107

BLADDER CANCER
PHILIP W. KANTOFF, MD ANTHONY L. ZIETMAN, MD KENNETH WISHNOW, MD

Bladder cancer is the second most common malignancy affecting the genitourinary system. It is largely a preventable disease because most cases probably result from exposure to environmental carcinogens, the most important of which is cigarette smoke. Most tumors arising in the bladder are transitional cell carcinomas; other pathologies are far less common. Most tumors diagnosed in the United States are confined to the epithelial or transitional cell layer of the bladder and are easily treated by transurethral resection. These tumors generally are low grade and have low potential for metastatic spread. Tumors that are considered to be high grade and/or invade the deeper layers of the bladder wall have a much greater potential for metastatic spread. Such tumors can be cured if no evident or occult metastasis exists. The treatment of metastatic disease still is marginal, although recent improvements in therapy have been achieved, leading to a small fraction of patients (< 10%) who are long-term survivors and possibly cured. EPIDEMIOLOGY In 1999, there were 54,200 new cases of bladder cancer diagnosed in the United States, and approximately 12,100 people died of the disease.1 For reasons that are poorly understood but may relate in part to environmental exposures, in particular cigarette smoking, almost three times as many men as women are diagnosed with bladder cancer. The lifetime risk of developing bladder cancer is highest among white men, at 2.8%. The lifetime risks among black men, white women, and black women are 0.9, 1.0, and 0.6%, respectively. The incidence of bladder cancer has increased in all of these groups over the past 2 decades, rising most dramatically for black men (23%), although the mortality rate is falling in all groups.2 The increasing incidence of bladder cancer may result from an improved detection rate of the early stages of disease (i.e., superficial bladder cancer), whereas the decreasing mortality rate results either from a decrease in the incidence of invasive and metastatic forms of the disease and/or improvements in therapy. Cigarette smoking is widely accepted as a major risk factor for bladder cancer and probably accounts for 50% of bladder cancer cases diagnosed in the United States.35 There appears to be a relationship between the quantity of cigarettes smoked and risk, with moderate to heavy smokers demonstrating a three- to five-fold increased risk over nonsmokers. Smoking cessation reduces the risk within the first few years. Some studies, however, show a return to a risk level comparable to that of nonsmokers, but others show a persistently increased risk.68 Exposure to aromatic amines has long been known to increase the risk of bladder cancer. Rehn9 noted an increased risk in dyestuff workers, and Case and colleagues10 tied this risk to exposure to two aromatic amines, 2-naphthalamine and benzidine. Since then, numerous studies have supported a strong link between several other occupations wherein aromatic amines are present and the development of bladder cancer, including leather workers,11 rubber workers,12,13 painters,14 truck drivers,15 and aluminum workers.12 Phenacetin, which is an analgesic no longer used in most countries, is associated with a heightened risk for the development of bladder cancer.16 Thus far, no studies have linked acetaminophen, the commonly used analgesic, to bladder cancer. Long-term, chronic administration of cyclophosphamide has been associated with bladder cancer, but whether the cyclophosphamide must first induce a hemorrhagic cystitis for bladder cancer to occur is uncertain.1719 Schistosoma haematobium is believed to increase the risk of bladder cancer because the incidence is high in endemic areas.20 Most cancers believed to be attributable to S. haematobium infection are squamous cell carcinomas, but transitional cell carcinomas are seen as well.

Case reports support a familial predisposition for bladder cancer. Familial risk is especially apparent, however, among those with environmental exposures, such as cigarette smoking, thus suggesting genetic/environmental interaction. One possible component to genetic risk for bladder cancer is the so-called acetylator phenotype.2123 Because aromatic amines are detoxified by N-acetylation and the Nacetyltransferase enzyme is polymorphic, displaying two different phenotypes (slow and rapid acetylation), the allele that confers a slow acetylator phenotype is thought to be associated with an increased risk of bladder cancer. BIOLOGY Environmental factors likely play a major role in the development of most bladder cancers. Presumably, this is because the bladder epithelium is exposed to chemicals we ingest or their metabolites, often in high concentrations and sometimes for extended periods of time. The genetic events that characterize transformation are just beginning to be understood, and a range of genetic changes have been noted in tumors, depending on the methodology used and the tumors selected for analysis. Cytogenetic analysis of bladder tumors has demonstrated nonrandom changes in multiple chromosomes and chromosome segments. The most commonly seen abnormalities are monosomy 9 or 9q2, 17,1p- or 1q-, 5q-, 11p-, 6p- or 6q, and 17p-.2427 Abnormalities in chromosome 9 have been seen so commonly in all stages and grades of bladder cancer that some investigators believe a critical tumor-suppressor gene resides in this location and that its alteration is an early event in tumor progression.28 When alterations in chromosome 9 have been investigated using polymorphic microsatellite markers, two regions seem to be involved, one on 9p and the other on 9q. Orlow and colleagues29 found that Ta lesions were more frequently associated with 9q abnormalities and T1 with 9p changes, suggesting that 9p abnormalities are associated with a more aggressive phenotype. Fluorescent in situ hybridization studies of tumors support the range of chromosomal abnormalities seen in cytogenetic data.25 When molecular probes representative of the genome have been used, similar results have been obtained; in addition, several other abnormalities have been seen, including changes at 18q, 13q, 4q, and 3p.30 In two studies, 9q allelic loss was commonly seen in tumors, but allelic loss of 11p and 17p was more frequently seen in high-grade tumors, suggesting that 11p and 17p changes were events that more likely occurred later in carcinogenesis.25 Several candidate genes have been studied, most notably p53, which is located on chromosome segment 17p13.1. Several studies have demonstrated that mutations in p53 are common in bladder cancers.3133 Some studies also have suggested a critical role for p53 in tumor progression. Esrig and colleagues34 found that p53 nuclear accumulation in tumors, which is a correlate of mutated p53 species, predicted for relapse and impaired survival in patients who had undergone a cystectomy for bladder cancer. Other studies have confirmed the adverse effect of overexpressed p53 in bladder tumors.35 The impact of p53 overexpression on the efficacy of treatment has been looked at. In one study,36 tumors from patients with invasive bladder cancer who were enrolled in a randomized adjuvant chemotherapy trial were analyzed for p53 status. Interestingly, patients who had p53altered tumors benefitted from adjuvant chemotherapy, whereas those whose tumors were characterized by normal p53 did not benefit. These results need to be confirmed. Several studies have suggested a role for epidermal growth factor (EGF) and EGF receptor, the expression of both correlating with increasing grade and stage of tumor.37 The retinoblastoma (Rb) gene located on chromosome segment 13q14 is another tumor-suppressor gene that has been studied. Alterations in Rb are seen in less than 50% of cases analyzed, but early results indicate that inactivation is associated with disease progression. Larger, more definitive studies are awaited. The frequency of H-ras gene alterations in bladder cancer has been debated as well. In a recent study, 44% of urinary sediments from patients with active bladder tumors showed mutations by single-strand conformational polymorphism in the first exon of the H-ras gene.38 This study suggests a role for H-ras in early

1544 SECTION 30 / Neoplasms of the Genitourinary Tract

tumorigenesis. Expression of blood group antigens has long been an area of interest in bladder cancer,3951 and these antigens are believed to participate in a range of functions, including cell-cell interaction as well as cell growth and differentiation. Several studies also have correlated the loss of expression of these antigens on the surface of cells with likelihood of progression. Some studies52,53 have suggested that E-cadherin expression predicts clinical behavior in patients with bladder cancer. Decreased expression of E-cadherin, a cell adhesion molecule, is associated with advanced stage and poorer survival. These findings need to be confirmed in larger studies. Two unique aspects of bladder cancer are multifocality and polychronotropism. Although the mechanism by which these phenomena occur has been debated, the most commonly held theories include a genetic field defect or a reimplantation of tumor cells. Evidence strongly suggests that tumor reimplantation and/or submucosal migration are operative. In one study, multifocal tumors occurring in the same individuals demonstrated clonality when analyzed by X-chromosome inactivation.54 In another study, clonality was demonstrated between upper tract (i.e., ureteral and renal pelvic) and lower tract (i.e., bladder) tumors arising in the same individual. In addition to supporting the reimplantation model, these findings help to explain the high incidence of bladder tumors in patients previously diagnosed with upper tract tumors (20%) and the comparatively low incidence of upper tract tumors (2%) in patients with prior bladder tumors. Presumably, reimplantation of dislodged tumor cells can occur more readily in the direction of urine flow. PATHOLOGY Most cancers arising in the bladder are transitional cell carcinomas (TCCs). Some TCCs show a mixed pattern with squamous features or a glandular component.55a Less common pathologies are adenocarcinoma, squamous cell carcinoma, and small-cell carcinoma, which comprise approximately 6, 2, and less than 1% of bladder tumors, respectively. Metastases to the bladder are uncommon but usually are of colon, prostate, or female-reproductive-tract origin. Two different configurations of TCCs are seen, papillary and solid. Most tumors are papillary, and low grade and do not invade the muscularis propria of the bladder wall. Solid tumors typically are high grade and invasive. Tumor grading (typically grades I III) is based on the number of mitoses, presence of nuclear abnormalities, and cellular atypia. A significant correlation exists between grade and prognosis.56 DNA ploidy as determined by flow cytometry recently has been demonstrated to have prognostic significance.57,58 Tumor staging is based on the degree to which the tumor has invaded into or through the bladder wall. Prognosis correlates with stage. Carcinoma in situ (CIS) of the bladder is used to describe a flat, nonpapillary lesion with cytologic features that are consistent with a high-grade malignancy involving a portion of or the entire bladder epithelium. By definition, this lesion is confined to the epithelial layer, but in some patients, it has a high propensity to invade deeper layers. The affected mucosa is friable, granular, and red in appearance. SIGNS AND SYMPTOMS Hematuria and irritative symptoms are the most frequent presenting manifestations of bladder cancer. Gross hematuria, which is the presenting symptom in 80% of patients with bladder cancer, usually is painless, present through urination, and episodic.59,60 Severe bleeding causing clot retention occurs in one-sixth of patients. Twenty percent of patients experience bladder irritative symptoms, commonly urinary urgency, frequency, and dysuria, which may suggest CIS or muscle-invasive disease.61 Some patients are asymptomatic and usually diagnosed during evaluation for microscopic hematuria or, less frequently, pyuria. Failure to control the neoplastic process in the bladder (i.e., local control) can lead to significant bladder irritative symptoms, including stranguria (i.e., pain with straining to urinate), urinary retention, ureteral obstruction, sepsis, and life-threatening hematuria. Regional pelvic disease may cause severe pain because of nerve invasion, edema because of lymphatic obstruction, or ureteral obstruction. The signs

