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Purpose: We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer., Patients and Methods: Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m(2) with subsequent dose levels of 20, 27, 30, and 33 mg/m(2). The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation., Results: Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m(2) twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m(2). Intermediate dose levels of 27 and 30 mg/m(2) were then evaluated. The MTD of gemcitabine was 27 mg/m(2). The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months., Conclusion: Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m(2). There is a high rate of bladder preservation in this selected group of patients.

Objectives: To assess, in a Phase I study, whether bladder preservation with concurrent gemcitabine and radiotherapy (RT) influenced patient-reported quality of life (QOL) as determined by the Functional Assessment of Cancer Therapy-Bladder (FACT-BL)., Methods: Between January 1998 and March 2002, 24 patients with urothelial carcinoma of the bladder were enrolled, and 23 patients underwent transuretheral resection of bladder tumor, followed by twice-weekly gemcitabine with concurrent RT. The initial dose was 10 mg/m2 given twice weekly and increased as tolerated. To assess treatment-related QOL, patients completed the FACT-BL questionnaire., Results: Of the 24 patients enrolled, 23 (96%) were assessed for toxicity and response. The FACT-generic (G) QOL assessment was obtained from 22 (92%) of 23 patients. No statistically significant difference was found in the FACT-G or FACT-BL or the combination before, during, or after treatment. The FACT-BL values were lower in patients who received higher doses of gemcitabine (greater than 20 mg/m2 versus 20 mg/m2 or less). At least one dose-limiting toxicity (DLT) was experienced by 5 (23%) of 22 patients. The FACT-G values were lower for those patients who experienced DLT (difference of -13.1, P = 0.07). The physical well-being scores for patients who experienced DLT were lower after treatment (difference of -5.2, P = 0.03) compared with those without DLT., Conclusions: Concurrent RT and gemcitabine failed to statistically influence patient-reported QOL, although patients who received higher doses reported lower FACT-BL scores. The results of this study suggest that concurrent gemcitabine with conformal RT is a tolerable treatment regimen for bladder preservation, as demonstrated by the excellent treatment compliance and similar FACT measurements.

Background: Mutations in the p53 tumor suppressor gene may correlate with an increased risk of recurrence and disease progression in patients with bladder carcinoma. The ability to accurately and sensitively detect p53 mutations in cytology specimens may be of benefit in the treatment of bladder carcinoma patients with superficial, minimally invasive disease., Methods: Genomic DNA was isolated from 49 cases, each of which was comprised of matched bladder tumor tissue, bladder wash, and voided urine specimens obtained concurrently at a single institution. The genomic DNA was analyzed for mutations in the p53 tumor suppressor gene using a p53 mutation detection assay. Automated dideoxy sequencing of mutant specimens also was performed., Results: Of the 49 cases, 29 (59%) showed no evidence of p53 mutations in the tumor, bladder wash, or voided urine specimens. Of the remaining 20 cases, 19 showed evidence of mutations in the tumor. Of these 19 p53 mutant bladder tumors, 16 (84%) were detected in the matched bladder wash and 16 (84%) were detected in the matched voided urine specimens. One case resulted in the detection of mutant p53 in the voided urine and the bladder wash, but not in the tumor. Analysis of the results between tumor tissue and bladder wash or tumor and voided urine showed 84.2% sensitivity, 96.8% specificity, and 91.8% accuracy. Sequence analysis of the mutant cases showed that the mutations detected in the tumor tissue were the same mutations detected in the bladder wash and the voided urine specimens., Conclusions: Both voided urine and bladder wash specimens from patients with bladder carcinoma were found to provide a high rate of clinical accuracy for the determination of the p53 gene status in patients with bladder tumors., (Copyright 2001 American Cancer Society.)

