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© 2001 American Society for Clinical Oncology Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 PatientsFrom the Departments of Urology, Medicine, Pathology, and Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA. Address reprint requests to John P. Stein, MD, University of Southern California, Norris Comprehensive Cancer Center, MS no. 74, Department of Urology, 1441 Eastlake Ave, Suite 7416, Los Angeles, CA 90089; email: stein{at}hsc.usc.edu
PURPOSE: To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. PATIENTS AND METHODS: All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. RESULTS: A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node–negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node–negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node–negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. CONCLUSION: These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.
BLADDER CANCER is the second most common genitourinary malignancy, with transitional-cell carcinoma (TCC) comprising nearly 90% of all primary bladder tumors. It was estimated that 54,200 new patients would be diagnosed with bladder cancer in 1999 and that there would be 12,100 projected deaths from the disease.1 Although the majority of patients present with superficial bladder tumors, 20% to 40% either present with or develop invasive disease. Most TCCs that are or become invasive are high-grade tumors. These tumors originate in the bladder mucosa, progressively invade the lamina propria, and move sequentially into the muscularis propria, perivesical fat, and contiguous pelvic structures, with increasing incidence of lymph node involvement with progression.2,3 During the past 30 years, radical cystectomy has emerged as one of the standard forms of therapy for patients with high-grade, invasive bladder cancer. However, early results of radical cystectomy indicated that only about 50% of patients treated for high-grade invasive disease were cured and that most patients subsequently died of metastatic disease within 3 years of diagnosis. Lack of universal acceptance of this procedure was attributable largely to the considerable morbidity, in particular the need for urinary diversion. During the 1960s and 1970s, in an effort to improve survival after cystectomy, various regimens of preoperative radiation were implemented but failed to demonstrate convincingly any additional benefit. Furthermore, the operation was associated with considerable morbidity.4 Since the early 1980s, various protocols of single agent and combination chemotherapy trials have been proposed for use in the adjuvant setting for patients considered at high risk for developing metastasis based on pathologic findings at the time of cystectomy. Although the precise role of adjuvant or neoadjuvant chemotherapy in this setting has not been definitively established, results from small trials are encouraging.5 We have developed an aggressive surgical approach for patients with invasive TCC of the bladder. This includes en bloc cystectomy, bilateral pelvic iliac lymph node dissection, and some form of lower urinary tract reconstruction. Improvements in medical, surgical, and anesthetic therapy have clearly reduced the morbidity and mortality associated with contemporary surgery. Radical cystectomy also provides an accurate evaluation of the primary bladder tumor as well as the regional lymph nodes. This evaluation allows for adjuvant treatment strategies based on clear pathologic rather than clinical staging, the latter of which has been associated with significant errors in 30% to 50% of patients.3,6,7 This, coupled with the evolution of continent urinary diversion, especially orthotopic lower urinary tract reconstruction to the native urethra, now provides both male and female patients a more acceptable means for storing and eliminating urine, thus lessening the impact of cystectomy on their quality of life.8,9 We believe radical cystectomy with pelvic lymphadenectomy and orthotopic lower urinary tract reconstruction play a central role in the treatment of patients with invasive bladder cancer and provide excellent results with regard to survival and prevention of local recurrence. As the role of chemotherapy or other forms of adjuvant therapy are further defined in this setting, the long-term freedom from metastasis and overall survival will continue to improve. We present our long-term surgical experience and clinical outcomes in a large group of patients treated with radical cystectomy for invasive TCC of the bladder.
Indications for Cystectomy The indication for radical cystectomy was based on cystoscopic and biopsy findings, including tumor invasion of the muscularis propria or prostatic stroma, high-grade, invasive bladder tumors associated with carcinoma-in-situ, carcinoma-in-situ refractory to intravesical chemotherapy or immunotherapy, or recurrent multifocal superficial disease refractory to repeat transurethral resection with/without intravesical therapy. Overall, 94% of patients undergoing cystectomy in this series demonstrated high-grade bladder tumors.
Patients The remaining 1,054 patients underwent radical cystectomy for primary TCC of the bladder with the intent to cure and are the focus of this analysis. Of these 1,054 patients, 843 were men (80%) and 211 were women. The median age was 66 years (range, 22 to 93 years).