and symptoms of bone, liver, pulmonary, and central nervous system (CNS) metastases may be present during systemic disease dissemination. Although bladder cancer is lethal when metastatic, diagnostic tests are available that can identify early, curable lesions; however, screening for bladder cancer is still of uncertain value.62 Single dipstick determination for microscopic hematuria lacks the sensitivity and specificity worthy of a good screening test, but a prospective study using multiple home-dipstick testing yielded promising results, with a high percentage of lesions found being potentially curable.63 Larger studies are needed. Urinary cytology is more sensitive for high(5080%) than for low-grade lesions (20%). High-grade lesions are more likely to invade and metastasize and thus are more difficult to cure. Using decision analysis, Ellwein and Farrow64 predicted that screening by urine cytology would result in an average 3-year gain in life expectancy. Prospective trials have not been performed, however. DIAGNOSTIC EVALUATION CYSTOSCOPY Cystoscopy provides direct visualization of the bladder and, when necessary, facilitates biopsy of the bladder. This procedure can be performed on an outpatient basis with minimal patient discomfort using the 17-Fr flexible cystoscope and 2% xylocaine urethral jelly. During cystoscopy, the endoscopist notes the number, size, shape, and location of tumors as well as the appearance of the surrounding mucosa, urethra, and ureteral orifice. Visualized characteristics with predictive value include size (.2 cm or .5 cm), shape (papillary, sessile, or flat), and nature of the surrounding mucosa. URINARY CYTOLOGY Urinary cytology is less useful than cystoscopy for the diagnosis of most common, low-grade papillary tumors because the individual neoplastic cells comprising grade I TCC appear to be identical cytologically to normal urothelial cells. On the other hand, cytology is extremely valuable for the diagnosis of high-grade TCC especially CISthat may be difficult for the endoscopist to visualize. Urine cytology therefore should be used to complement the findings of cystoscopy.6567 The presence of high-grade TCC in the cytology specimen from a patient with low-grade papillary TCC suggests either unrecognized CIS or high-grade disease in the upper urinary tracts (ureter or renal pelvis) or urethra. Flow cytometry, quantitative fluorescence image analysis, monoclonal antibody immunocytology, quantification of nuclear roundness, nuclear/cytoplasmic ratio, fibrin degradation products, and measurement of nuclear matrix protein are additional diagnostic aids that generally are considered to be investigational but may have clinical usefulness in selected patients.68,69 IMAGING Although fewer than 60% of bladder tumors are seen on intravenous urography,70 this study is still necessary because it provides valuable information about the status of the upper urinary tracts. In patients with bladder cancer, the incidence of concomitant or subsequent upper tract tumors is 2 to 5%. The finding of ureteral obstruction or a nonfunctioning kidney in a patient with bladder cancer predicts muscle invasion in 90% of cases.71 Despite the fact that sophisticated computed tomographic (CT)7275 and magnetic resonance imaging scans7679 can provide dramatic visualization of the extent of disease in individual cases, these studies have not been completely reliable in evaluating the extent of local or regional disease. In addition, both generally tend to overestimate degree of extension through the bladder wall but underestimate the presence of pelvic lymph node metastasis. The need to evaluate patients for metastases depends on the outcome of the bladder evaluation. Most patients whose disease is superficial do not require an extensive metastatic work-up, with perhaps the exception of patients having high-grade tumors or CIS. Patients with tumors that invade the muscularis are at a much higher risk of dissemination and therefore should undergo an abdominal CT scan, chest radiography, and bone scan. TRANSURETHRAL RESECTION AND BLADDER BIOPSY Transurethral resection provides tissue for histopathologic diagnosis and staging and may provide definitive therapy for many superficial, as well as some invasive, cancers. Although biopsy of normal-appearing bladder mucosa at a distance from overt tumors is somewhat controversial,80 pathologic evidence of dysplasia (13.5%) and frank CIS (4.5%) may be found.81 When diffuse CIS is present, the prostatic urethra should

undergo biopsy because it may contain neoplastic cells in as many as 25% of patients.82 Additionally, the prostate may be a site of persistent disease after intravesical treatment. The presence of TCC in the prostate may occur by direct extension of tumor (T4) or as part of a generalized transformation of the transitional epithelium. In either case, it is important to document because it is ill advised to create a neobladder in such patients without doing a radical urethrectomy as urethral recurrences are high in such patients. Resection technique is an important but unstudied aspect of patient management. When muscle invasion is suspected, the resection must include sufficient muscle to provide adequate pathologic staging. An overly aggressive resection may lead to bladder perforation, however, and possible regional or distant disease dissemination. Conversely, an inadequate resection will lead to tumor persistence and regrowth. As previously mentioned, recent studies highlight the possible importance of tumor implantation as a cause of tumor recurrence. BIMANUAL EXAMINATION For years, the assessment of disease extent has been based on bimanual palpation of the bladder during anesthesia. By convention, the presence of palpable disease after complete transurethral resection indicates muscle invasion, either within or through the bladder wall. Unfortunately, most invasive cancers are located near the trigone or posterior bladder wall, which cannot reliably be palpated well even under anesthesia, so this crude and inexact technique leads to understaging in 50% of patients. STAGING The classic clinicopathologic studies by Jewett and Strong in 194583 and Jewett in 195284 correlate the probability of regional lymph node and distant metastases with the depth of tumor penetration into and through the muscular wall of the bladder. With slight modifications, these studies form the basis of the current major staging systems (Fig. 107.1 and Table 107.1). Despite their fundamental value, however, these staging systems have several shortcomings: (a) clinical staging underestimates disease extent (judged by pathologic staging) in up to 50% of cases, (b) the importance of vessel invasion (vascular and lymphatic) as an independent prognostic variable is ignored, (c) the danger of high-grade superficial bladder cancer (in which the lamina propria) is invaded (but there is no muscle invasion) is underrated, and (d) there is no mention of a separate, important disease category diffuse CIS of the bladder with associated CIS or invasive disease in the prostate. The 1997 AJCC clinical staging system is a compromise between clinical and pathologic staging systems. Although it finetunes

CHAPTER 107 / Bladder Cancer 1545

the prior AJCC system, it requires fractionated transurethral resection of bladder tumors (TURBT) or a cysrectomy to differentiate the T2 substages and a cystectomy to distinguish T2 from T3a. This may lead to inconsistencies in reporting and may create problems when comparing outcome of patients managed by cystectomy with those managed by an organ-sparing approach. SUPERFICIAL BLADDER CARCINOMA NATURAL HISTORY Superficial bladder carcinoma includes a diverse group of lesions, ranging from Ta grade I to T1 grade III tumors and low-grade papillary TCC to high-grade flat CIS.85,86 Although it is crucial to distinguish the small group of lesions that carry a serious risk of progression to life-threatening muscle invasion, the vast majority of superficial tumors rarely progress. Rather, they have a significant tendency to recur at multiple sites throughout the urothelium (Fig. 107.2). The natural history of superficial bladder carcinoma was evaluated in a longitudinal, multi-institutional prospective study reported by the National Bladder Cancer Group in 1983.87 The rate of progression to muscle invasion or metastasis was 2% for grade I, 11% for grade II, and 45% for grade III tumors in 207 patients analyzed for a median of 39 months. Only 4% of Ta tumors progressed, compared with 30% of T1 tumors (Table 107.2). When moderate to severe dysplasia was present elsewhere in the bladder, 33% progressed, compared with 8% when there were no associated mucosal abnormalities. Thirty-five percent of tumors greater than 5 cm progressed, compared with 9% when tumors were smaller than 5 cm. The progression rate was 2% for Ta grade I tumors, compared with 48% for grade III T1 tumors. In a large series of patients with low-grade, low-stage tumors reported by Fitzpatrick and colleagues,88 disease progression as defined by a change from grade I or II to grade III was noted in only two (0.25%), whereas changes in stage from Ta to pT1 (upstaging) occurred in 11 (1.25%) and to T1 (muscle invasion) in less than 5%. Malmstrom and colleagues89 found that T1 tumors were at a significantly higher risk of upstaging than Ta tumors at cystectomy. Anderstrom and colleagues90 reported that the 5-year survival in 99 patients with T1 tumors was 83% if the grade was II and 63% if III; 7 of 10 patients in whom small-vessel invasion (either lymphatic or vascular) was present in the lamina propria died. These studies have significantly improved our ability to predict the risk of death from superficial bladder carcinoma. Whereas the risk

Figure 107.1. TNM staging classification for bladder neoplasms. American classification (Jewett-Marshall) is shown for comparison. Tumors T1 (A) are considered superficial, with tumors T2 (B) or greater being invasive.

