadjuvant radiation therapy: Yes No Not applicable Intravesical therapy: No BCG Others Not applicable Cystectomy: Radical Partial

No. Pts. (%) 20 (6.7) 56 (18.7) 183 (61) 7 (2.3) 34 (11.3) 32 (10.7) 8 (2.7) 36 (12) 19 (6.3) 18 (6) 39 (13) 36 (12) 74 (24.7) 33 (11) 5 (1.7) 206 (69) 39 (13) 55 (18)

FIG. 2. Overall survival (Surv) of patients with pT2 treated with cystectomy for bladder cancer.

161 10 3 2 48 218 14 54 (21.7) 235 (78.3) 11 (3.6) 19 (6.3) 271 (90.3) 10 (3.3) 190 (63.3) 78 (26) 18 (6) 14 (4.7) 282 18

FIG. 3. Overall survival (Surv) of patients with pT3 treated with cystectomy for bladder cancer.

(94) (6)

FIG. 4. Overall survival (Surv) of patients with pT3 and pT4 treated with cystectomy for bladder cancer. FIG. 1. Overall survival (Surv) of patients treated with cystectomy for bladder cancer.

RESULTS

Our study was a retrospective review of 300 radical cystectomies performed between 1990 and 1993 to evaluate the new TNM staging system. The male-to-female ratio was 3.6:1. The median age for males was 67 years (mean 67, range 35 to 87) and for females was 66 years (mean 67, range 38 to 91). A total of 54 patients received systemic chemother-

apy before cystectomy and 19 received neoadjuvant radiation therapy. There were 18 patients who underwent partial cystectomy. The distribution of clinical and pathological stages is summarized in table 1. A total of 78 patients received intravesical BCG, and 18 were treated with other forms of intravesical therapy before definitive treatment. Followup data were available on 269 patients. The median and mean followup of the patients who had no evidence of disease were 65 and 60 months, respectively. The overall survival rate was 45% with a median survival of 50 months

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TABLE 3. Multiple proportional hazards analysis for the overall and specific survival of bladder cancer Parameter Estimates

p Relative Value Risk

95% CI

Overall survival

FIG. 5. Overall survival (Surv) of patients with pT0, pTa, pT1 and pT2 treated with cystectomy for bladder cancer.

TABLE 2. Univariate analysis for the overall and specific survival of bladder cancer Parameter Estimates

p Value

Relative Risk

95% CI

Overall survival Pt. age (yrs.): Younger than 60 60–70 Older than 70 Sex: Male Female Neoadjuvant radiotherapy: Yes No Neoadjuvant chemotherapy: Yes No Cystectomy: Partial Radical Stage: T0, Tis, Ta, T1 T2 T3 T4 Nodes: N0 Nx N⫹ Histology: Pure transitional cell Ca Aberrant differentiation

0.1973 0.4209 0.5648 0.0170

1.218 1.759

0.753–1.969 1.106–2.797

⫺0.0075 0.9720

0.992

0.652–1.511

⫺0.4212 0.3146

0.656

0.289–1.492

⫺0.2827 0.1727

0.754

0.502–1.132

0.5307 0.2038

1.700

0.750–3.854

0.3552 0.2098 1.1754 0.0001 1.0817 0.0003

1.427 3.239 2.950

0.819–2.485 2.109–4.975 1.644–5.292

0.1533 0.5025 0.5274 0.0367

1.166 1.695

0.745–1.825 1.033–2.780

0.0581 0.7807

1.060

0.704–1.595

Specific survival Pt. age (yrs.): Younger than 60 60–70 Older than 70 Sex: Male Female Neoadjuvant radiotherapy: Yes No Neoadjuvant chemotherapy: Yes No Cystectomy: Partial Radical Stage: T0, Tis, Ta, T1 T2 T3 T4 Nodes: N0 Nx N⫹ Histology: Pure transitional cell Ca Aberrant differentiation

0.0071 0.9795 0.3112 0.2424

1.007 1.366

0.586–1.731 0.810–2.305

⫺0.1514 0.5702

0.859

0.510–1.450

0.3611 0.6138

1.435

0.353–5.834

⫺0.3252 0.1809

0.722

0.449–1.163

0.5844 0.2524

1.794

0.659–4.880

0.5417 0.1342 1.4898 0.0001 1.4685 0.0001

1.719 4.436 4.343

0.846–3.492 2.553–7.707 2.160–8.731

⫺0.1530 0.6120 0.4928 0.0932

0.858 1.637

0.475–1.550 0.921–2.910

0.1537 0.5346

1.166

0.718–1.894

Pt. age (yrs.): Younger than 60 60–70 Older than 70 Sex: Male Female Neoadjuvant radiotherapy: Yes No Neoadjuvant chemotherapy: Yes No Cystectomy: Partial Radical Stage: T0, Tis, Ta, T1 T2 T3 T4 Nodes: N0 Nx N⫹ Histology: Pure transitional cell Ca Aberrant differentiation

