J.P. Stein, MD, Associate Professor of Urology, University of Southern California, Norris Comprehensive Cancer Center, Department of Urology, MS ♯74, 1441 Eastlake Ave., Suite 7414, Los Angeles, CA 90098, USA. e-mail: email@example.com
In the USA, bladder cancer is the fourth most common cancer in men and the eighth most common in women, with TCC comprising nearly 90% of all primary bladder tumours . In 2002 it was estimated that 56 500 new patients will be diagnosed with bladder cancer, with 12 500 projected deaths from the disease . Although most patients present with superficial bladder tumours, 20–40% will either present with or develop invasive disease. Invasive bladder cancer is clearly a lethal malignancy; if left untreated > 85% of patients die from the disease within 2 years of the diagnosis of a high-grade, invasive tumour .
The rationale for an aggressive treatment approach using radical cystectomy for high-grade, invasive bladder cancer is based on several important observations. First, the best long-term survival rates coupled with the lowest local recurrences for invasive bladder cancer are after radical cystectomy . Second, the morbidity and mortality of radical cystectomy has significantly improved over the past several decades. Third, TCC tends to be resistant to radiation therapy even at high doses. Fourth, chemotherapy alone or in combination with bladder-sparing protocols has yet to be shown to give long-term survival rates comparable with cystectomy . Fifth, radical cystectomy provides accurate pathological staging of the primary bladder tumour and regional lymph nodes, thus selectively determining the need for adjuvant therapy based on a precise pathological evaluation. Lastly, improvements in lower urinary tract reconstruction (particularly orthotopic diversion) have improved the quality of life of patients requiring bladder removal, eliminating the need for urostomy appliances, cutaneous stomas and the need for catheterization in most instances . For these reasons radical cystectomy has become a standard therapy for high-grade, invasive bladder cancer.
The purpose of this report is to update a previous review of our institutional clinical experience with high-grade, invasive bladder cancer in a large group of patients treated uniformly with radical cystectomy and extended bilateral pelvic lymphadenectomy over a 25-year period, with a long-term follow-up . These outcome data provide prognostic information for physicians treating patients with bladder cancer, and set a standard to which other therapies can be compared.
PATIENTS AND METHODS
From 1971 to 1997, 1054 patients (843 men, 80%, and 211 women; median age 66 years, range 22–93) underwent radical cystectomy for primary TCC of the bladder with the intent to cure. The results from these patients were reported previously . The indication for cystectomy was based on cystoscopic and biopsy findings including: tumour invasion of the muscularis propria or prostatic stroma; high-grade, invasive tumours associated with carcinoma in situ (CIS); CIS refractory to intravesical chemotherapy or immunotherapy; recurrent multifocal superficial disease refractory to repeat transurethral resection with/without intravesical therapy; and tumours involving a bladder diverticulum. Overall, 94% of patients had high-grade bladder tumours.
All patients underwent a previously described, standard surgical procedure including a meticulous bilateral pelvic iliac lymphadenectomy with en bloc radical cystectomy, and urinary diversion . The specific form of urinary diversion, either incontinent (conduit) or continent (cutaneous or orthotopic), relates primarily to the particular era in which the urinary system was reconstructed (Table 1). A conduit form of diversion was replaced by a continent cutaneous form of reconstruction in 1982, with orthotopic reconstruction ultimately becoming the primary form of urinary diversion in 1986 for men , and in 1992 for women  at our institution.
Table 1. The form of urinary diversion used at USC from 1971 to 1997
† Including rectal reservoirs; USO, ureterosigmoidostomy; CC, continent cutaneous.
The use of adjuvant therapies (radiation and/or chemotherapy) developed over the 25 years of treating patients for bladder cancer. From 1971 to 1978, 97 patients received a high-dose short course of radiation therapy (≈ 1600 rads) delivered over 4 days immediately before cystectomy; these patients were compared with 248 of similar pathological stage who underwent cystectomy between 1979 and 1986, and who received no adjuvant radiation or systemic chemotherapy . There was no significant difference in time to recurrence or overall survival between the groups. Furthermore, there was no difference in the incidence of pelvic recurrence.
From 1978 to the present, systemic chemotherapy was selectively given to 272 patients (26%), i.e. 211 in an adjuvant setting after surgery, based on pathological analysis of the primary bladder tumour and regional lymph nodes, and 48 in a neoadjuvant setting before surgery, while 13 received both chemotherapy and radiation therapy before surgery.