1546 SECTION 30 / Neoplasms of the Genitourinary Tract

Table 107.1. AJC Clinical Staging

TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Ta Noninvasive papillary carcinoma Tis Carcinoma in situ: flat tumor T1 Tumor invades subepithelial connective tissue T2 Tumor invades muscle T2a Tumor invades superficial muscle (inner half) T2b Tumor invades deep muscle (outer half) T3 Tumor invades perivesical tissue T3a microscopically T3b macroscopically (extravesical mass) T4 Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumor invades prostate, uterus, vagina T4b Tumor invades pelvic wall, abdominal wall N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension N2 Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node more than 5 cm in greatest dimension Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis STAGE GROUPING Stage 0a Stage 0is Stage I Stage II Stage III Ta Tis T1 T2a T2b T3a T3b T4a T4b Any T Any T Any T Any T N0 N0 N0 N0 N0 N0 N0 N0 N0 N1 N2 N3 Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

Figure 107.2. Decision tree for suspected bladder cancer. CIS = carcinoma in situ; IVP = intravenous pyelography.

Stage IV

is extremely low for the vast majority of low-grade, low-stage tumors, it is higher for grade III T1 lesions,91 especially when vessel invasion is present. The risk is intermediate for low-grade, low-stage tumors when there are associated mucosal abnormalities, including moderate to severe dysplasia or diffuse CIS. Recurrence is a more common problem than progression. In the National Bladder Cancer Group study,56 the recurrence rate at 1 year was 30% for grade I, 28% for grade II, and 70% for grade III tumors. At 3 years, it was 50% for grade I, 59% for grade II, and 80% for grade III. At 3 years, the recurrence rate was 48% for Ta tumors, compared with 70% for T1 tumors. Recurrence rates increased when there were associated mucosal abnormalities, positive cytology, four or more tumors, and tumors larger than 5 cm in maximum diameter.87 CARCINOMA IN SITU Defined as noninvasive, high-grade, flat cancer confined to the epithelium, CIS may be localized or diffuse, and it may occur in association with low-stage or muscle invasive TCC. It is recognized endoscopically as a friable red area indistinguishable from inflammation. CIS spreads laterally, displacing normal epithelium. Urine cytology is positive in 90% of patients because of a loss in the cohesiveness of cells. The diffuse nature of the disease was first documented by Melicow; he reported that the entire bladder was involved in 71% of cases, with associated distal ureteral and bladder neck carcinoma in 57% and urethral involvement in 62%.92,93 In a subsequent study of patients undergoing radical cystectomy for CIS,94 34% were found to have previously undiagnosed microscopic invasion, and

although pelvic lymph nodes were uninvolved in all patients at the time of cystectomy, 6% died of metastasis within 5 years. The behavior of CIS is highly variable. The likelihood of progression to muscleinvasive bladder cancer depends on the extent to which the mucosa is involved with CIS. With transurethral surgery as sole treatment, most patients with CIS demonstrate muscle invasion by 10 years. Most patients achieve durable complete responses to intravesical therapy, in particular, bacillus Calmette-Gurin (BCG). A proportion of patients who are resistant to therapy require cystectomy. INTRAVESICAL THERAPY The basis for intravesical therapy is the high therapeutic ratio that can be achieved with this approach. Agents can be administered directly into the bladder, thus exposing the mucosa to high concentrations of drugs with little systemic absorption. Intravesical therapy has been used for two general purposes: therapeutically, using the drugs to diminish or eradicate residual tumor in the bladder following resection, and prophylactically, using drugs to prevent or delay recurrence or progression. The exact indications for intravesical therapy as prophylaxis remains controversial. Prophylaxis has been widely used, however, in patients who demonstrate multiple primary tumors, multiple recurrences, high-grade tumor, T1 tumor, positive urinary cytology post resection, and diffuse CIS.95 Controlled studies have demonstrated that four cytotoxic chemotherapeutic agentsthiotepa,96100 doxorubicin (Adriamycin),98,101103 mitomycin C (Mutamycin), and ethoglucid97,103106 (Epodyl, not commercially available in the United States)have activity. An analysis from studies involving 1,582 patients with residual tumor after resection revealed that reduction in the size of residual tumor is seen in 29% of
Table 107.2. Stage and Grade as Predictors of Percent Progression of Superficial Bladder Cancer
Grade Stage

I 2 0

II 6 21

III 25 48

Ta T1
From Heney and colleagues.87

patients with thiotepa, 38% with doxorubicin, and 47% with mitomycin.107 Complete and durable responses are rare. Numerous studies addressed the issue of recurrence after resection, but few studies have addressed the issue of progression. Studies involving 3,000 patients have documented a reduction in short-term recurrence rates of 16 to 18% (Table 107.3). Unfortunately, however, conclusive documentation of reduction in long-term recurrence rates and, more importantly, disease progression have not been shown for intravesical chemotherapy.95 Intravesical immunotherapy using BCG has been effective in reducing recurrence rates and treating residual papillary TCC and, most significantly, for treating CIS.108 A review of five major series shows that the relative benefit of BCG was 45% in preventing tumor recurrence in 456 patients.109113 Moreover, the benefits of BCG immunotherapy appear to be durable. For example, in a long-term prospective study comparing doxorubicin with BCG reported by the Southwest Oncology Group,114 only 17% of doxorubicin-treated patients were disease-free at 5 years, compared with 37% in the BCG-treated group. Similarly, BCG is effective for treating residual papillary disease, with an average 55% response rate in major published series.115 Perhaps the most important use of BCG has been in the treatment of CIS. The average complete response rate was 73% in 663 patients with this disease treated in 15 studies.115,116 Again, the response appears to be durable. In the Southwest Oncology Group study comparing BCG with doxorubicin for CIS, 45% of the BCG-treated patients were disease-free at 5 years, compared with 18% of the doxorubicin-treated patients (Tables 107.4 and 107.5). Treatment with BCG also may reduce the risk of tumor progression. In a prospective, randomized study of patients at high risk for progression (i.e., those with CIS or high-grade superficial TCC) from Memorial Sloan-Kettering Cancer Center,117 a statistically significant reduction in disease progression was found. In addition, there was a statistically significant improvement in overall survival for the BCGtreated group. These data have recently been updated,118 and considTable 107.3. Effect of Intravesical Chemotherapy on Recurrence in Controlled Studies
Recurrence (%) Series Patients (n) Control Treatment Benefit (%) P

CHAPTER 107 / Bladder Cancer 1547

Table 107.4. Effect of BCG versus Surgery Alone in Controlled Studies
Percent Recurrence Series Patients (n) Control BCG Advantage with BCG (%)

Lamm Herr (1985) Herr (CIS) (1986) Pagano et al. Rbben et al.

57 86 49 98 77

52 95 100 83 42

20 42 35 15 35

32 53 65 68 7

< .001 < .001 < .001 < .001 NS

BCG = bacillus Calmette-Gurin; NS = not significant.

Thiotepa Burnand et al. 51 Byar & Blackard 88 Nocks et al. 42 Asahi et al. 1?6 Schulman et al. (1980) 1?? Pavone-Macaluso (1980) 94 Koontz et al. 93 Zincke et al. 58 Prout et al. 90 MRC 243 Totals 1,009 Mitomycin C Huland & Otto Niijima et al. Kim & Lee Tolley et al. Rbben et al. Totals Doxorubicin Niijima et al. Zincke et al. Kurth et al. Rbben et al. Totals Epodyl Kurth et al. Overall Totals 58 278 43 397 83 859 288 59 155 220 722 209 2,799

97 60 64 37 52 60 66 71 76 32 62 40 46 68 65 42 52 45 71 48 61 56 59 58

58 47 65 37 49 23 40 30 64 37 45 7 37 67 42 35 37 30 32 35 56 38 28 41

39 13 -1 0 3 37 26 41 12 -5

.001 .016 NS NS NS .01 .02 .002 .05 NS 17% Adv .01 NS NS .001 NS 15% Adv .05 .01 NS NS 18% Adv .0004 17% Adv

erable literature attempts to describe the optimal dosage schedules and treatment regimens for intravesical BCG. A standard regimen is weekly treatments for 6 weeks followed by cystoscopy 6 weeks after the last treatment. Persistence of tumor may be treated with another 6week course of BCG. The value of monthly maintenance therapy for 1 year or longer is debated. Approximately 5% of patients treated with BCG experience serious toxicity, including septic reactions, fever, hypertension, disseminated intravascular coagulation, and multisystem failure; hypersensitivity may contribute to this toxicity. Isoniazid (330 mg), rifampin (600 mg), and prednisone (40 mg daily) are currently recommended for the treatment of suspected systemic infection (so-called BCGosis).119 Intravesical recombinant human interferon-a2b was evaluated in 10 heavily pretreated patients with papillary and in situ TCC. Clear responses were noted in 4 of 16 patients with papillary TCC and 9 of 19 patients with CIS at doses of 50 to 1 million units given weekly for 8 weeks.120 In a randomized study of 87 patients with CIS treated with interferon-alpha2b weekly for 12 weeks followed by monthly instillations for 1 year,121 40% of patients had a complete response. Interestingly, 6 of 9 patients who were previously treated with BCG responded. Photodynamic therapy is effective in treating patients with papillary TCC and CIS. It also has prevented recurrence in some patients who have failed conventional intravesical treatment.122,123 Response rates of 70 to 95% have been reported in some series, but complete tumor ablation is generally limited to tumors less than 2 cm in diameter. Studies in Europe suggest that the highly antigenic respiratory pigment of the mollusk Megathura crenulta (Keyhole Limpet Hemocyanin) may have activity in preventing bladder cancer recurrence. Other immunologically active agents that have been used include intralesional and intravesical interleukin-2 (IL-2), maltose tetrapalmitate(OK-432), lyophized attenuated streptococcus vaccine, and the interferon-inducer Poly C: Brobriprimine.124