0.1908 0.3193

0.5093 0.2323

1.210 1.376

0.687–2.133 0.815–2.324

0.1431

0.5399

1.154

0.730–1.823

⫺0.1311

0.7669

0.877

0.368–2.088

⫺0.5053

0.0411

0.603

0.371–0.980

0.3789

0.3878

1.461

0.618–3.452

0.0273 0.9355 0.7997

0.9525 0.0258 0.0814

1.028 2.549 2.225

0.419–2.518 1.120–5.801 0.905–5.470

0.3861 0.4493

0.1535 0.0981

1.471 1.567

0.866–2.500 0.920–2.668

0.0867

0.6900

1.091

0.712–1.670

Specific survival Pt. age (yrs.): Younger than 60 60–70 Older than 70 Sex: Male Female Neoadjuvant radiotherapy: Yes No Neoadjuvant chemotherapy: Yes No Cystectomy: Partial Radical Stage: T0, Tis, Ta, T1 T2 T3 T4 Nodes: N0 Nx N⫹ Histology: Pure transitional cell Ca Aberrant differentiation

0.1288 0.1107

0.6890 0.7135

1.137 1.117

0.605–2.137 0.619–2.017

⫺0.0273

0.9233

0.973

0.558–1.696

0.6915

0.3471

1.997

0.472–8.439

⫺0.6899

0.0147

0.502

0.288–0.873

0.5453

0.3079

1.725

0.605–4.921

0.2075 1.2166 1.1761

0.7238 0.0236 0.0413

1.231 3.376 3.242

0.389–3.890 1.177–9.681 1.048–10.033

0.2385 0.4966

0.4669 0.1080

1.269 1.643

0.668–2.413 0.897–3.011

0.1800

0.4843

1.197

0.723–1.983

(fig. 1). The new TNM classification was adopted.2 Significant differences were not seen in patient outcome among pT0, pTa, pT1 and pTis, which all staged as superficial tumors. Additionally, a significant difference was not seen between pT2a and pT2b tumors (fig. 2), which staged as muscle invasive, organ confined tumors. Similarly, pT3a and pT3b (fig. 3) were staged as muscle invasive, nonorgan confined tumors. The pT4a and pT4b tumors were staged as involving surrounding organs. A significant difference was not observed between pT4a and pT3 tumors (fig. 4) or among pT0, pTa, pTis and pT2 tumors (fig. 5). This lack of significance was due to the impact of the staging transurethral resection on the final pathological stage as demonstrated by Herr.9 Thrasher et al suggested that the prognosis of a patient with a pT0 cystectomy specimen depends on the initial clinical stage.10 Patients with pathological pT0, pT1, pTa or pTis tumor and clinical T2

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FIG. 6. A, overall survival (Surv) of patients treated with cystectomy for bladder cancer stratified by pathological stage and B, those with N0 stratified by pathological stage.

tional cell carcinoma were pure and a third had varying amounts of squamous cell, adenocarcinoma differentiation or a small cell component (table 1). Significant differences were not observed in overall or disease specific survival rates among the different categories. Of the patients who received BCG 40% had extravesical disease. The proportion of patients with extravesical disease at cystectomy was 31% if BCG was given at Memorial SloanKettering Cancer Center versus 50% if it was administered elsewhere, underscoring the importance of the restaging of transurethral resection before starting intravesical BCG to improve staging accuracy. Overall, the proportion of patients with extravesical disease in those treated by BCG is not significantly different from the whole cohort (50%) nor is it different from those who underwent up-front cystectomy (52%). FIG. 7. Disease specific survival (Surv) of patients treated with cystectomy for bladder cancer.

disease should have a prognosis similar to those with pathological and clinical T2 disease. A difference was found between the pT2 and pT3 tumors. In the Cox regression analysis only patient age, pT stage and whether the patient received chemotherapy before cystectomy were significant factors for survival (tables 2 and 3, fig. 6). The disease specific survival rate was 67% with a median survival of 94 months (fig. 7). In a multiple proportional hazards analysis only pT stage and previous chemotherapy were significant factors of disease specific survival. Significant differences were not observed in stage distribution (table 4) nor in survival between sexes (fig. 8). Similarly, significant differences were not seen in stage distribution (table 4) or in disease specific survival among different patient age categories (fig. 9). Transitional cell carcinoma was the predominant histological type. Two thirds of the transi-