Treatment
Adjuvant Therapy The application of adjuvant therapies (radiation and/or chemotherapy) has evolved at our institution during the 26 years of patients treatment reported here. Although not the primary focus of this analysis, the role of adjuvant therapies remains an important component in the overall treatment of selected patients with high-grade, invasive bladder cancer. Initially, the management of patients with bladder cancer included the planned administration of preoperative radiation. From 1971 to 1978, 97 patients received a high-dose short course of approximately 1,600 rads delivered over a 4-day period immediately preceding cystectomy. We compared the 97 patients who received a high-dose, short course of preoperative radiation therapy, followed by cystectomy (1971 to 1978), with 248 patients of similar pathologic stage who underwent cystectomy between 1979 and 1986 and who received no adjuvant radiation or systemic chemotherapy. Notwithstanding the limitations of nonrandomized comparison, this comparison revealed no significant difference in time to recurrence or overall survival between the two groups.4 Furthermore, there was no difference in the incidence of pelvic recurrence. Preoperative radiation therapy has not been used routinely since 1979. We administered chemotherapy selectively in 272 patients (26%) in an adjuvant setting from 1978 to the present: 211 patients received chemotherapy in an adjuvant (postoperative) setting after surgery based on pathologic analysis of the primary bladder tumor and regional lymph nodes, and 48 received this in a neoadjuvant (preoperative) setting before surgery. Thirteen patients received both chemotherapy and radiation therapy before surgery.
Pathology All bladder tumors were primary TCC, with some demonstrating prominent histologic features of glandular (7%) or squamous (11%) differentiation. Histologic grading was performed according to the method of Bergkvist.12 Pathologic staging of the primary bladder tumor and lymph nodes was performed according to the 1987 tumor-node-metastasis (TNM) classification.13 We are currently comparing the old (TNM) system to the 1997 TNM classification by the American Joint Committee on Cancer,14 and this evaluation will be the subject of a future report. Pathologic subgroups were defined as organ-confined, lymph node–negative tumors (P0, Pa, Pis, P1, P2, P3a), nonorgan-confined (extravesical), lymph node–negative tumors (P3b, P4), and lymph node–positive disease.
Follow-Up The median follow-up for the entire cohort of 1,054 patients is 10.2 years; 91% of patients have 3 or more years of follow-up, with a maximum of 27 years.
Clinical Outcomes Outcomes were measured by time to clinical recurrence and overall survival. Time to clinical recurrence or recurrence-free survival was calculated as the time from cystectomy to the date of the first documented clinical recurrence or until last follow-up if the patient had not experienced a clinical recurrence; patients who died before clinical recurrence were censored at the time of death. Survival was calculated as the time from cystectomy to the date of death; all deaths regardless of cause, were counted as events; patients who are still alive were censored at the date of last contact. Bladder cancer recurrences were classified as local (pelvic), distant (metastatic), or both. Local recurrences, by definition, occurred within the soft tissue field of exenteration. Distant recurrences were defined as those that occurred outside the pelvis.
Analysis of Results
Mortality Perioperative death occurred in 27 (3%) of 1,054 patients. No obvious difference in mortality rate was observed in this series when evaluated by the form of urinary diversion performed: eight perioperative deaths among 278 patients (3%) undergoing an incontinent (conduit) form, and 19 (2%) of 776 patients undergoing a continent form of urinary diversion. In addition, no obvious difference in perioperative mortality was seen when stratified by the administration of preoperative therapy: 26 (3%) of 884 patients receiving no therapy, one (1%) of 108 patients receiving radiation only, none of the 49 patients receiving neoadjuvant chemotherapy only, and none of the 13 patients receiving both radiation and chemotherapy preoperatively ( Table 2).
Morbidity A total of 292 patients (28%) sustained an early complication. No apparent difference was observed in the early complication rate when evaluated by the form of urinary diversion: 83 (30%) of 278 patients undergoing an incontinent (conduit) form and 209 (27%) of 776 undergoing a continent form of urinary diversion. No obvious difference was observed in the early complication rate when stratified by the administration of preoperative therapy: 247 (28%) of 883 patients receiving no therapy, 30 (28%) of 108 patients receiving radiation only, 12 (25%) of 49 patients receiving neoadjuvant chemotherapy only, and three (23%) of 13 patients receiving both radiation and chemotherapy preoperatively (Table 2).
