A transitional cell epithelium lines the urinary tract from the renal pelvis to the ureter, urinary bladder, and the proximal two-thirds of the urethra. Cancers can occur at any point: 90% of malignancies develop in the bladder, 8% in the renal pelvis, and the remaining 2% in the ureter or urethra. Bladder cancer is the fourth most common cancer in men and the thirteenth in women; an estimated 70,530 new cases and 14,680 deaths in the United States were predicted for the year 2010. The almost 5:1 ratio of incidence to mortality reflects the higher frequency of the less lethal superficial variants compared with the more lethal invasive and metastatic variants. The incidence is three times higher in men than in women and twofold higher in whites than blacks, with a median age at diagnosis of 65 years.
More than 95% of urothelial tumors in the United States are transitional cell in origin. Pure squamous cancers with keratinization constitute 3%, adenocarcinomas 2%, and small cell tumors (with paraneoplastic syndromes) <1%. Adenocarcinomas develop primarily in the urachal remnant in the dome of the bladder or in the periurethral tissues; some assume a signet cell histology. Lymphomas and melanomas are rare. Of the transitional cell tumors, low-grade papillary lesions that grow on a central stalk are most common. These tumors are very friable, have a tendency to bleed, are at high risk for recurrence, and yet rarely progress to the more lethal invasive variety. In contrast, CIS is a high-grade tumor that is considered a precursor of the more lethal muscle-invasive disease.
The multicentric nature of the disease and high rate of recurrence have led to the hypothesis of a field defect in the urothelium that results in a predisposition to cancer. Molecular genetic analyses suggest that the superficial and invasive lesions develop along distinct molecular pathways in which primary tumorigenic aberrations precede secondary changes associated with progression to a more advanced stage. Low-grade papillary tumors that do not tend to invade or metastasize harbor constitutive activation of the receptor–tyrosine kinase–Ras signal transduction pathway and a high frequency of fibroblast growth factor receptor 3 (FGFR3) mutations. In contrast, CIS and invasive tumors have a higher frequency of TP53 and RB gene alternations. Within all clinical stages, including Tis, T1, and T2 or greater lesions, tumors with alterations in p53, p21, and/or RB have a higher probability of recurrence, metastasis, and death from disease.
The endoscopic evaluation includes an examination under anesthesia to determine whether a palpable mass is present. A flexible endoscope is inserted into the bladder, and bladder barbotage is performed. The visual inspection includes mapping the location, size, and number of lesions, as well as a description of the growth pattern (solid vs papillary). An intraoperative video is often recorded. All visible tumors should be resected, and a sample of the muscle underlying the tumor should be obtained to assess the depth of invasion. Normal-appearing areas are biopsied at random to ensure no field defect. A notation is made as to whether a tumor was completely or incompletely resected. Selective catheterization and visualization of the upper tracts should be performed if the cytology results are positive and no disease is visible in the bladder. Ultrasonography, CT, and/or magnetic resonance imaging (MRI) may help to determine whether a tumor extends to perivesical fat (T3) and to document nodal spread. Distant metastases are assessed by CT of the chest and abdomen, MRI, or radionuclide imaging of the skeleton.
TREATMENT: Bladder Cancer
Management depends on whether the tumor invades muscle and whether it has spread to the regional lymph nodes and beyond. The probability of spread increases with increasing T stage.
SUPERFICIAL DISEASE At a minimum, the management of a superficial tumor is complete endoscopic resection with or without intravesical therapy. The decision to recommend intravesical therapy depends on the histologic subtype, number of lesions, depth of invasion, presence or absence of CIS, and antecedent history. Recurrences develop in upward of 50% of cases, of which 5–20% progress to a more advanced stage. In general, solitary papillary lesions are managed by transurethral surgery alone. CIS and recurrent disease are treated by transurethral surgery followed by intravesical therapy.
Intravesical therapies are used in two general contexts: as an adjuvant to a complete endoscopic resection to prevent recurrence or, less commonly, to eliminate disease that cannot be controlled by endoscopic resection alone. Intravesical treatments are advised for patients with recurrent disease, >40% involvement of the bladder surface by tumor, diffuse CIS, or T1 disease. The standard intravesical therapy, based on randomized comparisons, is bacillus Calmette-Guerin (BCG) in six weekly instillations followed by monthly maintenance administrations for ≥1 year. Other agents with activity include mitomycin-C, interferon (IFN), and gemcitabine. The side effects of intravesical therapies include dysuria; urinary frequency; and, depending on the drug, myelosuppression or contact dermatitis. Rarely, intravesical BCG may produce a systemic illness associated with granulomatous infections in multiple sites that requires antituberculin therapy.
Following the endoscopic resection, patients are monitored for recurrence at 3-month intervals during the first year. Recurrence may develop anywhere along the urothelial tract, including the renal pelvis, ureter, or urethra. A consequence of the "successful" treatment of tumors in the bladder is an increase in the frequency of extravesical recurrences (e.g., urethra or ureter). Those with persistent disease in the bladder or new tumors are generally considered for a second course of BCG or for intravesical chemotherapy with valrubicin or gemcitabine. In some cases, cystectomy is recommended, although the specific indications vary. Tumors in the ureter or renal pelvis are typically managed by resection during retrograde examination or, in some cases, by instillation through the renal pelvis. Tumors of the prostatic urethra may require cystectomy if the tumor cannot be resected completely.
INVASIVE DISEASE The treatment of a tumor that has invaded muscle can be separated into control of the primary tumor and, depending on the pathologic findings at surgery, systemic chemotherapy to treat micrometastatic disease. Radical cystectomy is the standard, although in selected cases, a bladder-sparing approach is used; this approach includes complete endoscopic resection; partial cystectomy; or a combination of resection, systemic chemotherapy, and external-beam radiation therapy. In some countries, external-beam radiation therapy is considered standard. In the United States, its role is limited to patients deemed unfit for cystectomy, those with unresectable local disease, or as part of an experimental bladder-sparing approach.
