Bladder, Renal, and Testicular Cancer Part 1

Cancer of the Bladder

Bladder cancer accounts for more than 90% of urinary tract malignancies. It is the sixth most common cancer in the United States, with 50,000 new cases a year, and it causes over 10,000 deaths a year. The management of this disease has become a paradigm of the approach to solid tumor malignancy,1 because bladder cancer exhibits stem cell function (with the ability to differentiate along different histologic pathways); is associated with expression of several common oncogenes; and responds to surgery, radiation, and chemotherapy.

Epidemiology and etiology

The incidence of bladder cancer increases with age and is fourfold higher in men than in women. The disease is seen more often in whites than in African or Asian populations. The incidence is higher in urban areas, suggesting a possible role of environmental factors in carcinogenesis. Cigarette smoking is the primary risk factor, with a confirmed dose- and time-response relationship for both sexes.2 Occupational exposure to carcinogenic compounds found in dye, rubber, paint, plastics, metal, and motor vehicle exhaust significantly raises the risk of bladder cancer. Other established risk factors include chronic infection of the lower urinary tract, history of external-beam radiation to the pelvis, long-term indwelling urinary catheter, the use of cy-clophosphamide, high-fat diet, and low daily fluid intake. In the Mediterranean basin, schistosomiasis is still the main causative agent and is classically associated with squamous cell carcinoma.

More than 90% of bladder cancers are transitional cell carcinomas. The less common cell types are squamous cell carcinoma, adenocarcinoma, and small cell carcinoma; rare histologic types such as sarcoma, lymphoma, and melanoma comprise less than 1% of cases.3 Although the histogenesis is not fully understood, bladder cancer appears to originate from a stem cell tumor4 and, therefore, has the capacity to evolve different histo-logic patterns that are intermixed; for example, dominant transitional cell carcinoma may coexist with squamous and squamoid differentiation. Bladder cancer is often associated with a field defect of the urinary mucosa, implying an antecedent level of precancerous change that can affect multiple sites, with the result that the entire lining of the urinary tract may be at risk for developing malignancy.

Pathobiology

Pathologically, bladder cancer is categorized as superficial or invasive [see Figure 1]. Superficial bladder cancer, which constitutes about 80% of incident cases, is restricted to the level of the bladder mucosa and lamina propria. The seminal event in the development of superficial bladder cancer appears to be a loss of heterozygosity of chromosome 9 (i.e., that there is a potential oncogene located at that site).5Superficial bladder cancer is usually associated with a high level of histologic differentiation and with long patient survival.

Invasive bladder tumors are those that penetrate beyond the lamina propria. They are aggressive and tend to metastasize early. About 20% of patients have invasive cancer at presentation, although some superficial tumors recur as invasive disease. The most important prognostic factor is the depth of tumor invasion (stage). T2 tumors, which extend into the muscularis propria, carry a better prognosis than T3 and T4 tumors, which extend beyond the muscularis propria. The level of differentiation (grade) is also an important factor. Unfortunately, most invasive tumors are high grade. Vascular or lymphatic invasion predicts an increased risk of soft tissue invasion and of distant metastasis. Other adverse prognostic factors include the absence of expression of blood group antigens on the tumor cell surface, DNA ploidy, expression of epidermal growth factor receptor (EGFR), and presence of mutations of the p53 suppressor gene. Poorer prognosis has also been correlated with expression of other genes, including p16, p21, and Rb; these genes may work in concert with p53 to regulate tumor growth.

Figure 1 Carcinoma of the bladder can be staged according to the depth of penetration of the tumor into the bladder wall and, for advanced disease, by the location of metastases. Superficial disease comprises noninvasive papillary carcinoma (Ta); carcinoma in situ, or so-called flat tumor (Tis); and tumors that extend only into the submucosa (stage T1). Invasive disease is characterized by extension past the submucosa. Invasion into the muscle layer is designated stage T2: pT2a denotes tumor that invades superficial muscle (the inner half); and pT2b, tumor that invades deep muscle (the outer half). Stage T3 tumors are those that invade perivesical fat: pT3a tumors are microscopic, and pT3b tumors are macroscopic (i.e., there is an extravesical mass). Stage T4 tumor invades adjacent organs: T4a invades the prostate, uterus, or vagina; and T4b invades the pelvic or abdominal wall. Metastatic disease represents spread to regional lymph nodes (i.e., those below the aortic bifurcation [stages N1 through N3]); involvement of lymph nodes above the aortic bifurcation, or involvement of any bone or soft tissue (stage M1).