Pathologic Staging and Subgroups
A total of 246 patients (23%) in this series were found to have lymph node–positive disease on pathologic analysis after cystectomy. Increasing incidence of lymph node involvement was found with increasing p stage of the primary bladder tumor. Lymph node–positive disease was found in 19 (5%) of 421 patients with superficial (P0, Pis, Pa, P1) primary bladder tumors (p stage). The incidence of lymph node involvement increased with muscle invasive primary bladder tumors: 21 (18%) of 115 patients with P2, and 35 (26%) of 133 patients with P3a disease. Lymph node–positive disease was highest in patients with nonorgan-confined primary bladder tumors; 113 (46%) of 248 patients with P3b, and 58 (42%) of 137 patients with P4 primary bladder tumors (Table 3).
Recurrence-Free and Overall Survival
Recurrence-free and overall survival for the entire cohort was significantly related to pathologic stage and lymph node status (Table 3, Fig 2). Increasing pathologic stage and lymph node–positive disease were associated with significantly higher recurrence rates and worse overall survival (P < 0.001). The probability that the 594 patients (56%) with organ-confined, lymph node–negative bladder tumors (P0, Pa, Pis, P1, P2, P3a) would remain recurrence-free was not statistically different when stratified by each individual pathologic stage (P = .17). The 5- and 10-year recurrence-free survival for this pathologic subgroup of organ-confined lymph node negative tumors was 85% and 82%; and overall survival at 5 and 10 years was 78% and 56%, respectively ( Fig 3).
The chance of remaining recurrence-free for the 214 patients (20%) with nonorgan-confined (extravesical) lymph node–negative bladder tumors (P3b, P4) was not significantly different when stratified by individual pathologic stage (P = .10) (Table 3). The 5- and 10-year recurrence-free and overall survival for this pathologic subgroup of extravesical, lymph node–negative tumors was 58% and 55%, and 47% and 27%, respectively (Fig 3). Patients with lymph node–positive disease demonstrated significantly worse survival and higher recurrence rates compared with those with no lymph node involvement (P < 0.001). The recurrence-free and overall survival for the 246 patients (23%) with lymph node–positive disease at 5 and 10 years was 35% and 34%, and 31% and 23%, respectively (Table 3, Fig 3). Survival rates in this group of patients with lymph node positive disease could be stratified further by the primary bladder tumor (p stage) and by the total number of lymph nodes involved ( Fig 4). Patients with fewer than five positive lymph nodes had significantly higher survival rates than those with five or more lymph nodes involved (P = .003) (Fig 4A). Similarly, patients with lymph node–positive disease and organ-confined primary bladder tumors had significantly higher survival rates than lymph node–positive patients with nonorgan confined (extravesical) primary bladder tumors (P = .004) (Fig 4B).
Recurrence-free and overall survival were significantly related to pathologic subgroup (P < .001) (Table 3, Fig 3). Patients with organ-confined lymph node–negative tumors had the lowest recurrence and highest survival rates statistically compared with patients with lymph node–positive disease, who had the highest recurrence and worst survival rate. Patients with nonorgan-confined (extravesical) lymph node–negative tumors demonstrated intermediate recurrence and survival rates.
Recurrence Site Local tumor recurrences could be stratified by pathologic subgroups. Patients with organ-confined and extravesical lymph node–negative tumors had local recurrence rates, in which only local disease was present at the time of first recurrence, of 6% and 13%, respectively. Those with lymph node–positive disease demonstrated only a 13% local recurrence rate after cystectomy, with only local disease present at the time of first recurrence. Distant recurrences in these same pathologic subgroups increased progressively from 13% in those with organ-confined lymph node–negative tumors to 32% in those with extravesical lymph node–negative tumors. Overall, 52% of patients with lymph node–positive tumors developed a distant recurrence.
