Oncology

Bladder Cancer

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Bladder cancer

What every physician needs to know:

In 2012, it is expected that 73,510 new cases of bladder cancer will be diagnosed in the United States. During the same period of time, it is expected that 14,880 patients will die from bladder cancer.

There are multiple histologic subtypes of bladder cancer. In Western countries 90% of bladder cancers are urothelial carcinomas. Bladder cancer can be broadly categorized into three different groups: non-muscle invasive disease, muscle invasive disease, and metastatic bladder cancer.

Non-muscle invasive disease is the most common type of bladder cancer and is characterized by high local recurrence rates and prolonged survival. Bladder cancer is one of the most prevalent solid tumors. At any given time, more than 600,000 patients receive care for bladder cancer in the US. The high prevalence of the disease and need for ongoing surveillance makes bladder cancer one of the most expensive solid tumors.

In the US bladder cancer is the fourth most common malignancy in men. Bladder cancer is three times more common in males than females. The median age of diagnosis is 70. Bladder cancer is strongly associated with cigarette smoking.

Non-muscle invasive disease

Seventy to 80% of patients with newly diagnosed bladder cancer have non-muscle invasive disease. Non-muscle invasive bladder cancer includes a spectrum of tumors with different clinical behavior, management and prognosis. Low-grade papillary non-invasive tumors (Ta) are the most common non-muscle invasive tumors (70%).

Ta tumors have a high risk of recurrence within the bladder (50-70%) and a low risk of progression to higher stages of disease (10%). Tumors with invasion into the lamina propria of the bladder (T1) have a higher rate of recurrence (80%) and progression to higher stages of disease (30%-50%). Urothelial carcinoma in situ (Tis) is a high risk non-muscle invasive tumor (Figure 1). Tis tumors are flat, high grade lesions associated with high rates of recurrence (50-90%) and progression to higer stages of disease (>50%).

Figure 1.

Urothelial Carcinoma in Situ (Tis). The picture shows a high risk, high grade flat lesion associated with increased risk of progression to higher disease stage and invasion.

The treatment of choice for non-muscle invasive bladder cancer is transurethral resection of bladder tumor (TURBT) followed by intravesical chemotherapy or immunotherapy.

Muscle invasive disease

Twenty percent of patients with newly diagnosed bladder cancer have muscle-invasive disease (Figure 2). Muscle invasive bladder cancer (T2a and T2b) is characterized by invasion of tumor into or through the muscularis propria of the bladder wall.

Figure 2.

Muscle Invasive Urothelial Carcinoma of the Bladder. The picture shows urothelial carcinoma cells infiltrating the muscularis propria of the bladder wall. Muscle invasive bladder cancer is associated with increased rates of systemic micrometastatic disease.

Higher stage muscle invasive bladder cancer includes tumors with microscopic invasion into perivesical fat (T3a), macroscopic invasion into perivesical fat (T3b), tumors invading into adjacent organs (T4a) and tumors invading into the pelvic or abdominal wall (T4b).

Muscle-invasive bladder cancer can spread into the lymphatic system and hematogenously into visceral organs such as liver, lung, brain, and bone. Muscle invasive bladder tumors have a high potential for development of distant metastases.

Muscle-invasive bladder cancer (stages T2a to T4a) is best treated with induction cisplatin-based combination chemotherapy followed by radical cystectomy, bilateral pelvic lymphadenectomy, and urinary diversion.

Trimodality therapy or selective bladder preservation is an alternative to radical cystectomy for selected patients with muscle invasive bladder cancer. Trimodality therapy involves a complete TURBT of all visible tumor(s) followed by concurrent chemoradiotherapy to the bladder and regional lymph nodes, followed by three to four cycles of adjuvant cisplatin-based combination chemotherapy. Ideal candidates for trimodality therapy are patients with small, organ confined bladder tumors (T1 or T2), no evidence of extravesical extension of tumor, absence of tumor-related obstructive nephropathy, and no evidence of regional lymph node metastasis.

Unresectable bladder cancer

Bladder cancer invading into the pelvic or abdominal wall (T4b) is unresectable. The vast majority of patients with unresectable bladder cancer have incurable disease. Treatment modalities for unresectable bladder cancer include concurrent chemoradiotherapy and cisplatin-based combination chemotherapy. Treatment of unresectable bladder cancer is not curative.

Metastatic bladder cancer

Most patients presenting with metastatic bladder cancer do not have prior history of non-muscle invasive bladder tumors. The vast majority of patients with metastatic bladder cancer have incurable disease.

Treatment of metastatic bladder cancer is palliative. Metastatic bladder cancer is considered a chemosensitive malignancy. The treatment of choice for patients with metastatic bladder cancer, good functional status and adequate organ function (renal, hepatic and hematopoietic) is cisplatin-based combination chemotherapy. Tumor responses to chemotherapy are short lived.

Are you sure your patient has bladder cancer? What should you expect to find?

The vast majority of patients with bladder cancer present with microscopic or macroscopic hematuria (85%). Intermittent painless gross hematuria is the most common presentation. Irritative voiding symptoms (dysuria, frequency, nocturia, urgency) are seen in 25% of patients with bladder cancer at the time of diagnosis.

All adult patients with new onset hematuria should undergo a standard diagnostic workup including office cystoscopy, urine cytology, urinalysis and culture, and contrast-enhanced abdominal and pelvic cross-sectional imaging studies (CT or MRI). On cystoscopy, bladder tumors may appear as papillary lesions or flat high risk lesions (Figure 3).

Figure 3.

Cystoscopic appearance of a papillary non muscle invasive urothelial carcinoma of the bladder.

Imaging studies may show a thickened bladder wall, bladder mass, perivesical stranding changes, hydronephrosis, regional lymphadenopathy, visceral, or skeletal metastases. Cystoscopic findings may include papillary masses, sessile masses or erythematous patches. Flat, high grade Tis tumors may not be detected by cystoscopy. Urine cytology is useful to detect high grade bladder tumors including flat Tis.

If imaging, cystoscopic or cytologic findings are abnormal, the next step is to perform a transurethral resection of bladder tumor (TURBT). A definitive tissue diagnosis of bladder cancer is established at the time of TURBT. The TURBT pathology specimen must include the muscularis propria layer of the bladder. Presence of muscularis propria in the TURBT pathology specimen is fundamental for accurate evaluation of muscle invasive tumors.

A repeat TURBT with deeper resection of bladder tumor is mandatory if the initial TURBT pathology specimen does not include muscularis propria. Presence of muscularis propria in the TURBT pathology specimen is critical for accurate staging of theprimary bladder tumor (T staging).

Patients with metastatic bladder cancer may present with constitutional symptoms including fatigue, unexplained fever, lack of appetite, weight loss, and night sweats. Other manifestations of metastatic bladder cancer include dyspnea on exertion due to anemia; cough, hemoptysis, or chest pain due to lung metastases; flank pain due to hydronephrosis, abdominal pain due to liver metastases, severe back pain due to vertebral metastases.

Beware of other conditions that can mimic bladder cancer:

New onset painless gross hematuria and lower urinary tract symptoms (dysuria, frequency, urgency, nocturia) are the most common manifestations of bladder cancer. Isolated microscopic hematuria is commonly found in patients with bladder cancer. Several non malignant disorders of the urinary collecting system and kidneys can present with isolated microscopic hematuria or gross hematuria. These include:

  • Nephrolithiasis

  • Urinary tract infections (primarily in women and older men with obstructive uropathy)

  • Chronic irritation of the bladder mucosa (indwelling foley catheter)

  • Benign prostatic hyperplasia

  • Primary kidney disease (nephritic syndrome, IgA nephropathy)

  • Radiation cystitis in patients with history of radiotherapy to the pelvis (eg, prior radiotherapy for prostate cancer)

Isolated microscopic hematuria or gross hematuria with or without lower urinary tract symptoms can be the initial manifestation of other pelvic malignancies:

  • Urothelial carcinoma of the urethra

  • Advanced prostate cancer with invasion into the bladder

  • Advanced adenocarcinoma of the rectum with invasion into the bladder

  • Urothelial carcinoma of the upper urinary tract: ureter, renal pelvis

  • Collecting duct carcinoma

  • Renal cell carcinoma (RCC)

Intermittent painless gross hematuria in an adult may be a manifestation for bladder cancer and mandates urologic evaluation. The initial evaluation of a patient with painless gross hematuria includes a complete history and physical examination, urinalysis, urine cytology, complete blood count with differential, serum metabolic profile, coagulation profile (PT/INR and PTT) and office cystoscopy.