Pelvic recurrence following cystectomy is a devastating problem for both physician and patient. Patients who recur locally usually do so within the first 2 years following surgery. Stage, grade, and possibly p53 status of the tumor are prognostic indicators for local failure. Patients with extensive disease at the time of diagnosis may benefit from adjuvant or neoadjuvant treatment to attempt to decrease the rate of recurrence. Treatment of patients with local failure should use a multimodality approach that includes systemic chemotherapy with or without local radiation therapy or surgery. Although rare, long-term survival can be achieved in selected patients.

Purpose: To investigate the utility of computed tomographic (CT) virtual cystoscopy in the detection of bladder tumors., Materials and Methods: Twenty-six patients suspected or known to have bladder neoplasms underwent CT virtual and conventional cystoscopy. The bladder was insufflated with carbon dioxide through a Foley catheter. Helical CT of the bladder was then performed. The data were downloaded to a workstation for interactive intraluminal navigation. Two radiologists blinded to the results of conventional cystoscopy independently reviewed the transverse and virtual images, with consensus readings for cases with discrepant results., Results: Thirty-six (90%) of 40 bladder lesions proved at conventional cystoscopy were detected with a combination of transverse and virtual images. Four (10%) of 40 bladder lesions, all smaller than 5 mm, were undetected. Transverse and virtual images were complementary, since six polypoid lesions smaller than 5 mm depicted on the virtual images were not seen on the transverse images. In contrast, areas of wall thickening were more readily appreciated on transverse images. CT with patients in both supine and prone positions was necessary, since seven (19%) and five (14%) of 36 lesions were seen only on supine and prone images, respectively., Conclusion: CT virtual cystoscopy is a promising technique for use in bladder tumor detection of lesions larger than 5 mm. Optimal evaluation requires adequate bladder distention with the patient in both supine and prone positions and interpretation of both transverse and virtual images.

Purpose: Bacillus Calmette-Guerin (BCG) immunotherapy has been widely accepted as the optimal treatment for carcinoma in situ and high grade superficial transitional cell carcinoma. However, controversy remains regarding the role of maintenance therapy, and its long-term effect on recurrence and progression., Materials and Methods: All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical and percutaneous Connaught BCG. Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm). Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy. The 384 eligible patients who were disease-free at randomization constitute the primary intent to treat analytic group because they could be followed for disease recurrence. All patients were followed for adverse effects of treatment, recurrence, disease worsening and survival., Results: No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months (95% confidence interval 25.1 to 56.8) in the no maintenance and 76.8 months (64.3 to 93.2) in the maintenance arm (log rank p<0.0001). Estimated median time for worsening-free survival, defined as no evidence of progression including pathological stage T2 disease or greater, or the use of cystectomy, systemic chemotherapy or radiation therapy, was 111.5 months in the no maintenance and not estimable in the maintenance arm (log rank p = 0.04). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm., Conclusions: Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival.

We studied the expression of cytokeratin (CK)-7 and CK-20 in prostate adenocarcinoma and urothelial carcinoma and evaluated their usefulness for distinguishing high-grade forms of these tumors. We examined prostate adenocarcinoma in 59 radical prostatectomy specimens and in 10 autopsy specimens showing metastatic disease, and urothelial carcinoma of the bladder in 28 cystectomy specimens. Immunohistochemical staining for CK-7, CK-20, and prostate-specific antigen (PSA) was performed on paraffin sections. For prostate adenocarcinoma, 5 cases had only CK-7 positivity, 5 had only CK-20 focal positivity, 1 stained for both markers, and 48 were negative for both. PSA was positive in all but 1 poorly differentiated prostatic carcinoma. In the autopsy cases, PSA was expressed in the prostate and the metastatic tumors in most cases; few cases were focally positive for CK-7 or CK-20, but none was positive for both markers. For the urothelial tumors, CK-7 was the sole positive marker in 6 cases, and CK-20 in 1 case; 17 cases were positive for both, and 4 were negative for both. All urothelial carcinomas were PSA negative. Although PSA is useful for differentiating prostatic from urothelial carcinoma, CK-7 and CK-20 are helpful when both are positive, supporting the diagnosis of urothelial carcinoma. However, if only 1 marker is positive or both are negative, these markers have limited usefulness for distinguishing these carcinomas.