Impact of Additional Therapy
Invasive TCC of the bladder is generally a lethal disease requiring aggressive therapy, with fewer than 15% of TCC patients surviving 2 years if untreated.20 The optimal goals of treatment for any invasive bladder cancer should include (1) long-term survival, (2) prevention of pelvic recurrence or development of metastatic bladder cancer, and (3) an excellent quality of life. The development of metastatic bladder cancer after local treatment failure is nearly uniformly fatal, with few durable complete responses from any form of systemic chemotherapy. We demonstrate in a large series of patients with long-term follow-up that radical cystectomy with en bloc bilateral pelvic iliac lymphadenectomy and urinary diversion can be performed safely with excellent bladder cancer control and a low incidence of local pelvic recurrence. Furthermore, the quality of life after cystectomy has improved as lower urinary tract options have evolved into an orthotopic form of diversion; allowing most patients to store urine and void per urethra, without the need of a stoma, an ostomy appliance, or the need for catheterization. In this series of 1,054 patients treated with radical cystectomy for invasive bladder cancer, the chance of surviving 5 years without evidence of disease is 69%, with an overall survival of 60% at 5 years. Most deaths from bladder cancer occur within the first 3 years after cystectomy, after which very few patients die as a result of bladder cancer. The 5- and 10-year recurrence-free and overall survival information reported herein provide data with which other forms of therapy for invasive bladder cancer can be compared. This study demonstrates that pathologic stage is an important survival determinant in patients undergoing cystectomy for bladder cancer. In addition, certain pathologic subgroups can be identified that stratify patients into different prognostic categories. This stratification may help dictate the need for adjuvant therapy. Of the 1,054 patients followed, 56% had pathologically organ-confined, lymph node–negative bladder tumors. The survival results in this subgroup of patients were excellent. No survival difference was observed when comparing superficially noninvasive (Pis, Pa), lamina propria invasive (P1), and muscle invasive (P2, P3a) tumors, as long as the tumor was confined to the bladder (ie, negative nodes). Collectively, the recurrence-free survival in this pathologic subgroup of organ-confined, lymph node–negative bladder tumors was 85% at 5 years, and 82% at 10 years. Similar results for superficial bladder tumors treated with cystectomy have been reported.3,6 Nonorgan-confined (extravesical), lymph node–negative tumors were found in approximately 20% of the patients undergoing radical cystectomy in this series. No survival difference was observed between extravesical P3b and P4 tumors. The recurrence-free survival in this pathologic subgroup of nonorgan-confined lymph node– negative tumors was 58% at 5 years, and 55% at 10 years. Patients with extravesical tumors demonstrated significantly higher recurrence rates and worse survival compared with those with organ-confined tumors (P < .001). At the time of cystectomy, 23% of our patients demonstrated lymph node–positive disease. This underscores the virulent and metastatic capabilities of high-grade, invasive bladder cancer. Despite lymph node involvement, nearly 31% of these patients were alive at 5 years and 23% were alive at 10 years. It is possible that our approach, a meticulous, extended pelvic iliac lymph node dissection, may contribute to the long-term survival of many of these patients.2,21 The impact of neoadjuvant or adjuvant therapy in this group of patients, although difficult to assess and subject to selection bias, may also play a role in the outcomes of patients with lymph node–positive disease. The prognosis in patients with lymph node–positive disease in this study could be stratified by the number of lymph nodes involved and by the p stage of the primary bladder tumor. Patients with fewer than five positive lymph nodes had a 41% recurrence-free survival at 10 years, compared with 24% of patients with five or more lymph nodes at 10 years. Similar differences were noted when stratifying patients by p stage. Patients with lymph node–positive disease and organ-confined bladder tumors had a significant recurrence-free survival advantage (46%) compared with those with nonorgan-confined (30%) tumors at 10 years. Similar results with lymph node–positive disease after cystectomy have been reported previously.2,3,7,21,22 Patients with any lymph node involvement, however, remain at high risk for disease recurrence and should be considered for adjuvant treatment strategies. We have analyzed the data from our series and found that the only pathologic group of patients who benefited significantly from adjuvant chemotherapy, from a recurrence-free and overall survival standpoint, was