Which individuals are most at risk for developing bladder cancer:

Age: The median age at diagnosis is 70.

Gender:Bladder cancer is more common in males than females. The male to female incidence ratio is 3:1.

Environmental factors:

  • Tobacco smoking is the strongest environmental risk factor for bladder cancer. Tobacco smoking increases the risk of bladder cancer by two to four-fold. A significant reduction in the risk of developing bladder cancer after smoking cessation may take up to 20 years. Screening studies targeting smokers may have the highest yield in detecting bladder cancer at earlier stages.

  • Occupational exposure to aromatic amines including beta-naphthylamine, benzidine, aniline dyes, 4- aminobiphenyls and others increases the risk of bladder cancer. Occupations with increased exposure to aromatic amines include painters, leather workers, metal workers, dry cleaners, truck drivers, hairdressers, dental technicians, marine engineers, and petroleum workers.

  • Prolonged treatment with cyclophosphamide increases the risk of urothelial carcinoma of the bladder.

  • Chronic inflammation from indwelling catheters or bladder stones increases the risk of squamous cell carcinoma of the bladder.

  • Individuals with a nonfunctional bladder are at increased risk for developing squamous cell carcinoma of the bladder

  • Chronic infection with Schistosoma hematobium increases the risk of squamous cell carcinoma of the bladder. Chronic schistosomiasis is prevalent in the Nile delta valley in Egypt and in the Middle East.

  • Prior irradiation to the pelvis increases the risk of squamous cell carcinoma of the bladder.

Heredity: Bladder cancer is one of the extracolonic malignancies that may be seen in patients with Lynch Syndrome. Lynch Syndrome is a form of hereditary non polyposis colon cancer (HNPCC) characterized by mutations in one or more of the DNA miss match repair enzymes MLH-1, MSH-2, MHS-6, and PMS-2. The risk of urothelial carcinoma of the bladder is particularly increased in patients with Lynch Syndrome caused by MSH-2 mutations. Surveillance for urinary tract malignancies in patients with Lynch Syndrome include ultrasound of the bladder and upper urinary tract, urine cytology and sediment starting at age 40 every one to two years.

What laboratory and imaging studies should you order to characterize this patient's tumor (ie, stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Transurethral resection of bladder tumor (TURBT)

TURBT helps establish a tissue diagnosis of bladder cancer and determines the depth of tumor invasion into the bladder wall, whether non-muscle invasive or muscle-invasive. A complete resection of all visible bladder tumors, sessile lesions and areas suspicious for urothelial carcinoma in situ (Tis) should be performed. Biopsy of the bladder mucosa adjacent to the resected papillary tumor should be obtained.

After complete resection of all visible tumors multiple random biopsies of different regions of the bladder mucosa should be obtained. These include biopsies of the lateral walls, dome, neck, floor and prostatic urethra. Random biopsies of the bladder mucosa are particularly important when the following lesions are identified:

  • High risk flat or sessile bladder tumors.

  • Suspicion for presence of invasive bladder tumors (T1, T2 or higher T stage).

  • Suspicion for presence high grade tumors.

  • Suspicion for presence of Tis.

Key information obtained from initial TURBT:

  • Histologic subtype.

  • Histologic Grade.

  • Depth of invasion.

  • Presence of high-risk histologic features: micropapillary architecture, extensive Tis, lymphovascular invasion (LVI), squamous cell or small cell histology.

  • Presence of high risk flat or sessile tumors.

  • Location of bladder tumors relative to ureteral orifices. Invasion of ureteral orifices by tumor.

  • Size and number of tumors.

Incomplete resection of tumors at the time of initial TURBT is common and may lead to understaging and undertreatment. Up to 20% of tumors invading the lamina propria (T1) and 30-40% tumors invading the muscularis propria (T2) are understaged during initial TURBT. Bladder examination under anesthesia and a second TURBT performed six weeks after the initial TURBT is indicated when the initial TURBT shows the following findings:

  • High grade histology tumors.

  • Invasive tumors (T1 or T2).

  • Absence of muscularis propria in the pathology specimen from initial endoscopic resection.

  • Incomplete resection due to tumors size and location.

  • Presence of lymphovascular invasion (LVI).

  • High risk flat, sessile lesions, urothelial carcinoma in situ (Tis).

Pathologic information from initial and second TURBT guides the selection of appropriate therapy (e.g. adjuvant intravesical therapy for non-muscle invasive disease versus induction cisplatin-based combination chemotherapy followed by radical cystectomy for muscle invasive disease).

Urine cytology

Urine cytology has a high specificity (96%) and moderate sensitivity (50%) for the detection of high-grade tumors or Tis. In addition, urine cytology is one of the standard surveillance tests used after treatment of non-muscle invasive bladder cancer (Figure 4).

Figure 4.

Cytology of voided urine showing urothelial carcinoma cells in a patient with new onset intermittent painless gross hematuria caused by bladder cancer.

Urine multi target fluorecense in situ hybridization (FISH)

Detection of bladder cancer cells in voided urine with multi target FISH (Figure 5) is commonly used test in patients with bladder cancer. Multitarget FISH detects common chromosomal abnormalities in exfoliated bladder cancer cells in voided urine.

Figure 5.

Multi target fluorecence in situ hybridization (FISH). Chromosomal abnormalities are identified in exfoliated bladder cancer cells in voided urine.

UroVysion is a commercially available multi target FISH urine test. UroVysion is used in practice to clarify equivocal or discordant findings on urine cytology or cystoscopy. UroVysion has a sensitivity of 69% to 87% and a specificity of 89% to 96% detecting bladder cancer cells in voided urine.

The exact role of multi target FISH in the diagnosis and surveillance of bladder cancer needs to be established in prospective randomized clinical trials.

Basic laboratory tests

Complete blood count with differential and chemistry profile including serum creatinine, electrolytes, and liver functions tests should be obtained. Mild normocytic, normochromic anemia of malignancy is not uncommon in patients with bladder cancer.

Leukocytosis can be caused by urinary tract infection. Chronic leukocytosis and thrombocytosis can been seen as a paraneoplastic manifestation of metastatic bladder cancer. The serum creatinine and estimated glomerular filtration rate (GFR) help establish the patient's baseline renal function.

Cisplatin-based combination chemotherapy can be prescribed for patients with GFR more than 60 ml/minute. Elevations of the serum alkaline phophatase can be seen in patients with liver or bone metastases. Patients with elevation of the serum alkaline phosphatase should have a bone scan.

Imaging studies

All patients with a new diagnosis bladder cancer should undergo contrast-enhanced abdominal and pelvic cross-sectional imaging studies (CT or MRI). Imaging studies (Figure 6) may show organ-confined or locally advanced disease. Findings on imaging studies consistent with locally advanced disease include:

Figure 6.

Cross sectional imaging study showing a locally advanced muscle invasive urothelial carcinoma involving the lower right lateral wall of the urinary bladder.

  • Tumor invasion into extravesical space (T3), adjacent organs, pelvic or abdominal wall (T4).

  • Pelvic or lower retroperitoneal lymphadenopathy.

  • Hydroureteronephrosis.

Cross-sectional imaging studies (Figure 7) may underestimate the true extent of pelvic regional lymph node metastases in 25% of patients. Visceral (e.g. liver, adrenal glands) or skeletal metastases may be identified. Patients with resectable muscle invasive bladder cancer (T2a to T4a) should be strongly considered for induction (neoadjuvant) cisplatin-based combination chemotherapy followed by radical cystectomy. Patients with tumor invasion noto the abdominal or pelvic wall (T4b) have unresectable bladder cancer.

Figure 7.

Cross sectional imaging study showing right hydronephrosis caused by a locally advanced high grade urothelial carcinoma of the bladder with invasion into the right ureteral orifice.

