John P. Stein

Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients

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.

ACCUMULATION OF NUCLEAR P53 AND TUMOR PROGRESSION IN BLADDER CANCER

BACKGROUND We have previously demonstrated a strong association between nuclear accumulation of p53 protein, as determined by immunohistochemical analysis, and mutations in the p53 gene. The purpose of this study was to determine the relation between nuclear accumulation of p53 and tumor progression in transitional-cell carcinoma of the bladder. METHODS Histologic specimens of transitional-cell carcinoma of the bladder (stages Pa, noninvasive disease, to P4, disease with direct extension into adjacent organs or structures) from 243 patients who were treated by radical cystectomy were examined for the immunohistochemical detection of p53 protein. Nuclear p53 reactivity was then analyzed in relation to time to recurrence and overall survival. RESULTS The detection of nuclear p53 was significantly associated with an increased risk of recurrence of bladder cancer (P < 0.001) and with decreased overall survival (P < 0.001). In patients with cancer confined to the bladder, the rates of recurrence for stage P1, P2, and P3a tumors that had no detectable nuclear p53 reactivity at five years were 7, 12, and 11 percent, respectively, as compared with 62, 56, and 80 percent, respectively, for tumors that had p53 immunoreactivity. Similar results were obtained when the presence or absence of p53 in the nuclei of the tumor cells was studied in relation to overall survival. In a multivariable analysis stratified according to grade, pathological stage, and lymph-node status, nuclear p53 status was an independent predictor (and in cancer confined to the bladder, the only independent predictor) of recurrence and overall survival (P < 0.001). CONCLUSIONS In patients with transitional-cell carcinoma confined to the bladder, an accumulation of p53 in the tumor-cell nuclei detected by immunohistochemical methods predicts a significantly increased risk of recurrence and death, independently of tumor grade, stage, and lymph-node status. Patients with transitional-cell carcinoma confirmed to the bladder that demonstrates nuclear p53 reactivity should be considered for protocols of adjuvant treatment.

Prognostic markers in bladder cancer: a contemporary review of the literature.

PURPOSE We provide a contemporary review of bladder tumor markers and summarize their role as prognostic indicators. MATERIALS AND METHODS A comprehensive review of the literature on prognostic markers for transitional cell carcinoma of the bladder was performed. RESULTS Intense research efforts are being made to identify and characterize better various bladder cancers and their true biological potential. The need to predict which superficial tumors will recur or progress and which invasive tumors will metastasize has led to the identification of a variety of potential prognostic markers. Blood group antigens, tumor associated antigens, proliferating antigens, oncogenes, peptide growth factors and their receptors, cell adhesion molecules, tumor angiogenesis and angiogenesis inhibitors, and cell cycle regulatory proteins have recently been identified. The potential clinical applications of these tumor markers are under active investigation. Recent attention has focused on which tumor markers may predict the responsiveness of a particular bladder cancer to systemic chemotherapy. CONCLUSIONS At present conventional histopathological evaluation of bladder cancer (tumor grade and stage) cannot predict accurately the behavior of most bladder tumors. With a better understanding of the cell cycle, and cell to cell and cell to extracellular matrix interactions as well as improved diagnostic techniques (immunohistochemistry), progress is being made to identify and characterize other potential prognostic markers for transitional cell carcinoma of the bladder. The ultimate goal is to develop reliable prognostic markers that will accurately predict not only the course but also the response of a tumor to therapy. This information may then be used to dictate more aggressive treatment for tumors that are likely to progress and less aggressive treatment for those that are unlikely to progress. In the future these biological markers may also be used in gene therapy for the treatment of bladder cancer.

Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer

PURPOSE Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. PATIENTS AND METHODS Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. RESULTS The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001). CONCLUSION We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.

Combined Effects of p53, p21, and pRb Expression in the Progression of Bladder Transitional Cell Carcinoma

PURPOSE To determine the combined effects of p53, p21, and pRb alterations in predicting the progression of bladder transitional cell carcinoma. PATIENTS AND METHODS p53, p21, and pRb expression was examined immunohistochemically on archival radical cystectomy samples from 164 patients with invasive or high-grade recurrent superficial transitional cell carcinoma (TCC; lymph node-negative, 117 patients; lymph node-positive, 47 patients). Median follow-up was 8.6 years. Based on percentage of nuclear reactivity, p53 was considered as wild-type (0% to 10%) or altered (>10%); p21 was scored as wild-type (>10%) or altered (<10%); and pRb status was considered wild-type (1% to 50%) or altered (0% or >50%). RESULTS As individual determinants, the p53, p21, and pRb status were independent predictors of time to recurrence (P<.001, P<.001, and P<.001, respectively), and overall survival (P<.001, P=.002, and P=.001, respectively). By examining these determinants in combination, patients were categorized as group I (no alteration in any determinant, 47 patients), group II (any one determinant altered, 51 patients), group III (any two determinants altered, 42 patients), and group IV (all three determinants altered, 24 patients). The 5-year recurrence rates in these groups were 23%, 32%, 57%, and 93%, respectively (log-rank P<.001), and the 5-year survival rates were 70%, 58%, 33%, and 8%, respectively (log-rank P<.001). After stratifying by stage, the number of altered proteins remained significantly associated with time to recurrence and overall survival. CONCLUSION This study suggests that alterations in p53, p21, and pRb act in cooperative or synergistic ways to promote bladder cancer progression. Examining these determinants in combination provides additional information above the use of a single determinant alone.

Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure

Radical cystectomy with an appropriate lymphadenectomy remains the standard of therapy for high-grade invasive bladder cancer. This surgical approach provides the best survival rates with the lowest local recurrence rates and orthotopic diversion can be performed safely in most patients with an acceptable outcome and quality of life. Pathologic analysis of the bladder tumor and regional lymph nodes will help direct the need for adjuvant therapy in high-risk individuals. Equivalent long-term local control and survival are not seen with other forms of treatment including radiation therapy, chemotherapy, or a combination of the two. The rationale and clinical results of large, contemporary cystectomy series are presented, which provide a benchmark of outcomes with this form of surgical treatment.

Urethral Recurrence in Patients with Orthotopic Ileal Neobladders

PURPOSE We identified the risk of urethral recurrence following cystectomy for transitions cell bladder carcinoma, stratified by pathological characteristics of the bladder tumor and type of urinary diversion. MATERIALS AND METHODS The pathological characteristics and clinical courses of 174 men with a Kock ileal neobladder and 262 with a cutaneous urinary diversion were analyzed for time to urethral recurrence. RESULTS Urethral recurrence was identified in 34 patients at a median of 1.6 years after cystectomy, for an overall 7.9% 5-year risk of recurrence. Carcinoma in situ (p = 0.71) and multifocality (p = 0.17) did not independently confer an increased risk of recurrence. Prostatic urethral involvement, particularly stromal invasion, significantly increased the probability of recurrence (p < 0.001). Patients with a Kock ileal neobladder had a significantly lower probability of recurrence compared to those with cutaneous diversion (p = 0.015), even when associated with prostatic urethral involvement. CONCLUSIONS Patients with a Kock ileal neobladder have a lower risk of urethral recurrence than those with cutaneous urinary diversion, even when associated with a high risk pathological condition predicting increased risk of urethral recurrence.

Radical Cystectomy in the Elderly Comparison of Clinical Outcomes between Younger and Older Patients

The authors report their experience with radical cystectomy for transitional cell carcinoma (TCC) of the bladder comparing clinical outcomes, including complication rates, among older patients versus younger patients in a high‐volume center specializing in the treatment of patients with advanced carcinoma of the urinary bladder.

Super Extended Versus Extended Pelvic Lymph Node Dissection in Patients Undergoing Radical Cystectomy for Bladder Cancer: A Comparative Study

PURPOSE There is evidence from retrospective studies that radical cystectomy with extended pelvic lymph node dissection provides better staging and outcomes than limited lymph node dissection. However, the optimal limits of extended lymph node dissection remain unclear. We compared oncological outcomes at 2 cystectomy centers where 2 different extended lymph node dissection templates are practiced to determine whether removing lymphatic tissue up to the inferior mesenteric artery confers an additional survival advantage. MATERIALS AND METHODS Patients undergoing radical cystectomy and extended lymph node dissection with curative intent from 1985 to 2005 were included in analysis if they met certain criteria, including clinically organ confined urothelial bladder carcinoma (cN0M0), pathological stage pT2-pT3, negative surgical margins and no neoadjuvant therapy. Survival and recurrence data were analyzed. RESULTS Demographic data and pathological subgroup distribution (pT2 and pT3) were similar in the 554 University of Southern California and 405 University of Bern patients. University of Southern California patients had higher median number of lymph nodes removed than University of Bern patients (38 vs 22, p <0.0001) and a higher incidence of lymph node metastasis (35% vs 28%, p = 0.02). However, the University of Southern California and University of Bern groups had similar 5-year recurrence-free survival for pT2pN0-2 (57% vs 67%) and pT3pN0-2 (32% vs 34%) disease (p = 0.55 and 0.44, respectively). The overall recurrence rate was equal at the 2 institutions (38%). CONCLUSIONS Meticulous extended lymph node dissection up to the mid-upper third of the common iliac vessels appears to provide survival and recurrence outcomes similar to those of a super extended template up to the inferior mesenteric artery. Complete skeletonization in the extended lymph node dissection template is more important than nodal yield. This does not exclude the possibility that certain patient subgroups with suspicious nodes or after neoadjuvant chemotherapy may benefit from more extensive lymph node dissection.

The Kock Ileal Neobladder: Updated Experience in 295 Male Patients

PURPOSE Since 1986 orthotopic lower urinary tract reconstruction using the Kock ileal neobladder has been our diversion of choice in patients undergoing cystectomy. We report on the first 295 male patients undergoing this procedure from May 1986 through December 1993. MATERIALS AND METHODS Complications were assessed, tabulated, subdivided into early (3 months or less postoperatively) and late types, and further categorized with respect to relationship to neobladder construction. Continence was individually evaluated via a detailed patient questionnaire. RESULTS The pouch related early and late complication rates were 7.2 and 11.6%, respectively, and pouch related abdominal reoperation rates were 0.0 and 1.4%, respectively. Analysis of late pouch related complications revealed 4.1% stone formation and 2.4% afferent nipple stenosis rates, and only 1 case (0.3%) of ileal urethral anastomotic stricture. Of the patients 87 and 86% reported good or satisfactory daytime and nighttime continence, respectively. With regard to age, while overall continence was similar, a significantly greater percentage of patients younger than 70 years experience good daytime and nighttime continence relative to the older counterparts. Of the patients 5% perform regular intermittent catheterization and 2.7% required an artificial urinary sphincter due to unacceptable continence. CONCLUSIONS The Kock orthotopic ileal neobladder can be constructed with minimal morbidity and extraordinary functional results. We strongly advocate its use when possible.