the lymph node–positive group (data not presented). As a result of improved medical, surgical, and anesthetic techniques, the mortality and morbidity from radical cystectomy have decreased dramatically . We report a 3% mortality rate, comparable to other contemporary radical cystectomy series.3,6,7,23 In our series, the administration of preoperative therapy (radiation and/or chemotherapy) and the form of urinary diversion performed (continent or incontinent) did not noticeably alter the mortality. In addition, the reported early complication rate of 27% in this group of patients included all complications within the first 4 months of surgery: those related to the cystectomy, to perioperative care, and to the urinary diversion. The administration of preoperative therapy and the form of urinary diversion performed did not impact obviously on the overall complication rate. Similar results have been reported.6 Most of these early complications after cystectomy can be appropriately managed nonoperatively, without further sequelae.24 Strict attention to perioperative details, meticulous surgery, and a team-oriented surgical and postoperative approach are critical to minimize morbidity and mortality and to ensure the best clinical outcomes after radical cystectomy in these patients. Radical cystectomy provides excellent local (pelvic) control for the treatment of invasive bladder cancer. An overall local pelvic recurrence rate of 9% was observed in this series. Patients with organ-confined lymph node negative tumors demonstrated only a 6% local recurrence rate, compared with a 13% local recurrence rate in those with nonorgan- confined lymph node negative tumors. Even those at highest risk of a local recurrence (lymph node–positive disease) had only a 13% local recurrence rate after cystectomy. As reported previously, use of high-dose, short-course, preoperative radiation therapy does not seem to reduce the risk of pelvic recurrence4; nearly all patients suffering pelvic recurrence died of their disease despite additional therapeutic efforts. The development of orthotopic lower urinary tract reconstruction has dramatically lessened the impact of cystectomy on the quality of life of patients after removal of the bladder. Orthotopic diversion has eliminated the need for a cutaneous stoma, urostomy appliance, and the need for intermittent catheterization. Continence rates after orthotopic diversion are excellent, providing patients a more natural voiding pattern per urethra.8,9 Currently, approximately 90% of male and female patients are considered appropriate candidates for orthotopic urinary diversion with a low risk of a urethral tumor recurrence after reconstruction.25 The option of lower urinary tract reconstruction to the urethra has also been shown to decrease physician reluctance and increase patient acceptance to undergo earlier cystectomy for bladder cancer when the disease may be at a more curable stage.26 We believe the only contraindication to orthotopic urinary diversion is the presence of tumor within the urethra or extending to the urethral margin as determined by frozen section analysis of the distal surgical margin at the time of cystectomy; compromised renal function (creatinine > 2.5 ng/mL); or the presence of inflammatory bowel disease. Even in patients with locally advanced disease, orthotopic diversion can be employed without concern over subsequent tumor-related reservoir complications. Whether patients have a better quality of life after cystectomy or after bladder-sparing protocols, which require significant and prolonged treatment of the bladder with the potential for tumor recurrence, has not been clarified. Clinical staging errors in patients with invasive bladder cancer have been reported to occur in 30% to 50% of patients.3,6,7 Unlike any other therapy, radical cystectomy pathologically stages the primary bladder tumor and regional lymph nodes. This histologic evaluation provides important prognostic information and may help identify high-risk patients who may benefit from adjuvant therapy. Our data suggest that patients with extravesical tumor extension, or with lymph node positive-disease, seem to be at increased risk for recurrence and may be considered for adjuvant treatment strategies. Additionally, the recent application of molecular markers based on pathologic staging and analysis, may also serve to identify patients at risk for tumor recurrence who may benefit from adjuvant forms of therapy.27 The clinical results reported from this large group of patients over an extended period of time demonstrate that radical cystectomy provides good survival results, with excellent local recurrence rates for invasive bladder cancer. Furthermore, improvements in orthotopic urinary diversion have improved the quality of life in patients after cystectomy. The results from this large series of patients provide sound data and a standard with which other forms of therapy for invasive bladder cancer can be compared.