Very selected patients with muscle invasive bladder cancer and pelvic lymphadenopathy found on contrast enhanced cross sectional imaging studies may benefit from induction cisplatin-based combination chemotherapy followed by radical cystectomy. Patients in whom this approach is being considered should have the following clinical characteristics:

  • Resectable primary bladder tumor (T2a to T4a).

  • No evidence of primary bladder tumor invasion of pelvic or abdominal wall (T4b).

  • No evidence on physical examination or cross sectional imaging studies of distant metastases involving lymph nodes (e.g. retroperitoneal lymphadenopathy), visceral organs (e.g. adrenal gland) or the skeleton.

  • Very good functional status.

  • Adequate nutritional status.

  • Absence of advanced or severe comorbidities.

  • Adequate renal and hepatic function.

Imaging studies of the upper urinary tract should be obtained before the initial TURBT. Imaging studies of the upper urinary tract may uncover the presence of synchronous urothelial carcinoma of the upper urinary tract. A retrograde pyelogram may be used in patients with renal impairment, contrast allergy, or to clarify equivocal findings on cross sectional imaging studies.

A posterolateral chest X ray should be obtained. Contrast enhanced CT scan of chest should be obtained if the initial chest X ray is abnormal.

A bone scan should be obtained if the serum alkaline phosphatase is elevated or if the patient complains of bone pain.

Contrast enhanced MRI of the brain should be obtained in patients with new onset headache, with changes in the pattern of chronic headache, or with new focal neurologic symptoms or signs.

The role of FDG-PET scan in the staging, surveillance, and evaluation of response to therapy in bladder cancer has not been established yet.

Staging

The TNM staging of bladder cancer is listed in Table I.

Table I.

What therapies should you initiate immediately ie, emergently?

Management of patients with severe gross hematuria

A thorough history and physical examination should be obtained. Presence of hereditary or acquired coagulopathies should be recognized. A careful review of current medications is key. Use of anticoagulant, antiplatelet, and nonsteroidal anti-inflammatory medications should be recognized. Careful monitoring of vital signs and evaluation of the patient's hemodynamic status is fundamental.

Initial laboratory tests include a complete blood count (CBC) plus differential, chemistry profile, coagulation profile including PT/INR, PTT, thrombin time, serum D-dimers, and fibrinogen level. Blood type and cross match should be obtained for patients who require urgent or emergent transfusion of leukocyte depleted packed red blood cells. A urologic consultation is required.

Cystoscopy should be performed to identify the source of bleeding, look for clot formation and retention, and to initiate a three way Foley catheter irrigation. Emergent fulguration of a bleeding bladder tumor may be required. Antifibrinolytic agents such as epsilon aminocaproic acid should be avoided in the management of gross hematuria caused by upper urinary tract malignancies (e.g. urothelial carcinoma of the renal pelvis, collecting duct carcinoma, etc.) since it could lead to acute clot formation in the upper urinary tract and development of acute obstructive uropathy.

Management of patients with bladder cancer-related obstructive uropathy and concommitant renal insufficiency

Patients with locally advanced bladder cancer can present with tumor-related obstructive uropathy and concommitant renal insufficiency. Obstructive uropathy can be caused by unilateral or bilateral tumor invasion of ureteral orifices or by extrinsic compression of the ureter by metastatic retroperitoneal lymph nodes. Bladder cancer-related obstructive uropathy is a negative prognostic factor. The rates of local, regional and systemic recurrence of bladder cancer are higher in patients with tumor-related obstructive uropathy compared to patients without tumor-related obstructive uropathy.

Placement of a percutaneous nephrostomy or insertion of a ureteral stent should be considered in patients with bladder cancer-related obstructiveuropathy. Improvement or normalization of renal function may be seen after drainage of the urinary tract. If possible, a ureteral stent should be initially placed to avoid the external drainage bag. Ureteral stents however may be associated with significant bladder spasms and may inadequately relieve the obstruction. If, after the placement of ureteral stents, the obstruction is not relieved as evidenced by ongoing flank pain, elevated serum creatinine, or persistent hydronephrosis, then placement of percutaneous nephrostomy by interventional radiology is recommended. The decision to place a PCN or a ureteral stent is mainly base in institutional practice rather than specific clinical criteria.

Induction (neoadjuvant) cisplatin-based combination chemotherapy followed by radical cystectomy should be strongly considered in patients who have normalization or improvement of renal function (GFR > 60 ml/min) after treatment of obstructive uropathy

What should the initial definitive therapy for the cancer be?

Management of non-muscle invasive urothelial carcinoma of the bladder

The goals of treatment for patients with non-muscle invasive urothelial carcinoma of the bladder are to eradicate all visible tumors, prevent or delay local recurrence, and prevent progression to a higher disease stage and grade. Treatment for non-muscle invasive urothelial carcinoma of the bladder includes transurethral resection of bladder tumor (TURBT), adjuvant intravesical chemotherapy (e.g. mitomycin C), and adjuvant Bacillus Calmette-Guérin(BCG) immunotherapy.

Transurethral resection of bladder tumor (TURBT)

Non-muscle invasive urothelial carcinoma of the bladder includes noninvasive papillary tumors (Ta), tumors with invasion of the lamina propria of the bladder wall (T1), and urothelial carcinoma in situ (Tis). The standard treatment for non-muscle invasive urothelial carcinoma is TURBT. A complete endoscopic resection of all visible bladder tumors including flat or sessile lesions and areas suggestive of Tis should be performed. The clinical and pathologic findings from a complete TURBT guide further management and provide information about prognosis. The quality and completeness of TURBT has a significant impact on outcomes.

Second or repeat TURBT

Due to tumor size or location, complete endoscopic resection may not be achieved during initial TURBT. Incomplete resection of bladder tumor(s) leads to understaging and undertreatment. A second or repeat TURBT should be strongly considered in the following scenarios:

  • High grade histology tumors.

  • Invasive tumors (T1 or T2).

  • Absence of muscularis propria in the pathology specimen from initial endoscopic resection.

  • Incomplete resection due to tumors size and location.

  • Presence of lymphovascular invasion (LVI).

  • High risk flat, sessile lesions, urothelial carcinoma in situ (Tis).

Goals of second or repeat TURBT:

  • Obtain accurate staging of the primary bladder tumor.

  • Decrease the rates of understaging and undertreatment.

  • Improve local control of non-muscle invasive tumors.

  • Enhance the efficacy of adjuvant intravesical therapies.

  • Enhance the response of residual bladder tumors to intravesical therapies.

  • Provide pathologic information (grade of tumor, depth of invasion) that may help in the selection of treatment (intravesical chemotherapy, intravesical immunotherapy, early radical cystectomy, induction or neoadjuvant cisplatin-based combination chemotherapy, etc).

Intravesical therapy

Bladder cancer is characterized by high recurrence rates. Depending on stage and grade of tumor 50-100% of patients will have recurrence of bladder cancer. A small proportion of patients with non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis) can be cured with TURBT only. To reduce bladder tumor recurrence rates, adjuvant intravesical instillation of chemotherapeutic agents including mitomicyn C, doxorubicin, epirubicin, gemcitabine and valrubicin or intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) are prescribed.

Mitomycin C and BCG are the most commonly used first line intravesical agents, while gemcitabine and valrubicin are indicated for refractory cases. Intravesical therapy is an office based procedure performed by an experienced urologist. In the typical procedure an intravesical catheter is placed under sterile conditions. Subsequently the chosen intravesical agent is directly instilled into the bladder urothelium. After the bladder instillation is completed the intravesical catheter is removed. The patient is then asked to rotate in various positions to ensure coverage of all bladder surfaces (lateral walls, dome, trigone and neck). Finally the patient voids and the treatment is completed.

A less common use of intravesical therapies is for treatment of residual visible bladder tumor(s) after initial TURBT. Intravesical therapy is unlikely to eradicate residual bladder tumors that can not be completed resected endoscopically. An exception is urothelial carcinoma in situ (Tis). The majority of Tis bladder tumors are high risk flat lesions that can be missed at the time of cystoscopy. Up to two courses of induction intravesical BCG immunotherapy are associated with an initial complete response rate of 70% to 75% in patients with Tis. Intravesical therapy prescribed for visible residual bladder tumors after initial endoscopic resection is not considered a form of adjuvant therapy.