Diagnosis

Clinical Findings

Most bladder cancers present as gross or microscopic hema-turia that is painless and occurs suddenly or intermittently.7 Urinary frequency, nocturia, and urgency can be the result of bladder wall irritation or volume loss from space-occupying lesions and are often misdiagnosed as chronic interstitial cystitis. Abdominal discomfort, flank pain, pelvic pain, altered bowel habit, or a palpable mass can occasionally be the first clinical evidence of invasive bladder cancer. Obstruction of the ureteral orifice with subsequent hydronephrosis and renal insufficiency may occur with an invasive tumor, although these tumors can remain clinically silent until locally advanced. Rarely, pneumaturia will suggest the presence of a fistula to the bowel.

Invasive bladder cancer may extend locally into the prostate, seminal vesicles, rectum, uterus or vagina, sacral vertebra, and the retroperitoneal soft tissue. It spreads via lymphatics and blood vessels to distant lymph nodes, the lungs, the liver, skin, peritoneum, and bones1 and may even cause brain metastases or carcinomatous meningitis.8 Depending on the practice setting, 5% to 20% of all patients with bladder cancer present with symptoms from metastatic lesions. Constitutional symptoms may occur with disseminated disease, but clinical paraneoplastic syndromes are relatively rare in transitional cell cancers.

Laboratory Findings

Routine urinalysis in patients with bladder cancer will usually show hematuria, the degree of which does not correlate with the extent of the lesion. Intravenous urography may reveal an in-travesical filling defect and also provides anatomic information about the urinary tract, such as the presence of hydronephrosis or hydroureter. Ultrasound is sometimes used to assess the bladder wall and to evaluate the kidneys and ureters. Urine cytology is a convenient and inexpensive method to obtain a tissue diagnosis and has a specificity and sensitivity of 80% in grade III tumors, but it has a relatively low sensitivity for grade I or II tumors (about 10% and 50%, respectively). It has been suggested that flow cytometric studies of urine specimens may reveal occult tumors via the demonstration of aneuploidy. Direct visualization and biopsy of the tumor is usually achieved by cys-toscopy, which has been facilitated in recent years by the introduction of flexible instrumentation.

Staging

The staging process for bladder cancer requires a thorough history and physical examination, along with laboratory studies that include a complete blood count and tests of hepatic and renal function. Renal function may be compromised by factors that caused the cancer, such as analgesic nephropathy, or by obstruction of renal outflow by the tumor mass. Occasionally, a patient will have a markedly elevated leukocyte count secondary to the production of granulocyte colony-stimulating factor (G-CSF) by the bladder cancer. A chest x-ray should be obtained in all patients. In some centers, CT scan of the chest is routinely performed instead of initial chest x-ray as part of routine staging. A CT scan of the abdomen and pelvis allows the assessment of lymphadenopathy and other organ involvement, although the yield of pelvic CT is relatively low. Radionuclide bone scans may be used for staging, but the yield in asymptomatic patients with normal serum alkaline phosphatase levels is low. MRI scanning may be helpful in defining the extent of abdominal or pelvic disease, especially in a patient with renal dysfunction who is not suitable for contrast-enhanced CT scanning. The role of positron emission tomography (PET) scanning has not yet been clearly defined in bladder cancer, although it is clear that false negative results limit utility.

It seems likely that in the future, more sophisticated molecular studies will become routine in the diagnosis and management of bladder cancer. For example, mutation of the p53 gene appears to be an important predictor of outcome in invasive bladder cancer.9 It is also clear that expression of the Rb gene, p16, p21, the epidermal growth factor receptor, thrombospondin-1, multidrug-resis-tance phenotype, and glutathione may be predictive of natural history or of response to therapy,6,9-12 and it seems likely that these assays will become a part of a routine staging protocol.

Management

Superficial Bladder Cancer

For superficial papillary bladder cancer, the initial treatment is careful and thorough endoscopic resection of the tumor or tu-mors.13 In patients at high risk for recurrence, bacillus Calmette Guerin (BCG) may be infused into the bladder through a urinary catheter as an adjuvant to transurethral resection. A common schedule is weekly administration for 6 weeks followed by monthly doses for 6 to 12 months, although the optimal approach has not been defined. The mechanism of action is incompletely understood, but it appears to be based on local immuno-logic response. Although there is great variability of published data, intravesical BCG appears to prevent recurrence in up to 30% of cases and delays recurrence in around 50%, compared with patients who do not receive adjuvant therapy.

Side effects of intravesical BCG include dysuria, frequency, hematuria, and a flulike syndrome. More significantly, because BCG is an attenuated mycobacterium, it can produce local, regional, and systemic infections. Granulomatous infections can occur at extravesical sites, including the prostate, epididymis, testes, kidney, liver, and lungs. BCG sepsis is the most serious complication and can be life-threatening. Systemic involvement (so-called BCGosis) is treated with triple-antibiotic antitubercu-lous therapy for 6 months.