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49: 8-31, 1999 2. Lerner SP, Skinner DG, Lieskovsky G, et al: The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastases: Long-term results. J Urol 149: 758-765, 1993[Medline] 3. Ghoneim MA, El-Mekresh MM, El-Baz MA, et al: Radical cystectomy for carcinoma of the bladder: Critical evaluation of the results in 1,026 cases. J Urol 158: 393-399, 1997[Medline] 4. Skinner DG, Lieskovsky G: Contemporary cystectomy with pelvic node dissection compared to preoperative radiation therapy plus cystectomy in management of invasive bladder cancer. J Urol 131: 1069-1072, 1984[Medline] 5. Skinner D, Daniels J, Russell C, et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: A prospective comparative trial. J Urol 145: 459-467, 1991[Medline] 6. 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, 1994[Medline] 7. Frazier HA, Robertson JE, Dodge RK, et al: The value of pathologic factors in predicting cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. Cancer 71: 3993-4001, 1993[Medline] 8. Stein JP, Grossfeld GD, Freeman JA, et al: Orthotopic lower urinary tract reconstruction in women using the Kock ileal neobladder: Updated experience in 34 patients. J Urol 158: 400-405, 1997[Medline] 9. Elmajian DA, Stein JP, Esrig D, et al: The Kock ileal neobladder: Updated experience in 295 male patients. J Urol 156: 920-925, 1996[Medline] 10. Skinner DG, Lieskovsky G: Management of invasive high-grade bladder cancer, in Skinner DG, Lieskovsky G (eds): Diagnosis and Management of Genitourinary Cancer ( vol 1 ). Philadelphia, PA, Saunders, 1988, pp 295-312 11. Stein JP, Stenzl A, Esrig D, et al: Lower urinary tract reconstruction following cystectomy in women using the Kock ileal reservoir with bilateral ureteroileal urethrostomy: Initial clinical experience. J Urol 152: 1404-1408, 1994[Medline] 12. Bergkvist A, Ljungvist A, Moberger G: Classification of bladder tumours based on the cellular pattern: Preliminary report of a clinical-pathological study of 300 cases with a minimum follow-up of eight years. Acta Chir Scand 8: 371-378, 1965 13. Hemanek PS: l. H. UICC- International Union Against Cancer. TNM Classification of Malignant Tumors (ed 4). Heidelberg: Springer-Verlag, 1987, pp 133-135 14. AJCC Cancer Staging Manual ( ed 5 ). Philadelphia, PA, Lippincott-Raven, 1997, p 241 15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 16. Miller RGJ : Survival Analysis. New York, NY, John Wiley, 1981, pp 114-118 17. Gaynor JJ, Feuer EJ, Tan CG, et al: On the use of cause-specific failure and conditional failure probabilities: Examples form clinical oncology data. J Am Stat Assoc 88: 400-409, 1993 18. Breslow N : Comparison of Survival Cures. Oxford, United Kingdom, Oxford University Press, 1988, pp 398-403 19. Mantel N: Chi-square tests with one degree of freedom: Extensions of the Mantel Haenszel procedure. J Am Stat Assoc 58: 690-700, 1963 20. Prout G, Marshall VF: The prognosis with untreated bladder tumors. Cancer 9: 551-558, 1956[Medline] 21. Poulsen AL, Horn T, Steven K: Radical cystectomy: Extending limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 160: 2015-2020, 1998[Medline] 22. Viewig J, Gschwend JE, Herr HW, et al: Pelvic lymph node dissection can be curative in patients with node positive bladder cancer. J Urol 161: 449-454, 1999[Medline] 23. Frazier MHA, Roberston JE, Paulson DF: Complications of radical cystectomy and urinary diversion: A retrospective review of 675 cases in 2 decades. J Urol 148: 1401-1405, 1992[Medline] 24. Figueroa AJ, Stein JP, Dickinson M, et al: Radical cystectomy in the elderly patient: An updated experience in 404 patients. Cancer 83: 141-147, 1998[Medline] 25. Freeman JA, Tarter TA, Esrig D, et al: Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 156: 1615-1619, 1996[Medline] 26. Hautmann RE, Paiss T: Does the option of the ileal neobladder stimulate patient and physician decision towards earlier cystectomy? J Urol 159: 1845-1850, 1998[Medline] 27. Stein JP, Grossfeld GD, Ginsberg DA, et al: Prognostic markers in bladder cancer: A contemporary review of the literature. J Urol 160: 645-659, 1998[Medline] Submitted June 20, 2000; accepted September 20, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5,000 rads), 23 were found to be inoperable at the time of exploration, 46 demonstrated distant metastases at the time of cystectomy, and 43 had evidence of gross disease remaining after cystectomy (never free of disease). All were excluded from this analysis. The intent of this analysis is to focus on a relatively homogenous cohort of patients with high-grade, invasive TCC of the bladder who achieved a complete resection of all grossly evident tumors at the time of cystectomy. The aforementioned exclusions may create biases; however, the analysis of a completed cystectomy with curative intent remains a critical topic. 
2 test for associations or the Mantel-Haenszel test for trend