All bladder tumours were primary TCC, with a minority having prominent histological features of glandular (7%) or squamous (11%) differentiation. The tumours were graded histologically by the method of Bergkvist et al., and the primary bladder tumour and lymph nodes staged pathologically (p-stage) according to the 1987 TNM classification .
Pathological subgroups were defined as organ-confined, lymph node-negative tumours (P0, Pa, Pis, P1, P2, P3a), not organ-confined (extravesical), lymph node-negative tumours (P3b, P4), and lymph node-positive disease. The median follow-up for the entire 1054 patients was 10.2 years.
Of the 1054 patients, 27 (3%) died within 30 days of surgery or before discharge; there was no obvious difference in the mortality rate when stratified by the form of urinary diversion, with eight deaths in 278 patients (3%) with an incontinent (conduit), and 19 in 776 (2%) with a continent form of urinary diversion. In addition, there was no obvious difference in mortality when stratified by preoperative therapy, i.e. 26 of 884 patients (3%) receiving no therapy, one of 108 (1%) receiving radiation only, none of the 49 receiving neoadjuvant chemotherapy only, and none of the 13 receiving both radiation and chemotherapy.
In all, 292 patients (28%) had an early complication (within 3 months of surgery). There was no apparent difference in the early complication rate when stratified by the form of urinary diversion, i.e. 83 in 278 (30%) with an incontinent (conduit) form and 209 in 776 (27%) with a continent form of urinary diversion. Nor was there an obvious difference when stratified by the therapy before surgery, i.e. 247 of 883 patients (28%) receiving no therapy, 30 of 108 (28%) receiving radiation only, 12 of 49 (25%) receiving neoadjuvant chemotherapy only, and three of 13 receiving both radiation and chemotherapy preoperatively.
The pathological staging of the 1054 patients is shown in Table 2, with the pathological subgroups. In all, 246 patients (24%) had lymph node-positive disease; there was an increasing incidence of lymph node tumour involvement with increasing p-stage of the primary bladder tumour (Table 3). The incidence of lymph node involvement increased with muscle-invasive primary bladder tumours. Lymph node-positive disease was highest among patients with primary bladder tumours that were not organ-confined.
Table 2. The pathological staging and survival in the 1054 patients
No. (%)of patients
Survival, % at 5 and 10 years
Including P0, Pa, Pis, P1, P2, P3a (lymph node-negative);
The recurrence-free and overall survival for all 1054 patients was 66% and 43%, respectively, at 10 years (Table 2, Fig. 1a). Most deaths occurring within the first 3 years after cystectomy are attributed to bladder cancer but with continued follow-up (after 3 years), most deaths in this elderly group of patients were primarily related to other comorbid diseases, unrelated to bladder cancer.
The recurrence-free and overall survival for the entire cohort was significantly related to the pathological stage and lymph node status (Table 2, Fig. 1b); as both increased there was a significantly higher recurrence rate and worse overall survival (P < 0.001). The recurrence-free survival rates for the 594 patients (56%) with an organ-confined, lymph node-negative bladder tumour (P0, Pa, Pis, P1, P2, P3a) was not statistically different when stratified by each pathological stage (P = 0.17; Table 2, Fig. 1c).
The recurrence-free survival for the 214 patients (20%) with extravesical disease, lymph node-negative bladder tumours (P3b, P4) was not significantly different when stratified by individual pathological stage (P = 0.10; Table 2, Fig. 1c).
Patients with lymph node-positive disease had significantly worse survival and higher recurrence rates than those with no lymph node involvement (P < 0.001; Table 2, Fig. 1d). Survival rates in this group of patients with lymph node-positive disease could be stratified by the total number of lymph nodes involved (tumour burden), and by the primary bladder tumour (p-stage). Patients with fewer than five positive lymph nodes had significantly better survival rates than those with five or more (P = 0.003). Similarly, patients with lymph node-positive disease and organ-confined primary tumours had significantly higher survival rates than lymph node-positive patients with extravesical primary bladder tumours (P = 0.004).
Recurrence-free and overall survival rates were also significantly related to the pathological subgroups (P < 0.001; Table 2, Fig. 1c). Patients with organ-confined, lymph node-negative tumours had statistically the lowest recurrence and highest survival rates, compared with patients with lymph node-positive disease, who had the highest recurrence and worse survival rate. Patients with extravesical, lymph node-negative tumours had intermediate recurrence and survival rates.