Table 107.5.
Series

BCG Therapy for Carcinoma in Situ

Patients (n) Complete Response (%)

33 9 1 23 7

15 39 13 5

31

Herr (1983) Morales (1984) Lamm (1985) Brosman (1984) DeKernion (1985) Herr (1986) Schellhammer (1986) Catalona (1986) Badalament (1987) Herr (1989) Lamm (1989) Reitsma (1989) Brosman (1989) Steg (1989) Dejager (1990) Totals
BCG = bacillus Calmette-Gurin.

23 26 43 33 19 47 28 19 33 111 52 119 48 54 123 676

17 (74) 20 (77) 35 (81) 31 (94) 15 (79) 34 (72) 20 (71) 13 (68) 22 (67) 76 (68) 37 (71) 78 (66) 34 (71) 43 (80) 90 (73) 488 (72)

Adv = advantage; NS = not significant.

1548 SECTION 30 / Neoplasms of the Genitourinary Tract

In an unfortunate subset of patients, superficial bladder cancer is an aggressive, life-threatening condition. Patients who are most at risk are those with grade III T1 tumors, particularly when there is vessel invasion, multifocal CIS with prostatic involvement, and multifocal CIS that has failed two full courses of intravesical BCG.117 In these cases, prompt, radical cystectomy or cystoprostatectomy may be necessary. MUSCLE-INVASIVE BLADDER CANCER RADICAL CYSTECTOMY Radical cystectomy is regarded as the standard approach to the treatment of invasive bladder cancer in the United States. This involves the removal of regional pelvic lymph nodes followed by an en-bloc resection of the bladder, prostate, and seminal vesicles in men or, in women, an anterior exenteration in which the bladder is removed along with the ovaries, uterus, urethra, and a segment of the anterior wall of the vagina. The mortality rate is under 5% in modern series, with the expectation of local control in the pelvis of over 90%. The major determinant of outcome is the presence or absence of lymph node or occult distant metastasis at the time of surgery. The best correlate of outcome is pathologic stage (Table 107.6). Improvements in outcome over the past 50 years can be ascribed to better patient selection, improved surgical technique, and, possibly, adjuvant therapies. In 1946, Jewett and Strong83 correlated the relationship between depth of cancer and penetration through the bladder wall with the incidence of pelvic lymph node metastases in 107 autopsy cases of primary bladder cancer. The incidence of nodal metastases was 0% for stage A, 13% for stage B, and 74% for stage C. In a subsequent clinical study of 80 patients, Jewett84 reported a 5-year survival rate of 74% for stage B1, compared with 3% for stages B2 and C. In that era, prognosis was extremely poor when tumor penetrated through the bladder wall and invaded the perivesical fat (P3b) and adjacent structures such as the prostate, vagina, cervix, or uterus (P4), or was metastatic to regional pelvic lymph nodes (N1). In 1962, Whitmore and Marshall124126 reported 5- and 10-year survival rates of 17 and 5.6%, respectively, for 42 patients with stage P3b treated by radical cystectomy and 0% in 9 patients with P4a. Only 4% of 46 patients with nodal involvement were alive at 5 years. During this period, the local recurrence rates were high (up to 30%), as were perioperative morbidity and mortality. During the next 20 years, preoperative radiation therapy was routinely combined with radical cystectomy (i.e., integrated therapy). Observed survival rates for muscle-invasive disease improved to 50%, with local recurrence rates decreasing to 10 to 15% and perioperative morbidity and mortality decreasing markedly as well. Survival rates for patients with P3b and P4a, as well as N1, remained extremely low, however. In the past 10 years, several reports have shown more optimistic data in selected patients treated by radical cystectomy with or without radiation or perioperative chemotherapy.127 In 1991, Pagano and colleagues128 reported 5-year actuarial survival rates of 68 and 67% for stages P2 and P3a cancers, respectively, when the nodes were negative. In highly selected patients who were treated with and without adjuvant chemotherapy at the University of Texas M.D. Anderson Cancer Center (UTMDACC), survival rates were 75 to 85% for stage B, 60% for

Table 107.6. Survival

Relationship Between Pathologic Stage and Percent 5-Year

Stage

Series

Patients (n)

P2

P3A

P3B

Whitmore Montie Skinner Mathur Pagano Totals

137 99 197 58 261 752

60 62 83 88 63 69

26 74 69 57 50 54

11 57 29 40 15 25

stage C, and 50% in patients with low-volume pelvic lymph nodes with metastases.129 Similarly, Skinner and colleagues130 reported 5year survival rates of 55% in 155 patients with P3b and P4 disease, as well as 29% in 132 patients with N1 in 1992. These results were accompanied by marked decrease in the rate of local recurrence (8%) and perioperative mortality (2%). Although it is tempting to ascribe these dramatic improvements in survival data to specific changes in treatment such as use of adjuvant chemotherapy or radiation, careful evaluation of these nonrandomized series leads to the conclusion that improvements in outcome have resulted from dramatic changes in patient selection factors, pathologic stage migration (pathologic analysis of cystectomy specimens), and improvements in both surgical technique and perioperative care. Nonetheless, it is important to emphasize that the prognosis of very highly selected patients with invasive bladder cancer, stage for stage, has significantly improved from the classic results reported 30 years ago. URINARY DIVERSIONS One of the true advances in the treatment of patients with bladder cancer has been the development of improved methods of urinary diversion. Undoubtedly, this has resulted in enhanced quality of life for patients. Pawlik is generally credited with the first urinary diversion procedure in 1889, when he implanted the ureter into the vagina of a woman who survived 16 years after the procedure. The ileal conduit form was popularized by Bricker131 in the early 1950s and rapidly became the classic, standard form of supravesical urinary diversion. It provided a relatively safe, long-term form of diversion in which the urine constantly drained through a conduit of ileum leading to the skin and into a bag. New techniques for performing urinary diversion have been developed over the past 15 years: (a) formation of a urinary reservoir made of small bowel, which drains to a stoma that can be catheterized;132 or (b) creation of an orthotopic bladder (neobladder)133,134 in which a newly formed urinary reservoir made of bowel is anastomosed to the urethra, which permits the patient to void in a relatively normal fashion. These two approaches are used in selected patients for whom quality-of-life considerations are critical and the increased operative time will not increase morbidity or operative mortality. At present, orthotopic urinary diversion can be performed successfully only in men. The neobladder can actually be constructed out of small or large bowel or some combination of the two. It functions as a very rough equivalent to the patients normal bladder. Patients in whom this procedure is performed do have a somewhat higher incidence of infection, electrolyte abnormalities, and minor to troublesome incontinence. Early results suggest, however, that the frequency of long-term renal damage and morbidity is not prohibitive. Addition of these new forms of urinary diversion to the surgical armamentarium has dramatically altered the functional and psychological aspects of urinary diversion. Recent attempts at preserving sexual function in men by sparing the nerves controlling erectile function at the time of cystectomy have not been evaluated in a prospective fashion. PREOPERATIVE RADIATION THERAPY The recognition that moderate-dose radiation (2050 Gy) may reduce the volume of gross disease and eradicate microscopic TCC led to its frequent administration before cystectomy in the 1970s. In nonrandomized studies, these doses were found to reduce the frequency of metastases in the lymphadenectomy specimens by approximately 50%.135 By the 1980s, improvements in the technique of radical cystectomy, together with the introduction of more extensive therapeutic lymphadenectomies, made many question the need for radiation.136 It has been argued that radiation delays the time to definitive surgery, increases its morbidity, and may compromise the surgeons ability to perform continent urinary diversions. Furthermore, a number of randomized trials performed in the 1970s failed to show any survival advantage with preoperative radiation therapy. These studies were limited in value, however, because of their small size and the inclusion of patients with T2 disease, who have a low probability of extravesical tumor, and T4 disease, who did not stand to benefit from additional local therapy because of an extremely high probability of distant metastases. Parsons and Million137 demonstrated an apparent survival advantage of preoperative radiotherapy for the T3 subgroup by pooling all studies in the literature. The UTMDACC experience of 133 patients with T3b has also been reported.138 This retrospective review from the UTMDACC has