General indications for intravesical therapy

After complete endoscopic resection of all visible bladder tumor(s) intravesical therapy should be considered for the following groups of patients with non-muscle invasive bladder cancer:

  • Low grade noninvasive bladder tumors (Ta). In these patients a single dose of immediate intravesical mitomicyn C chemotherapy is a treatment option.

  • High grade noninvasive bladder tumors (Ta).

  • Low grade bladder tumors with invasion of the lamina propria (T1).

  • High grade bladder tumors with invasion of the lamina propria (T1).

  • Multifocal bladder tumors.

  • High grade flat lesions/urothelial carcinoma in situ (Tis).

  • Relapsed non-muscle invasive bladder tumors (Ta and T1).

Intravesical therapy for low grade noninvasive papillary urothelial carcinoma of the bladder (Ta)

After a first complete endoscopic resection of a low grade papillary noninvasive bladder tumor (Ta), four different management options can be considered:

  • Surveillance with periodic office cystoscopy and urine cytology.

  • A single dose of immediate intravesical chemotherapy (e.g. mitomycin C) within 24 hours of TURBT followed by surveillance.

  • One course of induction intravesical chemotherapy which includes six weekly instillations of intravesical chemotherapy followed by surveillance.

  • A single dose of immediate intravesical chemotherapy followed by one course of induction intravesical chemotherapy followed by surveillance .

Immediated intravesical chemotherapy for noninvasive papillary bladder tumors (Ta) involves the instillation of a single dose of intravesicalchemotherapy (mitomycin C) within 24 hours of TURBT. Adjuvant immediate intravesival mitomycin C is associated with an absolute risk reduction of local bladder tumor recurrence of 12%. This represents a 39% relative reduction in the risk of local disease recurrence.

Similar results are seen with a course of induction intravesical chemotherapy. Immediate adjuvant single dose mitomicyn C is well tolerated and is associated with minimal toxicity. The decision to choose between the four management options described above for a low grade noninvasive bladder tumor (Ta) should be individualized. Patient's preferences should be considered as well.

Intravesical therapy for high grade noninvasive urothelial carcinoma of the bladder (Ta) and urothelial carcinoma of the bladder with invasion of the lamina propria (T1)

Patients with high grade non-muscle invasive bladder cancer have a high risk of local recurrence of high grade tumors and progression to higher stages of disease. The majority of tumors invading the lamina propria (clinical T1 disease) have a high grade histology. After initial endoscopic resection of high grade T1 tumors, a second TURBT should be strongly considered. After complete endoscopic resection of high grade non-muscle invasive tumors, adjuvant intravesical therapy should be considered. In this setting, BCG is the preferred form of adjuvant intravesical therapy.Treatment involves six weekly instillations of intravesical BCG starting two weeks after TURBT.

Intravesical therapy for urothelial carcinoma in situ (Tis)

Urothelial carcinoma in situ (Tis) is a high risk, morphologically flat, high grade tumor. It is associated with high rates of recurrence (virtually 100%) and progression to higher disease stage (15%). Tis tumors can be missed by cystoscopy. They arise in the setting of a cancerization field effect of the bladder urothelium. Complete endoscopic resection of all Tis tumors may not be possible.

Intravesical BGG immunotherapy is mandatory after partial or complete resection of Tis tumors. In meta-analyses, intravesical BCG is associated with 70% to 75% initial complete response in patients with Tis. 40 to 50% of patients demonstrate a durable complete response over several years (> 5 years).Some studies suggest that intravesical BCG immunotherapy is associated with a 26% reduction in disease progression to higher stages of bladder cancer in patients with Tis.

Adjuvant intravesical therapy

The most common and important indication for intravesical therapy is as adjuvant treatment after complete endoscopic resection of all visible non-muscle invasive bladder tumor(s). Intravesical therapy has not been definitely proven to delay progression of non-muscle invasive bladder tumors, to higher disease stage or grade. Adjuvant intravesical therapy delays and decreases the rate of recurrence of non-muscle invasive bladder cancer.

Commonly prescribed forms of adjuvant intravesival therapies and their respective indications include:

1. Immediate intravesical chemotherapy

Immediate adjuvant intravesical chemotherapy involves the instillation of a single dose of chemotherapy into the bladder within 24 hours of TURBT.

Indication:

  • Low grade noninvasive bladder tumor (Ta)

A course of induction intravesical BCG immunotherapy is a prefered option for high grade noninvasive bladder tumors (high grade Ta), low and high grade bladder tumors with invasion of the lamina propria (T1). The presence of any urothelial carcinoma in situ (Tis) mandates treatment with induction intravesical BCG immunotherapy.

2. Induction intravesical chemotherapy

One course of induction intravesical chemotherapy includes six weekly instillations of chemotherapy into the bladder. Induction intravesical chemotherapy is prescribed three to four weeks after TURBT. Up to two courses of induction intravesical chemotherapy are prescribed.

Indication:

  • Low grade noninvasive bladder tumors (Ta)

3. Induction intravesical BCG immunotherapy

One course of induction intravesical BCG immunotherapy includes six weekly instillations of BCG into the bladder. Induction intravesical BCG is prescribed three to four weeks after TURBT. Up to two courses of induction intravesical chemotherapy are prescribed.

Indications:

  • High grade noninvasive bladder tumor (high grade Ta)

  • Urothelial carcinoma in situ (Tis)

  • Low grade or high grade bladder tumor with invasion into the lamina propria (T1)

4. Manitenance intravesical BCG immunotherapy

Maintenance intravesical BCG immunotherapy includes six to twelve monthly instillations of BCG into the bladder.

Indication:

  • Manitenance intravesical BCG immunotherapy is a treatment option after complete endoscopic resection of recurrent or residual bladder tumor(s) in patients who have recurrent or residual bladder tumor(s) after one or two courses of induction intravesical mitomicyn C chemotherapy or intravesical BCG immunotherapy.

Specific Intravesical Therapies:

5. Intravesical mitomycin C

The most commonly administered adjuvant intravesical chemotherapeutic agent is mitomycin C. Immediate adjuvant intravesical mitomycin C administered within 24 hours of TURBT benefits a significant proportion of patients with non-muscle invasive bladder cancer. Mitomycin C decreases the rate of non-muscle invasive bladder cancer recurrence. It does not affect or prevent the progression of non-muscle invasive bladder cancer to higher disease stages.

Immediate intravesical mitomicyn C chemotherapy within 24 hours after complete endoscopic resection of a bladder tumor(s) is one of the management options for low grade noninvasive bladder cancer (Ta). Adjuvant intravesical mitomicyn C is not considered a first line treatment after complete endoscopic resection of high risk non-muscle invasive bladder cancer including high grade bladder tumors, urothelial carcinoma in situ (Tis) and bladder tumors with invasion into the lamina propria (T1).

Side effects and complications of intravesical mitomycin C

  • Myelosuppression due to systemic absortion. Prolonged myelosuppression can be seen in the setting of bladder perforation and peritoenal absorbtion of chemotherapy.

  • Skin rash.

  • Non infectious cystitis with irritative lower urinary tract symptoms (LUTs): dysuria, frequency, urgency.

  • Superimposed bacterial cystitis, urinary tract infection.

  • Death.

BCG intravesical immunotherapy

Intravesical instillation of the biologic response modifier BCG after complete endoscopic resection of bladder tumor(s) is a well established form of intravesical immunotherapy for non-muscle invasive bladder cancer. Low-grade non invasive bladder tumors (Ta) are relatively resistant to BCG intravesical immunotherapy. In contrast, high grade bladder tumors, urothelial carcinoma in situ (Tis) and bladder tumors invading the lamina propria (T1) are more sensitive to BCG intravesical immunotherapy.