Purpose: The American Urological Association convened the Bladder Cancer Clinical Guidelines Panel to analyze the literature regarding available methods of treating nonmuscle invasive bladder cancer, and to make practice policy recommendations based primarily on treatment outcomes data., Materials and Methods: The panel searched the MEDLINE database for all articles related to nonmuscle invasive bladder cancer published from 1966 to January 1998. Outcomes data were extracted from articles accepted after panel review and meta-analyzed to produce comparative probability estimates for alternative treatments., Results: All of the intravesical agents (thiotepa, bacillus Calmette-Guerin, mitomycin C and doxorubicin) when used as adjuvant therapy after transurethral resection resulted in a lower probability of recurrence compared to resection alone. However, there is no evidence that intravesical therapy affects long-term progression., Conclusions: For patients with no prior intravesical therapy adjuvant intravesical chemotherapy or immunotherapy is a treatment option after endoscopic removal of low grade Ta bladder cancers. Intravesical instillation of bacillus Calmette-Guerin or mitomycin C is recommended for carcinoma in situ, and after endoscopic removal of T1 and high grade Ta tumors.

Purpose: The efficacy of bladder preservation strategies for invasive cancer of the bladder are evaluated., Materials and Methods: The literature was reviewed specifically regarding the relative success of bladder preservation therapy compared with total cystectomy., Results: Bladder preservation strategies currently available are substantially inferior to cystectomy for elimination of the existing cancer and prevention of pelvic recurrence (soft tissue after cystectomy or in the bladder after bladder preservation). The best bladder preservation protocols eliminate cancer from the bladder at first evaluation in 10 to 20% and 50 to 80% of patients with T3b and T2 cancers, respectively, while later recurrences in the bladder are seen in 40 to 60%. Cystectomy provides a local failure rate of 10 to 25% for T2 and T3b disease, respectively. In addition, bladder reconstruction with a neobladder after cystectomy minimizes deterioration of quality of life which is the motivating rationale for bladder preservation., Conclusions: While continuing clinical trials of new strategies for bladder preservation are necessary and laudable, clinical practice currently affirms cystectomy, possibly with neobladder formation, as optimal therapy in appropriate patients.

Urothelial tumors represent a spectrum of diseases with a range of prognoses. Once a diagnosis is established at any point on the urothelial tract, the patient remains at risk for developing a new lesion at a different or the same location, at a similar or more advanced stage. Continued monitoring for recurrence is an essential part of management, as most recurrences are superficial and can be managed by endoscopic means. Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development. These methods are aimed at optimizing the individual patient's likelihood of cure and chance for organ preservation. For patients with more extensive disease, newer treatments typically involve combined-modality approaches using recently developed surgical procedures, or three-dimensional treatment planning for more precise delivery of radiation therapy. While these are not appropriate in all cases, they do offer the promise of an improved quality of life and prolonged survival. Finally, within the category of metastatic disease, a number of new agents have been identified that appear to be superior to those currently considered to be standard therapies. It is thought, therefore, that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes for patients with all stages of disease.

An orthotopic neobladder has quickly become the preferred diversion after cystectomy in most women. The decision to proceed with a cystectomy for high-grade, superficially invasive transitional cell carcinoma is frequently difficult for the patient and physician alike. The availability of an orthotopic diversion to provide an excellent voiding pattern and continence may tip the scale toward earlier cystectomy with anticipated excellent cancer control.