DISCUSSION

Radical cystectomy remains the gold standard for muscle invasive and high risk superficial tumors resistant to intravesical therapy.11 We report 300 consecutive cystectomies reviewed by a referee pathologist, avoiding the interobserver staging errors. Pathological stage is the most important predictor of outcome. We did not find a significant difference between the pT2a and pT2b categories, confirming the observation of other investigators.12, 13 We did observe a significant decrease in survival between muscle invasive, organ confined tumors and muscle invasive tumors with extravesical extension, which has been reported in dated14 and more contemporary series.15 The distinction between pT2 and pT3 tumors is clinically justified. We also noted that significant differences do not exist among the different stages confined to the bladder. Therefore, we should consider 2 broad categories when making decisions regarding adjuvant therapy, including organ confined versus extravesical disease.

TABLE 4. Stage distribution between sexes and among different age groups No. (%)

Sex: Male Female Totals Age groups: 40–50 50–60 60–70 70–80 80–90 Totals

Superficial

Muscle Invasive, Organ Confined

79 (33.6) 16 (24.6)

41 (17.4) 16 (24.6)

95 (31.7)

57

Extravesical Disease

Tumors Involving Surrounding Organs

Total No.

83 (35.3) 27 (41.5)

32 (13.6) 6 (9.2)

(19)

110 (36.7)

38 (12.7)

8 (44.4) 21 (38.2) 35 (33) 27 (27.8) 4 (19)

3 (16.7) 5 (9.1) 25 (23.6) 17 (17.5) 6 (28.6)

7 (38.9) 20 (36.4) 32 (30.2) 39 (40.2) 10 (47.6)

0 9 (16.4) 14 (13.2) 14 (14.4) 1 (4.8)

18 55 106 97 21

95

56 (18.9)

108 (36.4)

38 (12.8)

297

(32)

235 65

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CYSTECTOMY FOR BLADDER CANCER

FIG. 8. Overall survival (Surv) of patients treated with cystectomy for bladder cancer.

FIG. 9. Disease specific survival (Surv) of patients treated with cystectomy and stratified according to age.

Tumors can invade the prostate through different mechanisms. The tumor could invade the prostate from the outside, and the prognosis would be worse or similar to those patients with extravesical disease.16 The prostate can also be involved by stromal invasion of urothelial carcinoma in situ in the prostatic urethra or prostatic ducts. In this patient group the prognosis should resemble that of those with organ confined tumors. In theory, the prostate can also be invaded by extension through the bladder neck with a prognosis similar to organ confined tumors (H. Herr, personal communication). The pT4a stage consists of organ confined and nonorgan confined tumors depending on the presence or absence of extracapsular extension. Patients with organ confined pT4a tumor should have a better outcome than those with extravesical disease. Pagano et al suggested that when prostatic involvement results from extension from the bladder tumor, the prognosis is significantly worse than if the prostate is associated with a noncontiguous bladder tumor.17 The 5-year survival rate was 7% versus 46%. However, we did not observe a difference in survival between patients with pT4a or pT3 tumors, suggesting that at diagnosis tumors involving the prostate have extravesical or extraprostatic extension. This finding does not confirm or disprove the mechanisms by which the prostate was involved. It seems that the overall outcome depends on tumor stage in the bladder and the presence of extraprostatic extension rather than the mere involvement of the prostate. A patient with pT2 or pT4 tumor without extraprostatic involvement will do better than one with pT3b pT4