One induction course of intravesical BCG immunotherapy involves six weekly instillations of BGC into the bladder urothelium starting two to three weeks after TURBT. Office cystoscopy and/or mapping bladder biopsies are performed 3 months after BCG administration to document treatment success. A second 6-week course of induction intravesical BCG may be used if residual bladder tumor is found and resected completely. Up to two courses of induction intravesical BCG are associated with a 20% to 60% decrease in the rate of bladder tumor recurrence at a median follow up ranging from 2 to 7 years.

Prospective randomized clinical trials and meta-analyses have demonstrated a significant decrease in the rate of bladder tumor recurrence with intravesical BCG compared to intravesical mitomicyn C in patients with high risk non-muscle invasive bladder cancer including:

  • High grade bladder tumors.

  • Urothelial carcinoma in situ (Tis).

  • Bladder tumors invading the lamina propria (T1).

Response of non-muscle invasive bladder tumors to intravesical BCG varies by different clinical factors including:

  • Patient's age.

  • General immune status.

  • Previous exposure to BCG.

  • Tumor characteristics such as location, stage, grade, antigenicity, and doubling time.

Studies evaluating novel predictive factors of bladder tumor response to intravesical BCG immunotherapy are under way. These include microarray gene expression profiling of bladder tumors, evaluation of cytokine gene expression variants among others. At the present time it is not clear if intravesical BCG reduces the rate of disease progression of non-muscle invasive bladder tumors to higher disease stages.

Randomized controlled studies indicate that maintenance BCG is associated with a further reduction of the risk of non-muscle invasive bladder cancer recurrence. Although the optimal maintenance schedule has not been defined by controlled comparison, maintenance BCG administration at 3, 6, 12, 18, 24, 30, and 36 months are recommended, but dose reduction and delay or suspension of treatments is frequently needed to reduce side-effects.

Immediate intravesical BCG immunotherapy within 24 hours of TURBT is not used in the management of non-muscle invasive bladder cancer.

Side effects and complications of intravesical BCG

The following side effects and complications can be seen after intravesical instillation of BCG:

  • Flu like symptoms: fever, malaise, fatigue, myalgias, arthralgias.

  • Systemic mycobacterial dissemination. This rare complication is seen most frequently in immunecompromissed hosts (e.g patient with lymphoproliferative disorder), debilitated and elderly patients.

  • Granulomatous prostatis.

  • Vesicocutaneous or enterovesical fistula tract formation.

  • Non infectious cystitis with irritative lower urinary tract symptoms (LUTs): dysuria, frequency, urgency.

  • Superimposed bacterial cystitis, urinary tract infection.

  • Death.

Management of BCG refractory non-muscle invasive bladder cancer

Bladder tumor relapse after intravesical BCG is a common and challenging clinical scenario in the management of patients with non-muscle invasive bladder cancer. Several definitions of BCG-refractory non-muscle invasive bladder cancer exist.

A clinically useful definition of BGC-refractory non-muscle invasive bladder cancer includes patients with the following characteristics:

  • Persistent bladder tumor (s) after two induction courses of BCG intravesical immunotherapy.

  • Urothelial carcinoma in situ (Tis) recurrence less < 6 months after achieving a complete response to one to two induction courses of intravesical BCG immunotherapy.

  • Recurrence of Tis while receiving maintenance BGC intravesical immunotherapy.

  • Relapse with bladder tumor invasive.

The management options of BCG-refractory non musle invasive bladder cancer include:

  • Radical cystectomy.

  • In patients who are not candidates for cystectomy intravesical chemotherapy with a different agent cn be tried: gemcitabine, valrubicin, docetaxel and others.

  • Participation in a clinical trial.

Contraindications for intravesical therapies

Patients in whom intravesical therapies should be avoided include:

  • Suspected bladder perforation at the time of TURBT. In patients with bladder perforation at the time of endoscopic resection of bladder tumor, intraperitoneal administration and absorption of mitomycin C can cause significant toxicity and prolonged myelosuppression.

  • Extensive TURBT.

  • Severe allergic reactions to the specific intravesical therapeutic agent.

  • Untreated urinary tract infection.

Complications directly related to bladder catheterization:

  • Traumatic injury to the bladder urothelium.

  • Bladder perforation (rare).

  • Bacterial cystitis, urinary tract infection.

Early radical cystectomy for non-muscle invasive bladder cancer

Definition of radical cystectomy:

  • Male patients: Cystoprostatectomy with or without urethrectomy, bilateral pelvic and lower retroperitoneal lymph node dissection plus some form of continent or incontinent urinary diversion.

  • Female patients: Resection of the anterior vaginal wall, cystectomy, hysterectomy (anterior pelvic exenteration) with or without urethrectomy, bilateral pelvic and lower retroperitoneal lymph node dissection and some form of continent or incontinent urinary diversion.

The indications for early radical cystectomy for patients with non-muscle invasive urothelial carcinoma of the bladder include:

  • Local recurrence of high grade non-muscle invasive disease after intravesical chemotherapy or intravesical BCG immunotherapy.

  • High grade T1 and Tis tumors refractory to intravesical chemotherapy or immunotherapy.

Early radical cystectomy for recurrent or refractory high grade non-muscle invasive disease results in improved overall survival and recurrence-free survival compared to delayed radical cystectomy. Patients with pathologic stage T1 ot Tis at the time of early radical cystectomy have improvement in overall survival compared to patients with pathologic stage T2 or higher (muscle invasive disease).

Management of muscle invasive bladder cancer

Radical cystectomy, bilateral pelvic lymphadenectomy and some form of urinary diversion remains the standard treatment of muscle invasive bladder cancer. A proportion of patients with muscle invasive disease have micrometastases at the time of radical cystectomy. Without additional treatment, most of these patients will develop gross metastatic disease and will die of metastatic bladder cancer. Patients with muscle-invasive bladder cancer treated with TURBT only have a poor outcome. Most patients with muscle invasive disease treated with TURBT only develop local, regional, and distant metastatic disease within 2 years of diagnosis.

Radical cystectomy

Radical cystectomy performed by an experienced urologic oncologists is the single most effective and successful treatment modality for muscle invasive bladder cancer. Radical cystectomy involves a standardized surgical procedure, including a meticulous pelvic iliac lymphadenectomywith en bloc radical cystectomy, and urinary diversion.

Radical cystectomy alone for muscle-invasive bladder cancer is associated with a low mortality rate (<1-2% in contemporary series), a small but significant rate of post-operative complications (15-20% have a Clavien Grade III or higher complication), and provides excellent local control of the cancer with low local recurrence rates (5-10% in contemporary series). Furthermore, improvements in orthotopic urinary diversion have improved the quality of life in patients after cystectomy. The five year overall survival after radical cystectomy based on tumor pathologic stage is shown below (Table II).

Table II.

Five year overall survival (OS) after radical cystectomy.
Pathologic T stage at the time of radical cystectomy 5 year OS (%)
pT2 66
pT3 35
pT4 27

The 5 and 10-year recurrence-free survival for patients with organ-confined, lymph node–negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymphnode-negative tumors had 89%, 87%, 78% and 76% 5 and 10-year recurrence-free survival, respectively.

Patients with non organ-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared to those with organ-confined bladder cancers. The 5 and 10-year recurrence-free survival for pT3b tumors was 62% and61%, and for pT4 tumors was 50% and 45%, respectively. Among patients with lymph node tumor involvement, the 5 and 10-year recurrence-free survival for these patients was 35% and 34%, respectively,which was significantly lower than that for patients without lymph node involvement.

Partial cystecyomy

Patients should be strongly counseled that a partial cystectomy for muscle-invasive transitional cell carcinoma may be associated with higher rates of local and systemic recurrence. Since functional bladder substitutes such as the orthotopic neobladder are widely available, partial cystectomies must be reserved only for select indications such as a urachal adenocarcinomas. In highly selected patients with muscle invasive bladder cancer partial cystectomies may be performed by an experienced urologic oncologist. The goals of a partial cystectomy are:

  • To remove the bladder tumor completely.

  • To maintain continence and adequate bladder capacity.

Partial cystectomies can be performed for patients with bladder tumors with the following characteristics:

  • Small unifocal tumor.

  • Tumors away from the ureteral orifices and bladder neck (e.g. tumors involving the dome of the bladder).

  • Complete resection of the tumor is safe and feasible.