In all, 311 patients (30%) developed a bladder cancer recurrence; of these, 234 patients (23%) developed a distant and 77 (7%) a local pelvic tumour recurrence only. The median time for distant and local recurrence was 12 and 18 months, respectively.
The incidence of local tumour recurrences could be stratified by pathological subgroups. Patients with organ-confined and extravesical, lymph node-negative tumours, had local recurrence rates of 6% and 13%, respectively, in which only local disease was present at the time of first recurrence. Those with lymph node-positive disease had only a 13% local recurrence rate after cystectomy. Distant recurrences in these same pathological subgroups progressively increased from 13% with organ-confined lymph node-negative tumours to 32% with extravesical, lymph node-negative tumours. Overall, 52% of patients with lymph node-positive tumours developed a distant recurrence.
Generally, most TCCs that are or become invasive are high-grade tumours; they originate in the bladder mucosa, and progressively invade the lamina propria and sequentially into the muscularis propria, perivesical fat and contiguous pelvic structures, with an increasing incidence of lymph node involvement with disease progression [3,12,13]. Over the past 30 years, radical cystectomy has emerged as a standard therapy for patients with high-grade, invasive bladder cancer. Radical cystectomy with pelvic iliac lymphadenectomy is an ideal form of therapy for this disease, as it effectively removes the primary bladder tumour and the regional lymph nodes that may contain metastases in up to 25% of patients undergoing the procedure .
The early results and outcome of radical cystectomy were disappointing and questionable . Lack of universal acceptance of this procedure was largely a result of the considerable morbidity, in particular the need for improvements in urinary diversion. Furthermore, the early results suggested that only half of patients treated for invasive disease were cured with surgery alone; a significant number developed metastatic disease and died from the disease, usually within 3 years of diagnosis. Improvements in medical, surgical and anaesthetic therapy have clearly reduced the morbidity and mortality associated with contemporary surgery.
We subsequently developed an aggressive surgical approach for patients with invasive TCC of the bladder and previously reported our results . This includes a meticulous en bloc cystectomy with bilateral pelvic iliac lymph node dissection, and some form of lower urinary tract reconstruction. Radical cystectomy provides an accurate evaluation of the primary bladder tumour, along with the regional lymph nodes. This evaluation allows the application of adjuvant treatment strategies based on clear pathological and not clinical staging, which has been associated with significant errors in 30–50% of patients [15–17]. This, coupled with the development of continent urinary diversion, especially orthotopic lower urinary tract reconstruction to the native urethra, provided both male and female patients with a more acceptable means to store and eliminate urine .
With contemporary medical, surgical and anaesthetic techniques, the mortality and morbidity from radical cystectomy have dramatically decreased. A 3% mortality rate in the present series is comparable with other contemporary series of radical cystectomy [12,15,16]. Furthermore, preoperative therapy (radiation and/or chemotherapy), and the form of urinary diversion used (continent or incontinent) does not apparently alter the mortality rate. Our early complication rate of 28% includes all complications within the first 3 months after surgery, i.e. those related to the cystectomy, perioperative care and to the urinary diversion. Furthermore, the administration of any preoperative therapy, and the form of urinary diversion used, does not apparently alter the early complication rate of cystectomy. Most early complications after cystectomy can be appropriately managed conservatively, with no further sequelae. Strict attention to perioperative details, meticulous surgery, and a team-orientated surgical and postoperative approach is critical to minimize morbidity and mortality, and to ensure the best clinical outcome after radical cystectomy in these patients.
The pathological stage of the primary bladder tumour and the presence of lymph node metastases are perhaps the most important survival determinants in patients undergoing cystectomy for bladder cancer . These pathological determinants can be categorized into certain subgroups that stratify patients into different prognostic groups. Pathological evaluation and subgroup stratification help to direct the need for adjuvant therapy. In this series of 1054 patients, 56% had pathologically organ-confined, lymph node-negative bladder tumours; this subgroup had the best survival results, with a recurrence-free survival of 85% at 5-years and 82% at 10 years. Importantly, there was no significant survival difference compared with superficially noninvasive (Pis, Pa), lamina propria-invasive (P1), and muscle-invasive (P2, P3a) tumours, as long as the tumour was confined to the bladder (i.e. negative lymph nodes). Similar outcomes for patients with pathological superficial bladder tumours treated with cystectomy have been reported [12,16]. These data also support the notion that the ideal outcome for patients with high-grade, invasive bladder cancer is when the primary bladder tumour is confined to the bladder, with no evidence of extravesical or lymph node metastases.