tumor without extraprostatic involvement. A hypothetical pT2 pT4 tumor with extraprostatic involvement and pT3 or pT4 tumor with or without extraprostatic involvement will have a similar biological behavior. The pT4a stage is heterogeneous and needs to be better defined. The status of the tumor in the bladder and prostate should be evaluated separately. The presence of stromal invasion with or without extraprostatic extension might indicate a different outcome. These subsets of pT4a stage should be evaluated prospectively. A high proportion of patients treated with intravesical BCG had extravesical disease, underscoring the importance of optimizing staging before instituting BCG therapy. The inaccuracies of transurethral resection have been supported by an excess of data on the inconsistencies between clinical and pathological stages. Richie et al compared the clinical to the pathological stage finding that 26% of patients studied were over staged and 40% were under staged.18 Paulson reported a 35% under staging for T1 tumors,19 and Herr noted a significant under staging in patients with superficial disease.20 Of superficial tumors 75% had residual noninvasive tumors on repeat transurethral resection and 29% were up staged to a muscle invasive tumor. Our data support a role for restaging transurethral resection before instituting intravesical therapy. A lower proportion of patients was seen with extravesical disease after cystectomy if they underwent repeat transurethral resection before BCG therapy, implying better staging in this cohort. Does BCG therapy delay cystectomy in patients who are potentially curable? This question is difficult to address in our retrospective review. However, we noted no significant difference in outcome between patients who underwent cystectomy after receiving BCG and those with clinical superficial tumors (Ta, Tis, T1) who initially underwent cystectomy. Nonetheless, this analysis is speculative and introduces a significant bias in the statistical method. A subset of patients who received BCG, even with careful followup, will undergo definitive treatment too late. Cookson et al reported a 63%, 15-year disease specific survival of patients with high risk superficial bladder cancer treated with intravesical BCG.21 At 15 years 34% of patients were dead from bladder cancer. The 15-year followup data suggest that a subset of patients will benefit from treatment and survive with an intact functioning bladder. A second group of patients will have a delay in stage progression and will undergo cystectomy when the tumor is still at a curable stage, and a third group will be treated too late. Despite our conservative approach, survival data gathered from our patient group are not significantly different from other reported series, some of which have a more liberal approach in offering definitive therapy.22 Of patients with muscle invasive tumors on transurethral resection 25% had superficial disease or no tumor on the final pathological specimen. This observation favors a conservative approach for a subset of patients with muscle invasive tumors. Herr reported similar survival of patients with muscle invasive tumors treated endoscopically or with radical cystectomy.23 Solsona et al noted an 80% and 75% cause specific survival after radical transurethral resection.24 No difference was found in the survival rate in regard to a cohort with similar clinical stage treated with radical cystectomy. However, due to our inability to predict tumor behavior compounded by our lack of good staging modalities, bladder preservation should be offered to patients in the context of those limitations. CONCLUSIONS

Bladder cancer can be categorized into organ confined and nonorgan confined tumors. This dichotomous grouping is better suited for the evaluation of adjuvant clinical trials. The T stage of the bladder and prostate should be prospectively

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analyzed together to better define the clinical implications of prostatic involvement. The histological subtype of the transitional cell carcinoma does not affect outcome. The data presented do not support or disprove the role of early cystectomy in patients with high risk superficial bladder cancer. REFERENCES

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13. Pagano, F., Bassi, P., Galetti, T. P. 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, 145: 45, 1991 14. Pearse, H. D., Pappas, J. T. and Hodges, C. V.: Radical cystectomy for bladder cancer: 10-year survival. J Urol, 109: 623, 1973 15. Lerner, S. P., Skinner, E. and Skinner, D. G.: Radical cystectomy in regionally advanced bladder cancer. Urol Clin North Am, 19: 713, 1992 16. Esrig, D., Freeman, J. A., Elmajian, D. A. et al: Transitional cell carcinoma involving the prostate with a proposed staging classification for stromal invasion. J Urol, 156: 1071, 1996 17. Pagano, F., Bassi, P., Ferrante, G. L. et al: Is stage pT4a (D1) reliable in assessing transitional cell carcinoma involvement of the prostate in patients with a concurrent bladder cancer? A necessary distinction for contiguous or noncontiguous involvement. J Urol, 155: 244, 1996 18. Richie, J. P., Skinner, D. G. and Kaufman, J. J.: Radical cystectomy for carcinoma of the bladder: 16 years of experience. J Urol, 113: 186, 1975 19. Paulson, D. F.: Critical review of radical cystectomy and indicators of prognosis. Semin Urol, 11: 205, 1993 20. Herr, H. W.: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol, 162: 74, 1999 21. Cookson, M. S., Herr, H. Z., Zhang, Z. F. et al: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol, 158: 62, 1997 22. Esrig, D., Freeman, J. A., Stein, J. P. et al: Early cystectomy for clinical stage T1 transitional cell carcinoma of the bladder. Semin Urol Oncol, 15: 154, 1997 23. Herr, H. W.: Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol, 138: 1162, 1987 24. Solsona, E., Iborra, I., Ricos, J. V. et al: Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term followup of a prospective study. J Urol, 159: 95, 1998