Cytotoxic agents can also be used for intravesical treatment, although the superiority of BCG to such agents has been demonstrated in randomized clinical trials.13 Agents that may have a role for patients who refuse cystectomy after BCG failure include doxorubicin, thiotepa, and mitomycin-C. Because of their high molecular weight, doxorubicin and mitomycin-C have a lesser tendency to be absorbed systemically from the bladder than does thiotepa, which is a small molecule. Clinical trials are in progress to assess the utility of some of the newer cytotoxic agents, such as the taxanes and gemcitabine, for intravesical chemotherapy. These agents are relatively large molecules, so significant systemic absorption seems unlikely.

Table 1 Studies of Chemotherapy plus Radiation in Invasive Bladder Cancer

Series	Number of Patients	Clinical T Stage	Chemotherapeutic Regimen	Bladder Preservation (%)	Overall Survival	Median Follow-up (months)
Coppin¹⁸	42	T2-T4	Cisplatin	Not reported	61% at 2yr	50
Dunst¹³²	139	T1-T3	Cisplatin or carboplatin	79	40% at 7 yr	Minimum 12
Housset¹³³	54	T2-T4	5-FU, cisplatin	78	59% at 3 yr	18-58
Kaufmann¹³⁴	53	T2-T4	Cisplatin, methotrexate, vinblastine	85	53% at 4 yr	48
Sauer¹³⁵	67	T1-T4	Carboplatin	84	66% at 3 yr	Not available
Tester¹³⁶	46	T2-T4	Cisplatin	83	66% at 3 yr	36

Invasive Bladder Cancer

In North America and Europe, cystectomy is the standard treatment for organ-confined invasive bladder cancer.14 Radical cystectomy involves the en bloc removal of the anterior pelvic organs, which include the bladder, prostate, and seminal vesicles in men and the bladder, urethra, uterus, ovaries, and vaginal cuff in women.14,15 Bilateral pelvic lymph node dissection is often performed. The ureters are reconnected to an intestinal conduit as a urinary diversion. Traditionally, the conduit has been fashioned to drain into an external collecting bag attached to the abdominal wall. However, continent reservoirs such as the Koch pouch (using the ileum) and the Indiana and T pouches (using other segments of bowel) have become popular, because they afford greater degrees of continence and a return to more normal lifestyles. These procedures involve the creation of an internal conduit with an antireflux mechanism that is either brought to the abdominal wall or sutured to the urethra, thus allowing patients to self-catheterize or void in the normal position, which greatly improves their self-image and increases their acceptance of the procedure.

When performed in routine clinical practice, radical cystecto-my results in 60% to 75% 5-year survival rates in patients with T2 disease and 20% to 40% survival in those with T3 or T4 disease. Centers of excellence have reported superior long-term results, with 10-year survival as high as 85% for patients with organ-confined disease.15

For patients with localized invasive disease who are not surgical candidates, radiation is the alternative definitive therapy in North America, although it should be noted that radical radiotherapy is the standard definitive treatment in some British, Canadian, and European centers.16,17 To date, there have been no well-designed, randomized studies comparing radiation with surgery in patients with similar characteristics.

A relatively standard radiotherapy regimen is more than 65 to 70 Gy given over 6 to 7 weeks, with the major component of dosage focused on the tumor and surrounding areas, as defined by CT scanning in the prone position. Toxicities of radiation include dermatitis, proctitis that is occasionally complicated by bleeding and obstruction, cystitis or bladder fibrosis, impotence, incontinence, and development of secondary malignancies in the region surrounding the radiation field.

Combined-modality approaches, incorporating systemic chemotherapy with definitive local modalities, have been studied extensively in the past few years in the hope of sparing the bladder or improving overall survival.1 The rationale is that systemic chemotherapy may reduce the extent of local tumor while controlling occult metastases. Trials of concurrent chemotherapy and radiation have suggested that a high rate of bladder preservation is possible with this approach, compared with radiation alone [see Table 1].18 However, the one reported randomized trial did not show a statistically significant survival benefit, although it did not have sufficient statistical power to assess survival. When chemoradiation fails with local progression or relapse, salvage surgery becomes extremely difficult because of the formation of dense adhesions.

It is clear that neoadjuvant chemotherapy can often reduce the local tumor volume within the bladder, and complete remission is sometimes achieved. However, most randomized trials of neoadjuvant systemic chemotherapy followed by definitive radiotherapy or cystectomy have shown no significant survival benefit from the combined modality approaches [see Table 2].19-21 It should be noted that combination chemotherapy has been more effective, and the North American Intergroup study of the combination of methotrexate-vinblastine-doxorubicin (Adri-amycin)-cisplatin (MVAC) plus cystectomy versus cystectomy alone showed a statistically significant survival benefit.