documented that when pelvic wall recurrence occurs following modern radical cystectomy, it is usually only in patients with clinical stage T3b or T4 tumors. They report a 28% incidence of pelvic recurrence in stage T3b patients treated by radical cystectomy, with or without multidrug chemotherapy. However, when stage T3b patients were treated with preoperative radiation therapy (which this institution used extensively prior to 1980), the pelvic recurrence rate was only 10%. Before 1983, all patients underwent 50-Gy preoperative irradiation, followed 4 weeks later by cystectomy. Actuarial 5-year pelvic control was 91%. After 1983, radiation was discontinued, and subsequent pelvic control rates have fallen to 73% despite improvements in surgical technique, staging, and the addition of systemic chemotherapy. A survival decrement (5242%) was also seen. The extent to which patient-selection factors contributed to this observed difference is unknown. Others have reported lower rates of pelvic recurrence using cystectomy alone for this subset of patients, and it therefore remains uncertain whether these findings are widely applicable.136 The morbidity of preoperative irradiation is small. Whitmore135 reported comparable rates of wound healing and perioperative mortality for patients who received and those who did not receive irradiation before cystectomy. There is limited experience in the creation of continent urinary diversions after preoperative irradiation, although Housset and colleagues139 report that it is possible after the delivery of 44 Gy. Preoperative low-dose irradiation may diminish the propensity for TCCs to implant within the bladder during cystotomy or in the wound at the time of cystectomy. Van der Werf-Messing140 routinely used 10.5 Gy in three fractions before partial cystectomy, which is a regimen with essentially no morbidity still used occasionally in this setting today. POSTOPERATIVE RADIATION THERAPY When the cystectomy specimen shows extensive extravesical disease and positive surgical margins, the risk for pelvic recurrence is high. Postoperative radiation therapy has been evaluated in only one randomized study. The National Cancer Institute of Egypt141 reported on 236 patients with T3-4 tumors (68% squamous cell) who received either no adjuvant therapy or postoperative radiation. The incidence of pelvic recurrence was significantly reduced in the latter group (50 vs 10%). Whether this finding is as applicable to transitional as to squamous cell tumors remains an unanswered question. Today, patients with such extensive disease commonly receive adjuvant chemotherapy, although the ability of this modality to prevent local recurrence has been called into question by Cole and colleagues138 Radiation rarely cures patients with pelvic wall recurrences following radical cystectomy.141142 Perhaps some patients will be cured if given adjuvant radiotherapy. The morbidity of postoperative irradiation is high because of the large volumes of small bowel that occupy the pelvis after cystectomy. Two series reported a greater than 30% incidence of small-bowel obstruction when 50 Gy was delivered using conventional fractionation.137 If radiation is envisaged as an accompaniment to cystectomy for advanced disease, it appears to be safer if delivered preoperatively.

CHAPTER 107 / Bladder Cancer 1549

BLADDER PRESERVATION Partial Cystectomy. Proper patient selection is crucial for a successful partial or segmental cystectomy. Review of the literature reveals that partial cystectomy was considered to be suitable only for 5.8 to 18.9% of patients with apparently localized invasive bladder cancers.142 The indications for allowing partial cystectomy are solitary, primary, muscle-invasive cancers that are located in a suitable region of the bladder that allows for complete excision with a 2-cm tumor-free margin. There should be no associated atypia or CIS in the remaining bladder urothelium, proven by biopsy. Patients with tumor near the bladder neck or trigone in whom ureteral reimplantation would be required to achieve an adequate surgical margin are generally not considered to be good candidates. Local recurrence rates of 38 to 78% have been reported, with one half of recurrences appearing in the first year and two-thirds by 2 years. Fiveyear survival rates are 75 to 100% for grade 1 tumors, 46 to 75% for grade 2, and 22 to 55% for grade 3. Five-year reports of survival rates are 100% for stage Ta, 58 to 80% for T1, 29 to 80% for T2, 14 to 62% for T3a, 0 to 33% for T3b, and 0 to 20% for T4 (Table 107.7).143147 Although partial cystectomy is appropriate only for a relatively small subset of patients with invasive bladder cancer, survival rates for rigidly selected patients should approach those reported for radical cystectomy (Table 107.7). Moreover, in elderly, debilitated patients for whom radical cystectomy is not a viable treatment option, partial cystectomy may be the only feasible alternative. Radical Radiation Therapy. Many large series have used radical radiation therapy as the sole treatment modality.148154 An initial clinical complete response usually is achieved in 40 to 50% of cases (Table 107.8). The commonly employed strategy is one in which those who do not respond completely require salvage surgery or, if unfit, palliative measures.149 Of those who achieve a clinical complete remission, one-quarter to one-third will subsequently experience a local failure. Ultimately, only 30% of patients maintain a tumor-free bladder after radical radiation therapy alone. Several series have shown that prior transurethral resections of gross tumor may improve these rates, and this is a recommended feature in most modern protocols in which bladder preservation is the goal.155-158 The likelihood of durable local control with radiation therapy alone is determined by multiple tumor factors, of which size, stage, morphology, and the presence of factors such as ureteral obstruction and coexistent CIS have been found most consistently.153,155,156 The chance of tumor eradication may be as high as 66% for those with solitary T2 tumors or as low as 9% for those with multiple tumors and a hydronephrosis.153 One recent report has shown actuarial local control rates of 56% at 2 years using accelerated fractionation (1.82.0 Gy daily) to a total dose of 54 to 64 Gy. This regime currently is being tested against standard treatment (i.e., 64 Gy in 32 fractions) in a phase III study in the United Kingdom.159

Table 107.7.

Survival Rates by Stage After Partial Cystectomy

5-Year Survival (%) 10-Year Survival (%) T3 T4 Overall T0 T1 T2 T3 T54 Overall

Series

T0

T1

T2

Magri (1962) Long et al. (1962) 80 Resnick & OConnor (1978) 75 Ultz et al. (1973) Evans & Texter (1975) Novick & Stewart (1976) Brannan et al. (1978) 100 Cummings et al. (1978) Schoberg et al. (1979) 69 Faysal & Frieha (1979) 75 Merrell et al. (1979) 100 Lindahl et al. (1984) Kaneti (1986)

80 67 71 68 69 67 69 79 69 58 100 59 68

38 43 77 47 43 53 54 80 29 29 67 38 40

26.0 9.0 12.5 29.0 14.0 20.0 33.0 6.0 12.0 7.0 25.0 33.0

0 0 20 0 0 0 100 0 0 0

42 35 39 0 46 57 60 43 40 48 42 48

21

67 31 37 15 100 48

44 36 0 13 33 25

11.1 0.0 7.0 0.0

0 0 0 0

21 36 32 12 9 32 38

1550 SECTION 30 / Neoplasms of the Genitourinary Tract

Table 107.8. Alone
Series

Complete Responses After Radical Radiation Therapy

Stage Patients (n) CR (%)

London (1980) Inst. Urology (1982) Yorkshire (1983) Edinburgh (1986) London (1988) PMH (1989) Norway (1991) Australia (1995)
CR = complete response.

cT2-4 cT3 cT3 cT3 cT2-3 cT2-4 cT2-4 cT1-4

614 81 55 272 182 121 146 342

28 40 51 41 52 46 44 68

Two randomized studies compared cystectomy (with preoperative radiation therapy) with radical radiation therapy (with cystectomy reserved for salvage). The first, reported by Bloom and colleagues150 in 1982, involved 189 patients, all of whom were eligible for analysis of 5-year results. Survival at 5 years was 38% with preoperative radiation plus cystectomy arm versus 29% for radiation with salvage surgery. This difference was not statistically significant, however. A significant advantage for early cystectomy was seen only in patients under 60 years of age. The Danish Bladder Cancer Group160 also found no overall survival difference between the two arms in a comparable trial with median follow-up of 50 months. Although 27 of 95 patients randomized to receive radical irradiation underwent salvage cystectomy for recurrent tumor, the incidence of metastatic disease was similar in both groups (34 and 32%, respectively). This suggests that the persistence of local tumor in patients who were not randomized to planned cystectomy did not contribute to an increased risk of metastases when early salvage cystectomy was performed. The comparable survival between the two arms of these trials has encouraged use of radiation as first-line management of bladder cancer in much of Europe. Only those who prove a need for it by the persistence of tumor undergo cystectomy, thus allowing preservation of the bladder in the remainder. In a separate quality-of-life analysis,161 the Danish Bladder Cancer Study Group found that those patients randomized to preoperative irradiation and cystectomy reported the largest reduction in their social and sexual activities 18 to 24 months after treatment. Primarily, this was because all of those undergoing planned cystectomy voided via a urostomy and 100% of men in this arm became impotent. The recent popularity of continent diversions and use of nerve-sparing techniques may be expected to narrow this difference.131133 Lynch and colleagues162 illustrated the good quality of life that can be anticipated in patients who remain disease-free following irradiation. They compared the bladder and rectal function of 69 Royal London Hospital patients who had a complete response following radical irradiation (60 Gy in 30 fractions) with an age-matched group of controls who had no known bladder or bowel disease and had never had pelvic irradiation. No significant differences were found. Chemoradiation. The rationale behind combining chemotherapy with radiation therapy is two-fold. First, certain cytotoxic agents, in particular cisplatin and 5-fluorouracil (5-FU), are capable of sensitizing tumor tissue to radiation, thus increasing cell kill in a synergistic fashion.163165 This action enhances both primary tumor control and prospects for bladder preservation. Second, patients with muscleinvading TCC harbor occult metastases in approximately 50% of cases. Thus, treatment of the primary tumor with radical resection or radiation alone ignores the systemic nature of the disease. Chemotherapy, either in an adjuvant or neoadjuvant fashion, addresses this concern early in treatment. Many phase II studies employing a range of drugs with a variety of radiation doses in differing sequences have been published (Table 107.9).166183 Overall, there is a clear increase in the complete response rate compared with series employing radiation therapy alone. Four randomized studies have compared radiation alone with a combination of chemotherapy and radiation,178,179,184,185 and all used chemotherapy