Introduction: Determination of the risk of invasive bladder tumors progressing is still imprecise due to the heterogeneous biological behavior of this neoplasm. The goals of this study were to evaluate the patterns of expression of the epidermal growth factor (EGF) system in invasive bladder cancer and to assess its prognostic value., Methods: This immunohistochemical study was performed using fresh frozen tumor samples and a panel of monoclonal antibodies on a series of 43 invasive bladder cancers treated by cystectomy., Results: EGF was detected in 45% of the tumors and did not correlate with survival from bladder cancer. Transforming growth factor alpha (TGF alpha) was expressed by 60% of the tumors and correlated strongly with death from bladder cancer. Epidermal growth factor receptor (EGF-R) expression was seen in 86% of cases and had no prognostic significance. c-erbB2 was expressed in 50% of cases and was inversely related to a poor prognosis. When EGF and TGF alpha were both expressed, there was little or no expression of c-erbB2., Conclusion: The accumulation of several growth factors and the relevant receptor are necessary for the progression of invasive bladder cancers. They could be used as indicators of tumor aggressiveness.

Objectives: Many attempts have been made during decades to identify factors predictive of prognosis in patients with transitional cell carcinoma (TCC) of the bladder. The present study attempts to determine the predictive factors in a large series of patients with long follow-up homogeneously treated at three institutions from 1983 to 1992., Methods: The clinical and histological factors with presumed prognostic value were retrospectively evaluated in a series of 331 patients with a mean follow-up of 7.2 years, and a study of survival was performed., Results: Univariate analysis showed tumor stage, growth pattern, grade, size, coexisting dysplasia, histologic type, topography of the lesion and patient age are useful parameters for the prediction of prognosis. The Cox analysis revealed tumor stage is the most important prognostic variable (Beta = 1.23, p < .001), followed by growth pattern as determined by the presence or absence of a papillary phenotype (Beta = 1.18, p < .001), tumor size (Beta = .98, p < .001), WHO modified histologic grading considering persistence or loss of cell polarity (Beta = .73, p < .01), tumor location (Beta = .48, p < .05), and histology (presence or absence of phenotypes other than pure TCC, Beta = .45, p < .05). Coexisting dysplasia, tumor multiplicity, age and sex did not independently influence survival., Conclusion: Despite the advancements in the field of molecular biology relative to prognostic markers in bladder cancer, the conventional morphological parameters and tumor stage continue to be the main source of prognostic information in clinical practice.

Objectives: Confidence has increased in the use of an orthotopic reservoir to the urethra after a cystoprostatectomy for bladder cancer; however, many surgeons would welcome a method to simplify the operative procedure. The availability of absorbable staples on a GIA stapler allows study of the incorporation of stapling procedures into formation of a reservoir. Because of the success of hand-sewn W-configured ileal reservoirs, we initiated a Phase II study to evaluate absorbable staples in formation of a W-configured reservoir. We now present an expanded contemporary series comparing a W-stapled ileal neobladder with hand-sewn ileal (Studer) or hand-sewn ileocolic (Le Bag) reservoirs., Methods: Forty-five selected patients underwent orthotopic urinary diversion after cystoprostatectomy for bladder cancer (n = 42) or prostate cancer (n = 3) using one of the three methods of reservoir construction. There were 43 men and 2 women. The evaluation included a urodynamic evaluation and a questionnaire sent to patients inquiring about urinary function., Results: Most patients did well with the W-stapled ileal reservoir but 6 of 19 evaluable patients had unsatisfactory reservoir characteristics. Three patients needed an augmentation cystoplasty and 3 had higher pressure, smaller volume reservoirs. Reservoir function appeared to be consistently more favorable in patients with either of the hand-sewn reservoirs using an ileal or ileocolic segment., Conclusions: Although the W-stapled ileal reservoir is safe and allows reservoir formation quickly, the inconsistencies of the results discourage its use in the particular configuration described. Failure of the reservoir to distend could be a function of reservoir design, areas of ischemia in the reservoir, or reaction to staple material. Absorbable staples on the GIA instrument may work satisfactorily for formation of an ileocolic reservoir for continent cutaneous diversion. However, the W-configured orthotopic reservoir as constructed using absorbable staples in this study is inferior to a hand-sewn ileal or ileocolic neobladder.