  • Obtaining a surgical margin free of malignancy more than 2 cm from the primary bladder tumor is feasible.

  • Bladder reconstruction after partial cystectomy is feasible and results in a functional bladder with adequate bladder capacity.

  • Random biopsies elsewhere in the urothelium does not show high risk flat lesions (e.g urothelial carcinoma in situ, Tis).

  • Urachal adenocarcinomas in the dome of the bladder.

These bladder tumor characteristics are present in a very small minority of patients with muscle invasive bladder cancer. All patients must have negative random bladder biopsies of the "normal" bladder regions. In addition, pre-operative MRI evaluation of the abdomen and pelvis should be performed to evaluate the local extent of the malignancy. Induction cisplatin-based combination chemotherapy should be considered for patients with muscle invasive bladder cancer candidates for a partial cystectomy. Finally, whenever possible, a radical cystectomy should be offered for patients with muscle-invasive transitional cell carcinoma, due to the field effect.

Extent of lymphadenectomy

A thorough bilateral pelvic lymph node dissection at the time of radical cystectomy (Figure 8) results in accurate pathologic staging, improves disease local-regional control and provides key information about management and prognosis. A more complete lymphadenectomy is associated with a higher likelihood of a complete resection, a higher chance of negative surgical margins and a lower local and systemic recurrence rate. Patients with micrometastatic disease to the pelvic lymph nodes may be cured by a thorough lymphadenectomy. On the other hand, patients with bulky involved lymph nodes are unlikely to be cured by an extended lymphadenectomy.

Figure 8.

Lower retroperitoneal and extended bilateral pelvic lymph node dissection performed at the time of radical cystectomy for a muscle invasive bladder cancer. Radical cystectomy should be performed by an experienced urologic oncologist at high volume centers of excelence.

Currently, there is no recommended minimum number of pelvic lymph nodes that should be resected. The optimal extent of bilateral pelvic lymphadenectomy is being established in a prospective randomized clinical trial. Patients with metastases to regional pelvic lymph nodes have a high risk for distant micrometastatic disease and development of gross visceral and skeletal metastases and should be strongly considered for adjuvant chemotherapy.

Types of urinary diversion

Two main classes of urinary diversions are performed at the time of radical cystectomy: non continent and continent urinary diversions.

1. Ileal conduit urinary

The ileal conduit urinary diversion is a non continent urinary diversion. It is the simplest and the most common type of urinary diversion performed. The ileal conduit is the standard type of urinary diversion to which newer types of urinary diversion are compared. The ileal conduit is a resected segment of ileum that serves as a simple passage of urine. It is anastomozed proximally to both ureters and distally to an externalized stoma through the abdominal wall. There is free and constant urinary flow via the ileal conduit into an external urinary bag applied around the abdominal wall stoma.

2. Orthotopic neobladder urinary diversion

Orthotopic neobladder is a type of continent urinary diversion. The neobladder is created from detubularized segments of small intestine. The neobladder is anastomozed proximally to both ureters and distally to the proximal urethra through a Foley catheter. Urinary continence is preserved as the native urethral sphincter and its function are preserved. In carefully selected patients, the orthotopic neobladder is the preferred form of urinary diversion.

3. Continent cutaneous urinary diversion

In the continent cutaneous urinary diversion an ileal pouch is anastomozed proximally to the ureters and distally to a detubularized, aperistaltic segment of ileum which in turn is anastomozed to the abdominal wall. The urine accumulates in the ileal pouch and needs to be drained by clean self catheterization. The patient needs to perform life-long clean self catheterization.

Continent urinary diversions are more complex, demanding, and longer surgical procedures compared to the standard ileal conduit urinary diversion (Figure 9). Patient selection for urinary diversion is complex and should be individualized. Relevant clinical factors that influence the choice of urinary diversion include:

Figure 9.

Patient with surgical scar after radical cystectomy with orthotopic neobladder urinary diversion for muscle invasive bladder cancer. Urinary continence is preserved as the native urethral sphincter and its function are preserved.

  • Patient's health.

  • Weight.

  • Renal function.

  • Hepatic function.

  • Local and regional extent of bladder cancer at the time of presentation.

  • Patient's ability and commitment to perform clean self catheterization.

  • Presence of gastrointestinal disease (e.g inflammatory bowel disease).

Patients with significant renal or hepatic dysfunction, obesity, locally or regionally advanced bladder cancer are not considered candidates for orthotopic neobladder urinary diversion.

Induction cisplatin-based combination chemothetapy for muscle invasive bladder cancer

Half of all patients with muscle invasive bladder cancer have micrometastases at the time of radical cystectomy. Without additional therapy, the majority of these patients will develop gross metastases within the first two to three years after radical cystectomy and will die from distant metastatic disease. For these patients, radical cystectomy as a single treatment modality is not enough to achieve a long term remission.

The results of two prospective randomized controlled clinical trials and two metaanalysis demonstrate the safety and efficacy of induction (neoadjuvant) cisplatin-based combination chemotherapy administered before radical cystectomy for patients with muscle invasive (T2) or higher stage (T3, T4a) bladder cancer.

The goals of induction cisplatin-based combination chemotherapy are:

  • Treatment of micrometastases.

  • Down staging of the primary bladder tumor.

  • Decrease the rate of relapse.

  • Improve overall survival.

At five years of follow up, induction-cisplatin based combination chemotherapy is associated with a 14% relative risk reduction in the rate of bladder cancer related death and a 5% absolute improvement in overall survival.

Induction cisplatin-based combination chemotherapy regimens

1. Methotrexare, vinblastine, doxorubicin, and cisplatin (M-VAC)

Three cycles of methotrexare, vinblastine, doxorubicin, and cisplatin (M-VAC) is a standard induction cisplatin-based combination chemotherapy regimen. Each cycle of induction chemotherapy is administered every 28 days:

  • Methotrexate 30mg/ m2 on days 1, 15, and 22.

  • Vinblastine 3mg/m2 on days 2, 15, and 22.

  • Doxorubicin 30mg/m2 on day 2.

  • Cisplatin 70mg/m2 on day 2.

Myeloid growth factor support therapy for prevention of febrile neutropenia should be initiated on day 3 of each cycle of M-VAC:

  • Filgrastim 5mcg/Kg subcutaneously daily on days 3, 4, 5, 6, 7, 8 and 9

Chemotherapy on days 15 and 22 (methotrexate and vinblastine) should be given to the patient only if the absolute neutrophil count is above 1500 and the platelet count is above 100,000.

38% of patients who receive induction cisplatin-based combination chemotherapy do not have residual tumor in the bladder (pathologic complete response) at the time of radical cystectomy. Pathologic complete response at the time of radical cystectomy is associated with improved overall survival and recurrence-free survival.

Overall, induction cisplatin-based combination chemotherapy is safe. It does not decrease the patient's chance of undergoing a radical cystectomy. No treatment related deaths have been reported in published prospective phase III randomized controlled clinical trials. Induction cisplatin-based combination chemotherapy does not increase the rate of postoperative complications. A third of patients treated with three cycles of induction M-VAC develop severe neutropenia (grade 4) and 17% develop moderate (grade 3) gastrointestinal toxicity (nausea or vomiting, stomatatis, or diarrhea).

2. Gemcitabine plus cisplatin (GC)

Gemcitabine plus cisplatin (GC) is a commonly prescribed induction chemotherapy regimen before radical cystectomy for patients with muscle invasive bladder cancer. This regimen includes three cycles of GC administered every 28 days:

  • Gemcitabine 1000mg/m2 on days 1, 8, and 15

  • Cisplatin 70mg/m2 on day 2

There are no published prospective randomized phase III clinical trials evaluating the safety and efficacy of induction GC followed by radical cystectomy for patients with muscle invasive bladder cancer. Despite the lack of evidence from prospective randomized studies, induction GC is commonly prescribed before radical cystectomy.