Extravesical, lymph node-negative tumours were present in ≈ 20% of patients in this series. In this pathological subgroup there was no obvious survival difference between extravesical P3b and P4 tumours. The recurrence-free survival in this subgroup was 58% at 5 and 55% at 10 years. Patients with extravesical tumours had significantly higher recurrence rates and worse survival than those with organ-confined tumours.
Despite an aggressive treatment policy and approach to bladder cancer, 24% of the patients had lymph node-positive disease at the time of cystectomy . This underscores the virulent and metastatic capabilities of high-grade, invasive bladder cancer. Although patients with lymph node tumour involvement are at high risk, nearly a third of them were alive at 5 years, and 23% alive at 10 years. It is possible that the surgical approach which includes a meticulous, extended pelvic iliac lymph node dissection may provide some advantage to the long-term survival in some of these patients. 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 outcome of patients with lymph node-positive disease.
The prognosis in patients with lymph node-positive disease can be stratified by the number of lymph nodes involved (tumour burden), and by the p-stage of the primary bladder tumour. In this series, patients with fewer than five positive lymph nodes had better survival rates than those with five or more involved. There was also a significant difference when stratifying patients by their p-stage; patients with lymph node-positive disease and organ-confined bladder tumours had a significantly better recurrence-free survival than those with extravesical, lymph node-positive tumours. Similar results with lymph node-positive disease after cystectomy have been reported [12,13,15,18,19].
Several studies recently suggested that the number of lymph nodes involved with tumour [18–22], and the extent of the lymph node dissection [18,20,21] are important variables for patients undergoing cystectomy for bladder cancer. We recently re-examined 246 patients with lymph node tumour involvement after radical cystectomy (data not presented)  to evaluate other prognostic factors in this high-risk group of patients. This re-evaluation lead to the concept of lymph-node density, a novel prognostic measure which may better stratify lymph node-positive patients. Lymph-node density (defined as the total number of positive lymph nodes divided by the total number of lymph nodes removed) accounts for the extent of the lymph node dissection (number of lymph nodes removed) and the tumour burden (number of positive lymph nodes) after radical cystectomy for patients with lymph node-positive disease. Therefore, lymph-node density incorporates both of these concepts simultaneously.
If lymph tumour burden and the extent of the lymphadenectomy are important variables in patients with bladder cancer and lymph node-positive disease, it would thus be logical that lymph-node density should also important. Indeed, lymph-node density is an important and independent prognostic variable in patients with lymph node metastases and may best stratify this high-risk group of patients . It is possible that future staging systems, and the application of adjuvant therapies in clinical trials, should consider applying these prognostic variables, e.g. tumour burden, stage of the primary bladder tumour, extent of the lymphadenectomy and lymph-node density, to help better standardise this high-risk group of patients after radical cystectomy. Nevertheless, patients with any lymph node involvement remain at high risk of disease recurrence and should be considered for adjuvant treatment strategies.
Radical cystectomy provides the best local (pelvic) control for treating invasive bladder cancer. The overall local pelvic recurrence rate was 7% in this series . Patients with organ-confined, lymph node-negative tumours had only a 6% local recurrence rate, compared with 13% in those with extravesical, lymph node-negative tumours. Even those at highest risk of a local recurrence (lymph node-positive) had only a 13% local recurrence rate after cystectomy. The use of high-dose, short-course preoperative radiation therapy does not appear to reduce the risk of pelvic recurrence ; nearly all patients with pelvic recurrence will die from their disease despite additional therapeutic efforts.
Clinical staging errors reportedly occur in 30–50% of patients with invasive bladder cancer [15–17]. Unlike other therapies, radical cystectomy pathologically stages the primary bladder tumour and regional lymph nodes. This histological evaluation provides important prognostic information and may help to identify high-risk patients who could benefit from adjuvant therapy. The present data suggest that patients with extravesical tumour extension, or with lymph node-positive disease, appear to be at greater risk of recurrence and might be considered for adjuvant treatment strategies. Also, the recent application of molecular markers based on pathological staging and analysis could identify patients at risk of tumour recurrence and who might benefit from adjuvant forms of therapy .
The clinical results reported from this large group of patients treated over a long period show that radical cystectomy provides good survival results, with excellent local recurrence rates for high-grade, invasive bladder cancer . Furthermore, improvements in orthotopic urinary diversion have improved the quality of life in patients after cystectomy . These results provide sound data and a standard to which other forms of therapy for invasive bladder cancer can be compared.