regimens that (as we know now) have limited activity against micrometastatic bladder cancer: single-agent methotrexate, single-agent cisplatin, or doxorubicin with 5-FU. No survival advantage was seen with combination therapy in these studies. In only one of the two trials employing single-agent cisplatin, however, was the drug given at the same time as the radiation for a sensitizing effect;178 this trial alone showed a significant local control advantage for chemoradiation. More recently, the case for a multimodality approach to bladder sparing has been strengthened by four studies from groups at the University of Erlangen186 and ISSA, University of Paris,139 Massachusetts General Hospital (MGH),158 and the Radiation Therapy Oncology Group (RTOG).172 Three employed aggressive transurethral resection with radiation and cisplatin-based chemotherapy, and three also employed selection by initial tumor response. All reported overall survival figs. of 45 to 64% at 3 to 5 years. This approach has not yet been compared in a randomized fashion, but these figures are as good as any of the modern, radical cystectomy series, despite a bias in favor of cystectomy that results from reporting by pathologic stage. This has been further highlighted by the recent publication of a meticulously detailed, randomized study in which 122 patients underwent radical cystectomy between 1984 and 1989, with 50% of patients receiving neoadjuvant cisplatin.180 These results were reported by clinical stage and therefore may be easier to compare with bladder-conserving strategies. The 5-year survival rate of 41% (only 48% for cT2) is inferior to the results of modern bladder-preserving strategies, although, conceivably, patient selection factors are operative. A critical element of these four bladder-conserving programs is their recognition that patients at high risk for local failure can be identified early and cystectomy promptly performed. Cystoscopies were carried out 4 to 8 weeks following completion of chemoradiation, and any patient with persistent, invasive tumor was referred for salvage cystectomy before local regrowth (and a second chance for metastasis) could occur. In the MGH and RTOG studies, re-evaluation was performed after only 40 Gy of radiation. In the absence of a complete response, cystectomy is then recommended before the bladder has received radical doses. The Parisian combined-modality program reported by Houssett and colleagues139,174 first used concomitant cisplatin, 5-FU, and radiation before radical surgery. The first 18 complete responders underwent cystectomy as planned, but no histologic evidence of residual tumor was found in any of the bladder specimens. Following this evidence of tumor eradication, the program philosophy changed to one of bladder conservation. In this series, 74% have had complete responses, and only 10% subsequently have failed within the preserved bladder. In the MGH, RTOG, and Erlangen studies, the complete response rates at cystoscopic rebiopsy were 58 to 80%. Of those who had complete responses, 83 to 89% remained free from invasive recurrence. Some patients develop subsequent superficial disease following a bladder-sparing approach, but they are still amenable to standard management with transurethral resections and intravesical agents. Kachnic and colleagues175 reported that 15 of 21 patients who developed CIS following chemoradiation have been maintained in remission using BCG with 13 to 97 months of follow-up. Bladder morbidity for patients receiving chemoradiation after TURBT appears to be comparable with those reports of patients treated by radiation alone. In the Erlangen series, only three cystectomies were necessary for bladder shrinkage among 192 preserved bladders (1.6%).172 At the MGH, no cystectomies for shrinkage were required, and a recent quality-of-life study in which patients evaluated their bladder, bowel, and sexual function demonstrated good
Table 107.9.
Series Stage N Treatment Sequence CR

RTOG Erlangen 1998155A MGH 1997170A Paris 1997136A

1998175A

T2-4 T1-4 T2-4 T2-4

123 205 106 120

RT + C + MCV RT + C* RT + C MCV RT + C/5FU

CONC NEO CONC CONC NEO CONC

66 80 70 77

*Cisplatin or carboplatin.

Table 107.10. Overall 5-year Survival and Bladder Preservation: Modern Series (19971998)
Survival (%) CR (%) Tumor-free Bladders (%)

CHAPTER 107 / Bladder Cancer 1551

Series

Treatment

RTOG 1993 RTOG 1998175A MGH 1997170A Paris 1997136A Erlangen155A

48 123 106 120 205

RT + C RT + C + MCV RT + C + MCV RT + C/5FU RT + C*

64 49 52 63 53

66 66 70 77 80

73 78 82 79

*Cisplatin or carboplatin. For cisplatin, CR was 85% vs 70% for carboplatin. At 3 years.

results.181 The Parisian group used less conventional radiation fractionation but still saw no late bladder problems.139 Furthermore, they were able to create continent diversions in the few patients who recurred locally, requiring salvage cystectomy. Results thus far with chemoradiotherapy are extremely encouraging (Table 107.10). Bladder preservation can be achieved in most patients with T2 and T3a tumors, although the relative contribution to bladder preservation afforded by either chemotherapy or radiotherapy remains uncertain. Patients with more advanced disease (T3b and T4) are less likely to achieve local control with this approach, but most ultimately will succumb to systemic disease. Randomized controlled studies are needed. Twice-a-day (accelerated) radiation regimens may be more effective than once-a-day regimens in their ability to induce and maintain a complete response.159 The MGH recently reported a pilot study from evaluating the use of twice-a-day radiation in conjunction with cisplatin, 5-FU, and a TURBT. The clinical complete response rate was 77% and, with a median follow-up of 32 months, the overall survival and survival with a functioning bladder at 3 years were 83% and 78%.183 When compared with our previous experience using once-aday radiation and cisplatin as the only radiation sensitizer, the results appear improved. This is now being tested in a prospective multicenter study organized within the RTOG. The RTOG is also to begin testing taxotere in combination with cisplatin as a radiation sensitizer. Adjuvant Chemotherapy. Despite low rates of pelvic recurrence following radical cystectomy, 5-year survival rates for T2-4 disease are only in the range of 40 to 60%. Most of the subsequent deaths arise from

metastatic disease unrecognized at surgery. The risk of metastatic death is particularly high for those who prove to have pT3b-4 or node-positive disease. Use of chemotherapy following radical cystectomy has been studied for this subset of patients in particular. Logethetis and colleagues187 compared the use of cisplatin, cyclophosphamide, and Adriamycin (CISCA) chemotherapy in a group of 71 patients at high risk for relapse based on pathologic criteria (pT3b, pT4, N1, and vascular or lymphatic invasion) to a historical control group of 62 patients who did not receive postoperative chemotherapy. Patients who received chemotherapy showed a 5-year survival rate of 70%, compared with 37% for those who did not. Although the differences were larger, the assignment of treatment was not randomized, thus raising the possibility that the groups were not comparable. Five randomized trials now have been reported that provide information on the value of adjuvant chemotherapy after radical primary therapy (Table 107.11). Reported from the United Kingdom in 1983, the first188 examined doxorubicin and 5-FU following radical irradiation. No survival advantage was seen, but this may have been because the most effective drug in bladder cancer, cisplatin, was not part of the regimen. The Swiss multicenter trial189 evaluated three cycles of single-agent cisplatin after cystectomy and again saw no survival advantage. This may illustrate the lack of efficacy of a single agent against micrometastatic disease; unfortunately, the statistical power to detect a difference in this trial was compromised by the inclusion of patients with pTa-T2 disease. Such patients have a relatively low risk of metastases and, therefore, a low probability of benefitting from systemic therapy. Skinner and colleagues190 compared four cycles of CAP (cyclophosphamide, Adriamycin, and Platinol) chemotherapy to observation in 91 patients with pT3 and pT4 tumors. Although this study was terminated before full accrual, more patients were free of disease at 3 years (70 vs 46%, P 5 .001) when given chemotherapy. Although not reaching statistical significance, median survival time also improved as well (4.25 vs 2.41 years). Another small, randomized study191 compared three cycles of M-VAC or M-VEC to observation in 49 patients with tumor stages pT3B, pT4A, and/or N1. There was a statistically significant difference in relapse-free survival (P 5 .0012), but the followup duration was too brief in this study to compare survival rates in both groups. Finally, Freiha and colleagues192 conducted a small, randomized study in which 55 patients with pT3b, T4, or N1 bladder cancer following cystectomy were randomized to receive either CMV or watched without treatment. With a minimum of 2 years and a median 62 months

Table 107.11.
Series

Randomized Trials of Neoadjuvant and Adjuvant Chemotherapy for Invasive Bladder Cancer
Stage Patients (n) Primary Therapy Chemotherapy Survival (%) Significance

Neoadjuvant CUGG (157) WMRURG/ABCSG (178) NCBSG (189) CUETO (179) Adjuvant UK (152) USC (126) Mainz (184) SAKK (183) Stanford (185)

cT3NxM0 cT2-T4NxM0 cT1 (grade 3) NxM0 cT2-T4NxM0 cT2-T4NxM0

376 255 311 122

XRT +/- cystectomy XRT XRT + cystectomy Cystectomy

Methotrexate Observation Cisplatin Observation Cisplatin + doxorubicin Observation Cisplatin Observation 5-FU + doxorubicin Observation CAP Observation M-VAC or M-VEC Observation Cisplatin Observation CMV Observation

39 (3 year) 37 ~39 (3 year) ~40 55 (5 year) 45 41 (5 year) 41 35 (3 year) 37 70 (3 year) 46 ~63 (3 year) 0 57 (5 year) 54 ~40 (5 year) ~38

No No Yes No

cT3NxM0 pT3-T4NxM0 pT3b-T4a, N+ , M0 pTa-T4, N+ , M0 pT3b-T4, N+, M0

129 91 49 77 55

XRT Cystectomy Cystectomy Cystectomy Cystectomy

No Yes Yes No No

CAP = cyclophosphamide, Adriamycin, and Platinol; CMV = cisplatin, methotrexate, vinblastine; 5-FU = 5-fluorouracil; M-VAC = methotrexate, vinblastine, doxorubicin, cisplatin; M-VEC = Mtx, VLB, epirubicin; XRT = x-irradiation.