Adjuvant Cisplatin based combination chemotherapy for muscle invasive urothelial carcinoma of the bladder

The role of adjuvant cisplatin-based combination chemotherapy administered after radical cystectomy is not clearly established. Published studies evaluating the safety and efficacy of adjuvant cisplatin-based combination chemotherapy are small and lack power to detect significant differences in overall survival or relapse-free survival. Recommendations about adjuvant cisplatin-based combination chemotherapy after radical cystectomy are based on expert opinion. In some patients with muscle invasive bladder cancer who did not receive induction chemotherapy before radical cystectomy, adjuvant cisplatin-based combination chemotherapy is recommended.

After radical cystectomy, three to four cycles of adjuvant M-VAC or GC administered every 28 days are recommended for patients with muscle invasive bladder cancer at very high risk for harvoring micrometastatic disease. These include:

  • Patients with tumor invasion into microscopic or macroscopic perivesical tissue, pathologic T3a or T3b.

  • Patients with tumor invasion into adjacent organs, pathologic T4a.

  • Patients with metastases to primary or secondary pelvic regional lymph nodes, pathologic N1, N2, or N3..

Trimodality therapy-selective bladder preservation for muscle invasive urothelial carcinoma of the bladder

Trimodality therapy and selective bladder preservation is an alternative to radical cystectomy for selected patients with muscle invasive bladder cancer. Trimodality therapy involves a complete TURBT of all visible tumor(s) followed by concurrent chemoradiotherapy to the bladder and regional lymph nodes, followed by three to four cycles of adjuvant cisplatin-based combination chemotherapy.

The goals of trimodality therapy are:

  • Preservation of the patient's original bladder.

  • Preservation of bladder function.

  • Decrease the rate of local, regional, and systemic relapse.

  • Achieve local, regional and systemic remission.

  • Achieve optimal overall survival.

External beam radiotherapy techniques in use are image guided radiotherapy and intensity modulated radiotherapy (IMRT). One of the most important factors determining the local and regional control with trimodality therapy is the total dose of radiotherapy delivered to the primary bladder tumor and to regional lymph nodes. The total dose of radiotherapy to the primary bladder tumor ranges from 55 Gy to 70 Gy. The dose of radiotherapy to regional lymph nodes ranges from 45 Gy to 50 Gy.

Systemic chemotherapy is administered concurrently with radiotherapy to radio sensitize and inhibit the repopulation of bladder cancer cells. The most frequently prescribed chemotherapeutic agent is cisplatin. Other chemotherapeutic agents frequently prescribed concurrently with radiotherapy include carboplatin, paclitaxel, 5 fluorouracil (5FU), mitomycin C and others.

In a prospective, randomized clinical trial, infusional 5FU plus mitomycin C given concurrently with radiotherapy to the bladder was associated with improved local regional control compared to radiotherapy alone in patients with muscle invasive bladder cancer. The chemotherapy regimen prescribed in this prospective randomized clinical trial was as follows:

  • 5FU 500mg/m(2)continuous intravenous infusion (CIV) during days 1 to 5 and 16 to 20 of radiotherapy (10 days total)

  • Mitomycin C 12mg/m(2) intravenous (IV) bolus infusion on day 1 of radiotherapy.

This non-platinum chemotherapy regimen is particularly useful in patients with renal dysfunction (GFR < 50mL/min).

After completion of concurrent chemoradiotherapy, adjuvant cisplatin-based combination chemotherapy is prescribed for the treatment of probable micrometastatic disease. The most frequently prescribed adjuvant combination chemotherapy regimen is GC.

Adequate selection of patients for trimodality therapy is fundamental to achieve optimal outcomes. Eligible patients for trimodality therapy include those with the following clinical parameters:

  • Small bladder tumor (< 5cm).

  • Early T stage (T2 or lower T stage).

  • Complete TURBT of all gross visible tumor(s).

  • No evidence of regional pelvic lymph node involvement on contrast enhanced cross sectional imaging studies.

  • Absence of tumor related obstructive uropathy, ureteral obstruction, or hydronephrosis.

Selected patients with resectable muscle invasive bladder cancer (primary bladder tumor T4a or lower T stage), pelvic or lower retroperitoneal lymph node metastases and no clinical or radiologic evidence of distant lymph node, visceral or skeletal metastases may be candidates for induction cisplatin-based combination chemotherapy followed by salvage radical cystectomy. These patients are not eligible for trimodality therapy.

Management of unresectable or metastatic bladder cancer

1. Systemic chemotherapy for unresectable or metastatic urothelial carcinoma of the bladder

Bladder cancer is a chemosensitive solid epithelial malignancy. Cisplatin-based combination chemotherapy is the mainstay of treatment for metastatic or unresectable bladder cancer. The current standard first line treatment for patients with unresectable or metastatic bladder cancer and preserved renal function (GFR > 60 mL/min) is cisplatin plus gemcitabine. Up to six cycles of cisplatin plus gemcitabine is the current standard first line therapy for patients with metastatic or unresectable bladder cancer. Each cycle of cisplatin plus gemcitabine is administered every 28 days as follows:

  • Gemcitabine 1000mg/m2 IV on days 1, 8, and 15.

  • Cisplatin 70mg/m2 IV on day 2.

Response to chemotherapy is evaluated with contrast enhanced cross sectional imaging studies (CT scan or MRI) every two to three cycles of chemotherapy (Figure 10).

Figure 10.

Radiographic response of lung metastases after two cycles of first line cisplatin plus gemcitabine in a patient with high grade urothelial carcinoma of the bladder with lung metastases. Urothelial carcinoma of the bladder is considered a chemosensitive solid tumor. Responses to cisplatin-based combination chemotherapy in the great majority of patients with unresectable or metastatic bladder cancer are short lived.

Patients with metastatic or unresectable bladder cancer treated with first line methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) combination chemotherapy have a similar median overall survival and objective response rates compared to patients treated with first line gemcitabine plus cisplatin. MVAC is associated with more frequent and severe side effects compared to gemcitabine plus cisplatin. These include severe mucositis (oral mucosal ulceration, diarrhea), myelosuppression, febrile neutropenia, severe fatigue and decline of quality of life. Gemcitabine plus cisplatin is considered the current standard first line combination chemotherapy regimen for patient with metastatic or unresectable bladder cancer.

The second generation platinum agent carboplatin is not equivalent to cisplatin in the treatment of metastatic or unresectable bladder cancer. The role of first line carboplatin-based combination chemotherapy for metastatic or unresectable bladder cancer is not clearly established. In patients with preserved renal function (GFR > 60 mL/min) cisplatin plus gemcitabine is the standard first line chemotherapy regimen. Carboplatin should not be prescribed in patients eligible for cisplatin-based combination chemotherapy.

2. Second-line chemotherapy for metastatic or unresectable bladder cancer

Second line chemotherapy may be considered for the following groups of patients with metastatic or unresectable bladder cancer:

  • Patients who have radiographic progression during or after completion of first line cisplatin-based combination chemotherapy.

  • Patients with disease resistant or refractory to first line cisplatin-based combination chemotherapy.

  • Patients who developed severe toxicity or unmanageable side effects caused by first line cisplatin-based combination chemotherapy.

Clinical factors influencing the decision to prescribe second-line chemotherapy include:

  • Performance and nutritional status of the patient.

  • Rate of progression of metastatic or unresectable disease during or after completion of first line combination chemotherapy.

  • Extent of metastatic or unresectable disease.

  • Patient's preference.

Goals of second-line chemotherapy include:

  • Palliation of symptoms.

  • Improvement of quality of life.

  • Prolongation of life.

Currently, there is no standard second-line single agent or combination chemotherapy regimen for patients with metastatic or unresectable bladder cancer who had progression after first line chemotherapy. Ideally, these patients should be enrolled in prospective randomized clinical trials evaluating the safety and efficacy of new antineoplastic or targeted therapies.

When prescribing second line systemic therapy it is important to avoid combination chemotherapy regimens associated with high rates of severe side effects that could have a negative impact on the patient's quality of life. In general, single agent chemotherapy is associated with lower rates of toxicity and side effects compared to combination chemotherapy. In addition to second line chemotherapy all patients should receive best supportive care as well.

Commonly prescribed second line single agent chemotherapy for patients with metastatic or unresectable bladder cancer include:

  • Paclitaxel 185mg/m2 IV every 21 days.

  • Docetaxel 75mg/m2 IV every 21 days.