Chemotherapy administered after radical cystectomy for patients with lymph node involvement may improve disease-free survival [see Table 2].22,23 However, in the extant trials, which have been flawed by poor design and inadequate sample size, overall improvement in survival has not been demonstrated with statistical significance. These flaws have been addressed in a large international randomized trial that is currently under way.

Metastatic Bladder Cancer

Chemotherapy is the treatment of choice for patients with metastatic bladder cancer. The first major step in the modern era of chemotherapy was the development of MVAC by Sternberg and colleagues.24 Several series demonstrated median survival of about 12 months in patients with advanced and metastatic bladder cancer treated with this regimen. At the time of the completion of that trial, median survival without chemotherapy was only 4 to 6 months.1 A landmark study conducted by an international consortium compared the MVAC regimen to cisplatin alone.25 The MVAC regimen produced a response rate of 39% with median survival of 12.5 months, which was statistically superior to the response rate of 12% and median survival of 8 months in the group that received cisplatin alone. The survival benefit persisted after a minimum follow-up of 6 years, although the vast majority of patients in both randomization arms had died by that time.26 The clear limitations of the MVAC regimen that were evident from this analysis opened the way for investigation of novel agents.

Table 2 Results of Clinical Trials of Neoadjuvant Chemotherapy for Invasive Bladder Cancer, Stages T1-T4

Series	Neoadjuvant Regimen	Definitive Therapy	Median Survival with/without Neoadjuvant Therapy (months)	Actuarial Long-term Survival with/without Neoadjuvant Therapy
Shipley¹⁹	CMV	RT/C	36/36	48%/49% at 5 yr
MRC-EORTC²¹	CMV	RT/cystectomy	44/37.5	55%/50% at 3 yr
Intergroup²⁰	MVDC	Cystectomy	72/45	55%/45% at 6 yr
Nordic 1 trial¹³⁷	DC	Cystectomy	Not reached/72	59%/51% at 5 yr

C—cisplatin

D—doxorubicin

M—methotrexate

MRC-EORTC—Medical Research Council/European Organization for Research and Treatment of Cancer

RT—radiotherapy

V—vinblastine

Novel cytotoxic agents are being actively studied; and in recent years, single-agent therapy with paclitaxel, gemcitabine, do-cetaxel, or ifosfamide has been shown to produce response rates between 20% and 30% [see Figure 2]. The combination of these agents with other standard or investigational drugs has resulted in response rates of 50% to 80%, with apparently less toxicity than the conventional-combination MVAC regimen.

A phase III trial comparing the regimen of gemcitabine and cisplatin with the MVAC regimen has been completed.31Al-though it was not designed to be an equivalence trial, this study suggests that there is no great difference in survival between the gemcitabine-cisplatin regimen and the MVAC regimen but does suggest that the gemcitabine-cisplatin combination is substantially less toxic. As a consequence, an international consortium (the International Intergroup) is now comparing gemcitabine-cisplatin with gemcitabine-cisplatin-paclitaxel for patients with previously untreated metastatic transitional cell carcinomas. These investigators have indicated that it is probably time to leave the MVAC regimen behind as the standard of care.

Of particular importance, there is emerging evidence that stage migration has occurred in the management of advanced bladder cancer (presumably because of increased use of chemotherapy for patients with asymptomatic or small volume metastatic disease detected by postoperative screening techniques, such as CT, MRI, and PET scans). At Memorial Sloan-Kettering Cancer Center, the initial experience with the MVAC regimen in the 1980s produced a median survival of about 12 months,24 whereas recent data from that institution showed a median survival of 18 months with a variant of MVAC that has a relatively minor dose escalation. This should be borne in mind when considering the utility of novel combinations, such as the ITP regimen (ifosfamide, paclitaxel, and cisplatin), which also yields a median survival of about 18 months. Before novel regimens are accepted into routine clinical practice, their safety and efficacy should be defined in randomized trials against accepted current standards.

In addition to chemotherapy, novel agents that target cell regulatory proteins may have application to the management of bladder cancer. Clinical trials are currently assessing the efficacy of agents that modulate the function of EGFR and other tyrosine kinase inhibitors. These agents are being tested both as mono-therapy and in combination with chemotherapy. The ability to identify expression of the HER-2/neu oncogene, EGFR, and other molecular predictors of response to treatment may allow tailoring of more specific therapeutic strategies.

Figure 2 CT scans of a patient with hepatic metastases from bladder cancer before (a) and after (b) treatment with gemcitabine-cisplatin.