Follow-up after cystectomy for carcinoma of the bladder requires special considerations. Patients must be monitored for "new" urothelial tumors, followed for a local pelvic recurrence or distant metastasis of the original primary cancer, and monitored for sequelae from the urinary diversion. Additional urothelial tumors may be amenable to salvage therapy if identified at an early stage. This is particularly true for a urethral carcinoma identified by urethral washing. Metastatic disease may be better palliated by earlier detection. The frequency of metabolic complications after either continent cutaneous or orthotopic urinary diversion may not be defined precisely at this time and lifelong follow-up will be necessary.

The combination of cisplatin and dichloromethotrexate is a pharmacologically rational strategy designed to avoid the nephrotoxicity associated with the systemic chemotherapy of bladder cancer. Of 97 patients with metastatic bladder cancer entered into this study 73 with good renal function received cisplatin and dichloromethotrexate, while 24 with impaired renal function received dichloromethotrexate alone. No responses were noted in the latter group. A 42% response rate (95% exact confidence interval 30.0 to 55.2%), including 9 patients (14%) who achieved a complete response, was observed in the combination group. The toxicity patterns in both groups of patients were consistent with the hypothesis that renal toxicity would be ameliorated with the use of the methotrexate analogue. However, the failure to achieve a higher overall response rate despite near maximum tolerated doses of dichloromethotrexate discourages future studies with this agent. New agents for metastatic bladder cancer should be tested as first line therapy.

Background: In carcinoma of the bladder, both intravesical chemotherapy and immunotherapy can induce tumor regression and reduce the rate of recurrence, but the relative merits of these two therapies are unclear. We conducted a multi-institutional study to address this question., Methods: Patients with rapidly recurrent (stage Ta and T1) or in situ transitional-cell carcinoma of the bladder were randomly assigned to receive either doxorubicin administered intravesically or bacille Calmette-Guérin (BCG) administered both intravesically and percutaneously. The 262 eligible patients were followed for a median of 65 months. Complete responses to treatment of carcinoma in situ were confirmed by biopsy and cytologic analysis of the urine., Results: For patients with Ta and T1 tumors without carcinoma in situ, the estimated probability of being disease free at five years was 17 percent after doxorubicin, as compared with 37 percent after immunotherapy with BCG (P = 0.015). The median times to treatment failure (termination of treatment, due to persistence, recurrence, or progression of disease) were 10.4 and 22.5 months, respectively. For patients with carcinoma in situ the complete-response probability estimates (i.e., the estimated probability of documented disappearance of disease) were 34 percent for doxorubicin (23 of 67 patients) and 70 percent for BCG (45 of 64 patients) (P less than 0.001); the median times to treatment failure were 5.1 and 39 months, respectively. The probability of being disease-free at five years survival among the patients with carcinoma in situ was 18 percent after treatment with doxorubicin and 45 percent after BCG therapy. Patients treated with BCG had a higher incidence of toxic systemic effects and a larger number of local irritative symptoms than patients treated with doxorubicin, but few of these adverse reactions were severe., Conclusions: As compared with intravesical doxorubicin, immunotherapy with BCG provides improved protection against the recurrence of superficial bladder cancer.

Percutaneous nephrostomy has become a well-established procedure for a wide variety of urologic disorders. However, its role in the management of patients with upper urinary tract transitional cell carcinoma has not been defined. We utilized percutaneous nephrostomy in 23 renal units for the evaluation or treatment of 21 patients in whom standard techniques were inconclusive or inadequate. The percutaneous nephrostomy provided adequate relief of obstruction in the face of significant azotemia or infection. Diagnostic abilities were improved through the use of antegrade pyelography, selective cytologic examination, and, at times, by providing direct access for endoscopic visualization and biopsy. In select cases, the percutaneous access provided a route for definitive or adjunctive treatment of the lesion. Complications were few and seeding of the tract or local tumor spread has not occurred at follow-up ranging from one to one hundred twenty-one (mean 27.8) months.

Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. Complications from bacillus Calmette-Guerin therapy are usually minor but serious and even fatal reactions can occur. Five recent cases illustrate the gravity of bacillus Calmette-Guerin sepsis. One man with severe debility and the organic brain syndrome died acutely with a fever of 40 C. Two men had frank sepsis that progressed to multiorgan failure and death. Sepsis progressed despite the use of isoniazid, rifampin and streptomycin. Two men who had equally progressive sepsis with intravesical bacillus Calmette-Guerin survived with the use of cycloserine for the first 72 hours of treatment. Triple antituberculous antibiotics, including cycloserine, may be lifesaving. Sepsis resulted from intravenous absorption through inflamed or disrupted urothelium. Bacillus Calmette-Guerin treatment should not be administered in the presence of severe cystitis or after grossly traumatic catheterization.

The availability of potentially effective systemic chemotherapy for transitional cell carcinoma of the bladder and the functional improvements afforded by new methods of urinary diversion have both contributed to significant changes in the treatment of high-stage bladder cancer. The clinician must decide at the beginning of therapy whether to use a bladder-preservation or bladder-reconstruction approach. The decision may be based on survival or on quality of life--two different goals that require different studies. When multiple types of treatments are combined, cumulative toxicity must be examined carefully.

The prostate glands of 84 men undergoing cystoprostatectomy for bladder cancer were examined by whole-mount sections at 4-mm to 5-mm intervals to identify unsuspected prostate adenocarcinoma (PCa). Of 72 white patients with entirely normal digital rectal examinations (DRE), 33 (46%) were found to have PCa, including 12 (17%) who had a Gleason score of 6 or greater and seven (10%) who had penetration through the prostatic capsule. These observations are consistent with previous studies in autopsy populations but allow a more appropriate comparison with morphologic data generated from radical prostatectomy specimens. If these data can be extended to the age-matched general population, treatment at a 1% mortality rate for all white men 60 to 74 years of age with a PCa with a Gleason score of 6 or greater could cause between 6190 and 30,951 deaths, in contrast to 7335 deaths expected from the cancer. These data stress the need for a control group in a study designed to evaluate the benefit of early diagnosis and treatment of PCa.

The records of 119 men who had undergone radical cystectomy for cancer of the bladder were reviewed for involvement of the urethra at the time of cystectomy and for later recurrence of urethral tumor. Urethral recurrences contributed significantly to the over-all pelvic recurrence rate and were associated with a uniformly poor prognosis. Prophylactic urethrectomy is indicated when pathologic examination reveals multifocal tumors, concurrent upper tract tumors, diffuse carcinoma in situ, involvement of the trigone or prostatic urethra, or positive urethral margin on frozen section. Those patients not undergoing urethrectomy should be followed with periodic urethral wash cytology.

A review of a 20-year experience of radical cystectomy identified 99 patients who had not undergone preoperative radiation therapy. The 5-year survival rate of patients with clinical high stage lesions (T3, T4a) was 40 per cent. Life-table analyses showed that survival rate in this group was comparable with that reported for other groups receiving preoperative radiation therapy. The pelvic recurrence rate was 9 per cent and was frequently related to either urethral or nodal disease. Unquantifiable patient selection factors may well limit the reliability of these results.

Over the last 40 years the role of surgery in the management of bladder cancer has evolved from being the only treatment option to part of a multimodality approach which utilizes intravesical and systemic chemotherapy. Throughout this evolution, surgery has remained the mainstay of staging and treatment. Currently, conservative bladder-sparing endoscopic surgery is possible in patients with superficial bladder cancer, and continent cutaneous or orthoptic diversions are improving the quality of life in many patients who require a radical cystectomy. Unfortunately, surgery alone is insufficient to cure advanced stages of bladder cancer. Continued research in systemic chemotherapy is necessary to significantly improve long-term survival rates.