Indications for cystectomy include muscle-invading tumors not suitable for segmental resection; low-stage tumors unsuitable for conservative management (e.g., due to multicentric and frequent recurrences resistant to intravesical instillations); high-grade tumors (T1G3) associated with CIS; and bladder symptoms, such as frequency or hemorrhage, that impair quality of life.
Radical cystectomy is major surgery that requires appropriate preoperative evaluation and management. The procedure involves removal of the bladder and pelvic lymph nodes and creation of a conduit or reservoir for urinary flow. Grossly abnormal lymph nodes are evaluated by frozen section. If metastases are confirmed, the procedure is often aborted. In males, radical cystectomy includes the removal of the prostate, seminal vesicles, and proximal urethra. Impotence is universal unless the nerves responsible for erectile function are preserved. In females, the procedure includes removal of the bladder, urethra, uterus, fallopian tubes, ovaries, anterior vaginal wall, and surrounding fascia.
Previously, urine flow was managed by directing the ureters to the abdominal wall, where it was collected in an external appliance. Currently, most patients receive either a continent cutaneous reservoir constructed from detubularized bowel or an orthotopic neobladder. Some 70% of men receive a neobladder. With a continent reservoir, 65–85% of men will be continent at night and 85–90% during the day. Cutaneous reservoirs are drained by intermittent catheterization; orthotopic neobladders are drained more naturally. Contraindications to a neobladder include renal insufficiency, an inability to self-catheterize, or an exophytic tumor or CIS in the urethra. Diffuse CIS in the bladder is a relative contraindication based on the risk of a urethral recurrence. Concurrent ulcerative colitis or Crohn's disease may hinder the use of resected bowel.
A partial cystectomy may be considered when the disease is limited to the dome of the bladder, a margin of at least 2 cm can be achieved, there is no CIS in other sites, and the bladder capacity is adequate after the tumor has been removed. This occurs in 5–10% of cases. Carcinomas in the ureter or in the renal pelvis are treated with nephroureterectomy with a bladder cuff to remove the tumor.
The probability of recurrence following surgery is predicted on the basis of pathologic stage, presence, or absence of lymphatic or vascular invasion, and nodal spread. Among those whose cancers recur, the recurrence develops in a median of 1 year (range, 0.04–11.1 years). Long-term outcomes vary by pathologic stage and histology (Table 41-1). The number of lymph nodes removed is also prognostic, whether or not the nodes contained tumor.
Chemotherapy (described later) has been shown to prolong the survival of patients with invasive disease but only when combined with definitive treatment of the bladder by radical cystectomy or radiation therapy. Thus, for the majority of patients, chemotherapy alone is inadequate to clear the bladder of disease. Experimental studies are evaluating bladder preservation strategies by combining chemotherapy and radiation therapy in patients whose tumors were endoscopically removed.
METASTATIC DISEASE The primary goal of treatment for metastatic disease is to achieve complete remission with chemotherapy alone or with a combined-modality approach of chemotherapy followed by surgical resection of residual disease, as is done routinely for the treatment of germ cell tumors. One can define a goal in terms of cure or palliation on the basis of the probability of achieving a complete response to chemotherapy using prognostic factors, such as Karnofsky Performance Status (KPS) (<80%), and whether the pattern of spread is nodal or visceral (liver, lung, or bone). For those with zero, one, or two risk factors, the probabilities of complete remission are 38, 25, and 5%, respectively, and median survival times are 33, 13.4, and 9.3 months, respectively. Patients who are functionally compromised or who have visceral disease or bone metastases rarely achieve long-term survival. The toxicities also vary as a function of risk, and treatment-related mortality rates are as high as 3–4% using some combinations in these poor-risk patient groups.
CHEMOTHERAPY A number of chemotherapeutic drugs have shown activity as single agents; cisplatin, paclitaxel, and gemcitabine are considered most active. Standard therapy consists of two-, three-, or four-drug combinations. Overall response rates of >50% have been reported using combinations such as methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC); cisplatin and paclitaxel (PT); gemcitabine and cisplatin (GC); or gemcitabine, paclitaxel, and cisplatin (GTC). M-VAC was considered standard, but the toxicities of neutropenia and fever, mucositis, diminished renal and auditory function, and peripheral neuropathy led to the development of alternative regimens. At present, GC is used more commonly than M-VAC, based on the results of a comparative trial of M-VAC versus GC that showed less neutropenia and fever and less mucositis for the GC regimen. Anemia and thrombocytopenia were more common with GC. GTC is not more effective than GC.
Chemotherapy has also been evaluated in the neoadjuvant and adjuvant settings. In a randomized trial, patients receiving three cycles of neoadjuvant M-VAC followed by cystectomy had significantly better median (6.2 years) and 5-year survival (57%) rates compared with cystectomy alone (median survival time, 3.8 years; 5-year survival rate, 42%). Similar results were obtained in an international study of three cycles of cisplatin, methotrexate, and vinblastine (CMV) followed by either radical cystectomy or radiation therapy. The decision to administer adjuvant therapy is based on the risk of recurrence after cystectomy. Indications for adjuvant chemotherapy include the presence of nodal disease, extravesical tumor extension, or vascular invasion in the resected specimen. Another study of adjuvant therapy found that four cycles of CMV delayed recurrence, although an effect on survival was less clear. Additional trials are studying taxane- and gemcitabine-based combinations.
The management of bladder cancer is summarized in Table 41-2.