1552 SECTION 30 / Neoplasms of the Genitourinary Tract

of follow-up, 12 of 25 treated patients (48%) remained relapse-free, compared with 5 of 25 (25%) in the observation group. Although time to progression (37 vs 12 months) and median survival (63 vs 36 months) were superior in the treated group, overall survival in both groups was not different. This was because 3 of 19 patients in the observation arm remained disease-free long term after being treated with CMV at recurrence. These studies strongly suggest an advantage regarding freedom from relapse with the use of adjuvant chemotherapy in high-risk subsets of patients with invasive bladder cancer. An overall survival benefit for the use of adjuvant chemotherapy, however, thus far has not been proven. Neoadjuvant Chemotherapy. Use of chemotherapy before definitive local therapy, or neoadjuvant therapy, has been used in two general settings: before radical cystectomy to enhance local control and decrease the likelihood of systemic relapse and in conjunction with radiation for bladder preservation. The use of chemotherapy before local therapy offers several potential advantages: (a) patients ultimately die of occult metastases present at the time of local therapy, and it thereby provides systemic therapy at the earliest opportunity, when the chance of eradication theoretically is highest; (b) chemotherapy sensitivity can be judged on a case-by-case basis; (c) down-staging of the primary tumor may allow for complete resection of a tumor that has extended beyond the bladder. There is abundant evidence that tumor down-staging can be achieved with neoadjuvant chemotherapy. The European Organization for Research in Therapy of Cancer (EORTC) reported a major response (p0, pTis, pTa, or pT1) in 42% of 147 patients receiving a median three cycles of preoperative M-VAC. Those with a major response show a 5year survival of 75% compared with 20% in nonresponders. In a study from Memorial Sloan-Kettering Cancer Center, 13 of 27 patients (48%) with invasive bladder cancer treated using M-VAC achieved a clinical complete response, but only 14 of 60 (23%) were free of tumor at cystectomy. The proportion of T2 and T3a tumors that achieved a complete response was higher than that for T3b and T4 (34 vs 9%);193 other studies have reported similar results.194196 The conclusions from these studies are that responses in the bladder are seen in approximately 50% of patients and that approximately 20% of patients will achieve a complete pathologic response with multiagent chemotherapy. The selection of patients who do not require further therapy still is somewhat problematic; thus, further therapy is advisable. Other conclusions are that the contribution of chemotherapy to achieving of local control is still uncertain, the contribution of neoadjuvant chemotherapy to survival is uncertain, and the response to chemotherapy selects a group of patients with particularly good survival characteristics. Chemotherapy may contribute to the good outcome seen in responsive patients, but a greater proportion of major responses are obtained in patients with smaller tumors, thus raising the possibility that the good prognosis of responders reflects their natural destiny. Only one of the reported, randomized trials of neoadjuvant chemotherapy before radical treatment has shown any survival advantage for the combination group, but all of these studies are seriously flawed by their use of single agents only (see Table 107.11). The Spanish genitourinary oncology group trial180 (CEUTO) used three cycles of cisplatin before cystectomy in the experimental arm. Major downstaging to pT0-1 was documented in 34% (59% for T2 tumors, 24% for T3, and 20% for T4a), but 5-year survival was identical to control patients. The pooled Australian and British studies, with 255 patients, had significant statistical power to detect differences in survival between those receiving and not receiving cisplatin before radical radiation therapy, but none was seen.179 Interestingly, survival following radiation therapy in this study was identical to survival following cystectomy in the similarly designed CEUTO trial. The third major trial, with 376 patients, saw no difference between patients who were randomized to methotrexate before and after radiation or to radiation alone.185 It is of note that in none of these trials did deferring the definitive treatment of the primary bladder cancer by 3 months affect the ultimate survival. This is of importance since response to neoadju-

vant therapy can be used safely as a method to select patients for organ conservation. The Nordic Co-Operative Bladder Cancer Study Group187 has completed a randomized trial in which the definitive treatment was preoperative irradiation (20 Gy) and cystectomy, with one half receiving two cycles of neoadjuvant cisplatin and doxorubicin.197 A significant survival advantage was seen for those receiving chemotherapy (55 vs 45% at 5 years). The Medical Research Council of the United Kingdom and the EORTC currently are completing a large, randomized trial that examines the use of MCV before radical therapy (either radiation or cystectomy). Over 1,000 patients have been accrued, and answers to important questions will be available soon. A large, prospective, randomized U.S. intergroup study examining the value of neoadjuvant M-VAC before cystectomy will be completed soon as well. The impact of neoadjuvant chemotherapy on local control of tumor and overall survival remains of uncertain value. With the realization that sometimes dramatic responses could be achieved with chemotherapy, this modality has been used in conjunction with TURBT and segmental resection to spare the bladder. Sternberg and colleagues193 reported on 46 T2-4N0M0 patients treated by neoadjuvant M-VAC. Seventy-eight percent had a response, 13% stable disease, and 9% progression. Twenty-nine (63%) were sufficiently down-staged clinically for an attempt at organ preservation by partial cystectomy or TURBT. Eight have since experienced a local relapse, and 16 of 46 (35%) were alive and disease-free with a functional bladder after 2.5 years of follow-up. The use of chemotherapy before radiation therapy was discussed in the previous section on chemoradiation. In 1998, the RTOG reported the results of a multicenter randomized trial to assess the long-term efficacy of neoadjuvant MCV chemotherapy prior to cisplatinum and radiation.176 With a median follow-up of 60 months, the 5-year overall survival rate was 49%: 48% in those receiving MCV and 49% in those who did not. There was no significant improvement in metastasis-free survival or freedom from invasive bladder relapse. The absence of any benefit in this and the MRC/EORTC study, coupled with the toxicity of this drug combination (only 67% completed protocol treatment in the RTOG trial), has led many investigators away from neoadjuvant therapy. CHEMOTHERAPY FOR METASTATIC DISEASE Bladder TCC is very responsive to cytotoxic chemotherapy. A small proportion of patients with metatastic disease can be long-term survivors following the use of chemotherapy. SINGLE AGENTS A variety of agents have significant single-agent activity. Cisplatin has been the most widely used and probably is the most active agent. In phase II studies in which the dose and patient populations differed, response rates have varied from 26 to 65%, with complete responses seen in 0 to 14%.198206 In phase III studies, the response rates generally have been lower, in the range of 12 to 31%, with complete responses seen in fewer than 10% of patients. Carboplatin has also been in the treatment of bladder cancer because of its more favorable toxicity profile, a particularly important issue in a frequently elderly patient population with frequent comorbidity and impaired renal function. Overall, the results as a single agent in phase II trials have been comparable, if not possibly inferior, to those with cisplatin.207,208 Comparative studies have not been conducted. Methotrexate is another very active drug, with phase II studies indicating a single-agent response rate of 29%. Other antifols that have been tested, such as trimetrexate and piritrexim, both having significant activity. Three newer agents, taxol, gemcitabine, and taxotere, have significant activity. Taxol209211 was given as a single agent to 26 patients with previously untreated bladder cancer at a dose of 250 mg/m2 over 24 hours every 3 weeks. Eleven (42%) patients responded including 7 (26%) complete responders. In a smaller study, five of nine patients responded to 175 to 250 mg/m2 over 24 hours every 3 weeks. Three of the nine patients were previously treated. Three studies involving single agent taxotere have been published.211213 All three used a dose of 100 mg/m2 over 1 hour every 3 weeks. The two studies in previously untreated patients demonstrated objective response rates in 9 of 29 (31%) and 5 of 11 (45%) patients. As a salvage therapy in patients who