The clinical courses of 119 patients with unresectable bladder cancer were analyzed. All patients had a laparotomy with the intent of cystectomy. TN categorization postlaparotomy did not identify variables significantly influencing the natural history of the disease, although previous definitive irradiation or T4aNx-4 categories were associated with especially poor survival. T category correlated more closely with survival than did N category. Supravesical urinary diversion palliated patients with urinary symptoms and/or bilateral ureteral obstruction. Patients without compelling urinary symptoms at the time of laparotomy uncommonly needed diversion later. Pelvic irradiation and systemic chemotherapy available in the interval from 1961 to 1976 had minimal if any demonstrable effect on the time course of the disease.

Regional chemotherapy with intra-arterial cis-platinum and doxorubicin as an adjuvant to total cystectomy and urinary diversion has been evaluated in a phase I to II study. In the first 17 patients chemotherapy consisted of 40 to 75 mg. per m. cis-platinum intra-arterially during 30 minutes, 30 to 40 mg. per m. doxorubicin intra-arterially during 60 minutes (11 patients) or 12 hours (6 patients) and 400 to 500 mg. per m. cyclophosphamide intravenously. The remaining 8 patients received 70 to 100 mg. per m. cis-platinum intra-arterially during 30 minutes. Intra-arterial chemotherapy was administered through a percutaneous catheter placed in the hypogastric artery before each course. Courses were repeated at 4-week intervals. A total of 25 patients received 58 courses (median 2 per patient). Clinical stages of disease in the patients entering the protocol were T3aNxMo (8), T3bNx-2Mo (12) and T4a-bNxMx-1 (5). Clinical response was assessed in 24 of 25 patients: 6 achieved a complete clinical response, 12 had a partial response and 7 had no response. Of 25 patients 16 underwent total cystectomy and urinary diversion with pathological staging as follows: ToNoMo in 3, T1NoMo in 1, T3aNoMo in 5, T3bNo-2Mo in 6 and T4NoMo in 1. Intra-arterial chemotherapy can produce a complete pathological response in patients with locally advanced bladder cancer and is tolerated well by most patients.

Transitional cell carcinoma involving the prostate in patients with bladder carcinoma impacts on the judicious use of intravesical chemotherapy, partial cystectomy and internal urinary reservoirs anastomosed to the urethra. We compared the accuracy of prostate needle biopsy, fine needle prostatic aspiration and transurethral resection biopsies of the prostate to detect the presence or absence of transitional cell carcinoma involving the prostate in 25 men undergoing radical cystectomy, of whom 40 per cent had transitional cell carcinoma of the prostate. The accuracy of the 3 detection methods was 20, 40 and 90 per cent, respectively. If any 1 of the 3 tests was positive all patients with transitional cell prostatic cancer were correctly identified. These tests should be performed in high risk patients, including those with transitional cell carcinoma in situ of the bladder, or with a positive urine cytology study and a cystoscopically as well as biopsy proved normal bladder urothelium.

The long-term results of regional chemotherapy plus intra-arterial cisplatin with or without doxorubicin as an adjuvant before cystectomy and urinary diversion in patients with invasive transitional cell carcinoma of the bladder were evaluated. A total of 27 patients with T3aNxMo (8), T3bNxMo (14) and T4NxMo (5) disease participated in a phase II trial completed in 1985. Of the patients 19 received cisplatin and doxorubicin intra-arterially, and cyclophosphamide intravenously, and the remaining 8 received 70 to 100 mg. per m.2 cisplatin intra-arterially. A total of 19 patients underwent cystectomy after chemotherapy. Patients in this group had a pathological complete response (no evidence of disease after surgical restaging) or the presence of residual disease at operation that could (surgical complete response) or could not (pathological partial response) be completely resected. Of the 19 patients undergoing cystectomy surgical complete response was observed in 47.4%, pathological complete response in 26.3% and pathological partial response in 26.3%. At a median followup of 27 months for the group 66% of the patients with a surgical complete response, 100% with a pathological complete response and 40% with a pathological partial response were alive with no evidence of disease. The over-all survival for patients with a pathological or surgical complete response is 76.9%. In the patients not operated upon because of persistent or advanced disease after chemotherapy survival was brief (less than 4 months). Prolonged survival in patients achieving a pathological or surgical complete response with neoadjuvant chemotherapy occurs, and this modality may have a role in patients with invasive tumors.