failed a cisplatin-containing regimen, 4 of 30 (13%) patients responded. Three studies214216 have tested gemcitabine in previously untreated patients. A dose of 1200 to 1250 mg/m2 IV three times weekly every 28 days was used. DeLena found 7 of 31 (23%), Sadler 9 of 39 (28%), and Moore217 9 of 37 (24%) responders. In one study of previously cisplatintreated patients 7 of 31 (23%) patients responded.199,200 Other active single-agent drugs in the treatment of bladder cancer include ifosfamide, which has a response rate of 20% (11 of 56 patients);218 gallium nitrate, which has a response rate of 24% (17 of 81 patients);219 doxorubicin, 17% (95% confidence intervals (CIS), 1223%); 5-FU, 15% (95% CI220, 1219%); vinblastine, 16% (95% CI, 428%)220; and mitomycin, 13% (95% CI, 323%).220 COMBINATION REGIMENS Countless combination regimens have been tested in the treatment of metastatic bladder cancer. Evaluation of these regimens has been made difficult, however, by variable patient selection and the paucity of comparative trials. The most widely used regimens have been cisplatin-based (Table 107.12). In phase II trials, cisplatin plus methotrexate produced responses in 32% of patients. In a randomized study comparing cisplatin (80 mg/m2 on day 1) with cisplatin (80 mg/m2) plus methotrexate (50 mg/m2 on days 1 and 15), the combination generated more responses (45 vs 31%, respectively), but survival was equivalent (8.7 months vs 7.2 months, P 5 .7).221 More complex multidrug regimens such as CMV and M-VAC generated more frequent responses and more frequent complete responses.222225 CMV (which consists of cisplatin, 100 mg/m2 given on day 2; methotrexate, 30 mg/m2; and vinblastine, 4 mg/m2 given on days 1 and 8 in 21-day cycles) produced responses in 28 of 50 patients treated and evaluated.226 One half of the responses were complete, but the median survival was only 8 months. In a study of 121 patients, M-VAC (which consists of methotrexate, 30 mg/m2 on days 1, 15, and 22; vinblastine, 3 mg/m2 on days 2, 15, and 22; doxorubicin, 30 mg/m2 on day 1; and cisplatin, 70 mg/m2 on day 2) demonstrated an overall response rate of 72%, with one half of the responses being complete.227 Median survival was 13 months. M-VAC proved to be superior to single-agent cisplatin in a large, randomized study, with a prolongation of median survival by 4 months (12.6 vs 8.7) (Fig. 107.3).228 In another study comparing CISCA,176 which is a regimen consisting of cisplatin, doxorubicin, and cyclophosphamide, to M-VAC, M-VAC proved to be superior, with a difference in median survival of 82 versus 40 weeks.229 Based on these studies, M-VAC became the standard regimen for treatment of metastatic bladder cancer. No randomized studies exist that compare CMV to other regimens, including M-VAC. Efforts directed at intensifying the M-VAC regimen have only given disappointing results. Response rates in these studies have not been convincingly higher, and toxicity has been substantial.230,231 In one such study at the UTMDACC, escalated M-VAC (methotrexate, 60 mg/m2 [day 1]; methotrexate, 30 mg/m2 [day 16]; vinblastine, 4 mg/m2 [days 2 and 16]; doxorubicin, 60 mg/m2 [day 2]; and cisplatin, 100 mg/m2 [day 2]) was given with or without recombinant human granulocyte megaleukocyte colonystimulating factor (rhGM-CSF) to 48 patients.215 The response rate was 85% (95% CI, 7297%), but the median survival did not appear to be altered from that of historical patients treated with standard doses of M-VAC.

CHAPTER 107 / Bladder Cancer 1553

Figure 107.3. INT0078 survival by treatment. DDP = cisdiamminedichloroplatinum; MVAC = methotrexate, vinblastsine, doxorubicin, cisplatin.

Table 107.12. Combination Chemotherapy Regimens for Metastatic Bladder Cancer

Response proportions Evaluable Trials Complete (n[%]) Overall (n[%]) 95% CI (%)

Agents

(n)

DDP/MTX CMV CAP M-VAC

9 4 10 12

293 157 293 526

41 (14) 35 (22) 65 (22) 106 (20)

135 (46) 82 (52) 166 (57) 281 (53)

39-53 43-59 49-64 48-58

CAP = cyclophosphamide, Adriamycin, and Platinol; CI = confidence interval: CMV = cisplatin, methotrexate, vinblastine; DDP = cisplatin; MTX = methotrexate; M-VAC = methotrexate, vinblastine, doxorubicin, cisplatin. Modified from Scher et al. Semin Surg Oncol 1992;8:316-341.

The most encouraging aspect of treatment with combination chemotherapy with M-VAC is that a small proportion (< 10%) of patients treated will be long-term survivors. Prognostic factors that predict for prolonged survival with treatment include the absence of lung, liver, or bone metastasis; good performance status; and the absence of weight loss. With the development of chemotherapy that is effective at generating complete responses and prolonging survival, an increasing proportion of patients are noted to relapse in the CNS, sometimes as an exclusive site. Careful consideration of this phenomenon is warranted in patients who have responded significantly to primary therapy. Several studies have attempted to reduce the toxicity of M-VAC by substituting carboplatin for cisplatin232 and epirubicin or mitoxantrone for doxorubicin.233 Results are encouraging but have not been compared with those of standard M-VAC. The toxicity from M-VAC is substantial; in one large randomized study of 126 patients, there were 5 treatment-related deaths (4%), 13 granulocytopenic fevers (10%), 21 cases of grade 3 or 4 mucositis (17%), and 15 cases of grade 3 or 4 nausea and vomiting (12%). Attempts at improving on the results of M-VAC are underway. At UTMDACC, Logothetis and colleagues234 established the activity of 5-FU plus interferon-alpha in previously treated patients. In their study of 30 such patients, 9 of 30 (30%) responded. In a subsequent study, FAP (5-FU, 500 mg/m2 [days 15 and 2227]; interferon-alpha, 5 mIU/m2 [days 15 and 2227]; and cisplatin, 25 mg/m2 weekly) was administered to 28 previously treated patients; 17 (61%; 95% CI, 4178%) responded. A randomized study comparing M-VAC to FAP is currently under way. In another phase II study, the regimen VIG (vinblastine, 0.11 mg/kg [days 1 and 2]; ifosfamide, 1.2 g/m2 [days 15]; and gallium nitrate, 300 mg/m2 [days 15]) has been tested by Einhorn and colleagues.235 Responses were seen in 18 of 27 previously untreated patients (67%; 95% CI, 4684%). This regimen was highly toxic, with an associated 30% incidence of neutropenic fevers and 15% incidence of grade 3 or 4 nephroxicity. With the recognition that the taxanes and gemcitabine were active single agents in the treatment of bladder cancer, attempts at coupling these agents with other active agents have been made. Three trials235237 have examined the activity of cisplatin plus paclitaxel. In these three small phase II studies, 18 of 29 (62%), 8 of 11 (73%), and 13 of 18 (72%) patients responded. Complete responses were seen as well. Bajorin and colleagues238 added ifosfamide and noted that 23 of 29 (79%) patients responded. In the five studies239243 that combined paclitaxel with carboplatin, the response proportion was somewhat lower 17 of 33 (52%), 7 of 17 (41%), 18 of 35 (51%), 13 of 20 (65%), 10 of 23 (43%), and 18 of 53 (34%). Complete responses were simi-

1554 SECTION 30 / Neoplasms of the Genitourinary Tract

10.

larly noted. Two studies19,20 using docetaxel and cisplatin yielded similarly promising results with 15 of 25 (60%) and 5 of 8 (63%) patients responding. Three trials244246 have examined the activity of cisplatin plus gemcitabine. Responses were seen in 15 of 37 (41%), 23 of 38 (59%), and 17 of 29 (59%). In general, these doublets are well tolerated except for mydosuppression and have sufficient activity to warrant comparison to standard therapy. Thus, two phase III trials had been planned. One, a comparison of cisplatin plus gemcitabine to MVAC is now completed having accrued 400 patients. Another trial comparing carboplatin plus paclitaxel versus MVAC is planned. Although a small subgroup of patients who undergo resection of masses present after chemotherapy can be long-term survivors, this represents a highly select subgroup. Adjunctive surgery for patients who achieve a partial response to chemotherapy should not be considered standard. ADENOCARCINOMA OF THE BLADDER Adenocarcinoma of the bladder is categorized into three rare entities: (a) metastatic, (b) primary, and (c) urachal. These tumors comprise less than 2% of all bladder tumors. The most common adenocarcinomas that spread to the bladder, usually by direct extension, are colon, prostate, and tumors of the female reproductive tract. If complete resection is achievable, cure is possible. Primary bladder adenocarcinomas may be papillary, polypoid, or nodular.247 These tumors arise in patients who have a long history of cystitis; glandular cystitis frequently is associated with this lesion. Histologically, these tumors resemble colonic carcinoma, and most have invaded into muscle at the time of initial diagnosis. These tumors frequently produce mucin, with the signet cell variant being rare and particularly aggressive.248,249 Primary adenocarcinoma of the bladder is treatable and potentially curable with radical cystectomy or pelvic exenteration. Urachal adenocarcinomas are rare,250 and usually confined to the dome or the anterior wall of the bladder. Presumably, they arise intramurally, with secondary involvement of the mucosa. These are mucin producing as well and may have a signet cell appearance. On CT scan, these tumors may be cystic or solid and typically are situated in the region of the urachal tract directly behind the anterior abdominal wall.251 Surgical treatment with either partial or radical cystectomy coupled with umbilectomy generates comparable survival results, with fewer than 50% of patients surviving. Chemotherapy and radiotherapy are of uncertain value for adenocarcinomas of the bladder. SQUAMOUS CELL CARCINOMA Although TCC mixed with squamous metaplasia or frank carcinoma sometimes is seen, pure squamous cell carcinoma of the bladder is unusual in the United States but much more common in areas endemic to S. haematobium, such as Egypt. An association also exists between chronic bladder infection and/or longterm indwelling bladder catheterization and the development of these tumors.252 Although it is believed that patients with squamous cell carcinomas of the bladder fare particularly poorly, at least part of the reason is because they frequently are diagnosed with more advanced disease. In general, such patients are treated in a similar fashion as those with TCC, although responsiveness to radiotherapy and chemotherapy is less robust. REFERENCES
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