Specimens from 84 radical cystectomies for bladder carcinoma performed between January 1984 and July 1986 were reviewed to characterize the involvement of the prostate with transitional cell carcinoma. Whole-mount sectioning of the prostate was performed at 4 mm. intervals and processed in the same manner as radical prostatectomy specimens. A total of 36 patients (43 per cent) had transitional cell carcinoma of the prostate: 94 per cent of these had prostatic urethra involvement and 6 per cent had a normal prostatic urethra but transitional cell carcinoma was present in the periurethral structures. In situ prostatic duct or acini, ejaculatory duct and seminal vesicle involvement occurred, respectively, in 67, 8 and 17 per cent of the patients with prostatic involvement. Of the patients with prostatic involvement 39 per cent had stromal invasion (22 per cent focal and 17 per cent diffuse invasion). The incidence of carcinoma in situ of the bladder neck or trigone (59 per cent), previous intravesical chemotherapy (59 per cent) and ureteral carcinoma (79 per cent) was significantly increased in patients with prostatic involvement. In patients with carcinoma in situ of the trigone or bladder neck, or in whom previous intravesical chemotherapy treatments have failed prostatic involvement should be suspected so that this disease can be detected before stromal invasion occurs.

The clinical staging of bladder carcinoma traditionally has relied on transurethral resection of the bladder tumor, urinary cytology, excretory urography and an examination with the patient under anesthesia. Recent evidence has shown magnetic resonance imaging to be effective in the staging of bladder cancer. Whether magnetic resonance imaging is more accurate than conventional clinical staging techniques has not been answered. To determine the usefulness of magnetic resonance imaging in this regard 34 patients with bladder carcinoma underwent staging by this technique before radical cystectomy. The magnetic resonance imaging stage and conventional clinical stage were compared to the final pathological stage. Magnetic resonance imaging had an over-all accuracy of 50 per cent versus 57 per cent for conventional staging techniques and it identified 2 of 5 patients with nodal disease. To date magnetic resonance imaging does not appear to be better than conventional clinical staging techniques in patients with bladder carcinoma.

Between 1979 and 1984, 136 patients underwent radical cystectomy and urinary diversion for the treatment of invasive carcinoma of the bladder. Of the patients 38 were 70 years old or more and they were considered elderly. The mortality rates for those less than 70 compared to those more than 70 years old were 1 and 5 per cent, respectively, and the morbidity rates were 39 and 34 per cent, respectively, with wound separation being the most common complication. There was no statistically significant difference with respect to age in the morbidity or mortality rates. The median hospital stay was 14 days but if a complication occurred the hospital stay was significantly longer. For elderly patients in general good health, radical cystectomy and urinary diversion should not be withheld on the basis of age alone.

Several different methods of urinary diversion currently are available for use in conjunction with radical cystectomy. The method of urinary diversion performed at the time of radical cystectomy was reviewed for patients undergoing surgery from April 1984 through March 1986. A total of 91 urinary diversions was performed. Of the patients 74 per cent had a diversion with an external appliance (including 68 per cent with an ileal conduit), 14 per cent had a continent urinary reservoir (Kock pouch) and 11 per cent had an internal reservoir anastomosed to the urethra and, thus, avoided any stoma. There are inherent disadvantages to each form of urinary diversion and patient selection will be important to identify the most appropriate method of diversion for an individual.