  • Pemetrexed 500mg/m2 IV every 21 days.

Commonly prescribed second line combination chemotherapy regimens for patients with metastatic or unresectable bladder cancer include:

  • Paclitaxel 175mg/m2 IV on day one plus gemcitabine 1000 mg/m2 on days one and eight every 21 days.

  • Paclitaxel 200mg/m2 continuous IV infusion over 24 hours on day one plus ifosfamide 1000mg/m2 IV on days one, two, three and four every 21 days. Pegfilgrastim 6 mg subcutaneous on day five (TIP).

  • Docetaxel 40mg/m2 IV plus gemcitabine 800mg/m2 IV both on days one and eight every 21 days.

New chemotherapeutic agents undergoing evaluation in prospective clinical trials include vinflunine, ixabepilone as well as others.

3. First-line triple agent combination chemotherapy for patients with metastatic or unresectable bladder cancer

Front line combination chemotherapy with three different chemotherapeutic agents is not superior to standard front line cisplatin plus gemcitabine for patients with metastatic or unresectable bladder cancer. The safety and efficacy of first-line triple agent combination systemic therapy with novel chemotherapeutic or targeted agents needs to be evaluated in well designed prospective randomized clinical trials.

4. Systemic chemotherapy for patients with metastatic or unresectable bladder cancer not eligible for cisplatin-based combination chemotherapy

Patients with advanced bladder cancer with the following characteristics are not considered eligible for cisplatin-based combination chemotherapy:

  • GFR less than 60ml/min.

  • Grade 2 or higher hearing loss.

  • New York Heart Association heart failure class III or higher.

  • Pre existing moderate to severe or severe peripheral neuropathy.

At the present time, there is no standard first-line chemotherapy regimen for patients with metastatic or unresectable bladder cancer and concomitant renal insufficiency (GFR < 60 mL/min). Placement of a percutaneous nephrostomy tube or insertion of ureteral stent in patients with tumor-related obstructive uropathy may improve renal function and allow treatment with cisplatin-based combination chemotherapy. A standard first line combination chemotherapy regimen for patients with metastatic or unresectable bladder cancer and chronic renal insufficiency (GFR< 60 mL/min) needs to be established in prospective randomized clinical trials.

A commonly prescribed front-line combination chemotherapy for patients with advanced bladder cancer and GFR of 30 to 60ml/min includes:

  • Carboplatin AUC 5 on day one plus gemcitabine 1000mg/m2 on days one and eight every 21 days.

A commonly prescribed front-line combination chemotherapy for patients with advanced bladder cancer and GFR less than mL/min includes:

  • Pacltaxel 175mg/m2 IV on day one plus gemcitabine 1000mg/m2 on days one and eight every 21 days.

5. Maintenance systemic chemotherapy for patients with advanced bladder cancer

The role of maintenance systemic therapy (chemotherapy or targeted therapy) after completion of first line cisplatin-based combination chemotherapy is unknown. The safety and efficacy of maintenance systemic therapy for patients with unresectable or metastatic urothelial carcinoma of the bladder is under evaluation in prospective randomized clinical trials.

6. Post-chemotherapy salvage radical cystectomy for patients with bladder cancer with regional lymph node metastases

A proportion of patients with advanced bladder cancer with metastases to regional pelvic or lower retroperitoneal lymph nodes and absence of visceral or skeletal metastases may benefit from post-chemotherapy salvage radical cystectomy. In some retrospective studies 30% to 40% of such patients achieved a long term remission with salvage radical cystectomy performed after cisplatin-based combination systemic chemotherapy.

The selection of patients for salvage radical cystectomy performed after induction cisplatin-based combination chemotherapy should be performed by a multidisciplinary team on case by case basis. Patient's preferences should be considered in the decision to proceed with post-chemotherapy salvage radical cystectomy.

Potential candidates for post-chemotherapy salvage radical cystectomy include patients with the following clinical characteristics:

  • Resectable primary bladder tumor including tumors invading into adjacent organs (T4a).

  • Pelvic or lower retroperitoneal lymph node metastases (lymph node involvement at the level or below the level of the iliac, lower paraaortic or lower paracaval lymph nodes).

  • Patients with adequate functional and nutritional status.

  • No clinical or radiologic evidence of distant lymph node, visceral or skeletal metastases after completion of induction chemotherapy.

Patients with bladder tumors invading into the pelvic or abdominal wall (T4b), with lymph node involvement above the lower paraaortic or lower paracaval lymph nodes or with visceral or skeletal metastases have unresectable bladder cancer. These patients are not eligible for post-chemotherapy salvage radical cystectomy.

What other therapies are helpful for reducing complications?

Growth factor support therapy: neutropenia

Primary prophylaxis of neutropenic fever with growth factor support therapy (e.g. filgrastim or pegfilgrastim) is not routinely prescribed in patients with bladder cancer receiving induction (neoajuvant), adjuvant, or palliative chemotherapy.

Patients who develop neutropenic fever after chemotherapy should receive growth factor support therapy with subsequent cycles of chemotherapy:

  • Filgrastim 5 mg/kg SC daily starting 24 hours after infusion of chemotherapy and until the absolute neutrophil count (ANC) is more than 1000 for two to three consecutive days.

  • Pegfilgrastim 6 mg SC 24 hours after infusion of chemotherapy. Do not prescribe pegfilgrastim within 14 days before the next chemotherapy infusion.

Growth factor support therapy: anemia

Erythropoietin stimulating agents (e.g. erithropoietin, darbepoietin) should not be prescribed in patients receiving potentially curative induction (neoadjuvant) or adjuvant cisplatin-based combination chemotherapy. In this setting, transfusion of leukoreduced packed red blood cells may be needed in patients who develop symptomatic or severe anemia.

Management of bone metastases

Short course palliative external beam radiotherapy may be considered for painful bone metastatic lesions.

The parenteral bisphosphonate zoledronic acid or the monoclonal antibody denosumab are indicated for patients with bladder cancer with metastases to bones. Denosumab targets the receptor activator of nuclear factor kappa-B ligand (RANKL).

  • Zoledronic acid 4mg IV every four weeks.

  • Denosumab 120mg SC every four weeks.

Dose reductions of zoledronic acid are needed in patients with renal dysfunction. In patients with advanced renal insufficiency (GFR < 30mL/min), zoledronic acid should not be prescribed. Patients receiving zoledronic acid or denosumab should take oral calcium and vitamin D supplementation.

Osteonecrosis of the jaw is a potential complication of treatment with zoledronic acid or denosumab. A careful exam of the oral cavity should be done in patients receiving these agents.

Antiemetic therapy

Cisplatin-based combination chemotherapy is highly emetogenic. Cisplatin can cause acute and delayed emesis. Medications for the prevention of acute nausea should include selective 5-HT3 antagonists (eg, palonosetron, ondansetron, granisetron, or donasetron), a corticosteroid (e.g dexamethasone), plus a neurokinin 1 (NK1) receptor antagonist (e.g. aprepitant).

Preventive therapy of emesis after highly emetogenic chemotherapy:

Day 1: acute antiemetic therapy aministered before infusion of chemotherapy

  • Aprepitant 125mg PO.

  • 5 HT3 antagonist antiemetic agent e.g. palonosetron 0.25mg IV.

  • Dexamethasone 12mg PO or IV.

Day 2 and 3

  • Aprepitant 80mg PO daily.

Day 2, 3 and 4: delayed antiemetic therapy

  • Dexamethasone 8mg PO daily.

Days 1, 2,3, and 4: breakthrough antiemetic therapy (prn)

  • Lorarepam 0.5-2mg IV, PO, or sublingual every 6 hours.

  • Prochlorperazine 10mg PO every 6 hours or prochlorperazine 25mg suppositories every 12 hours or metoclopramide 10-40mg PO or IV every 6 hours.

An oral H2 blocker (e.g. ranitidine) or a proton pump inhibitor (e.g. omeprazole) should be prescribed for the prevention of corticosteroid-related upper gastrointestinal toxicity. Patients receiving lorazepam should be monitored for oversedation.

What should you tell the patient and the family about prognosis?

Non-muscle invasive bladder cancer

The five year risk of local recurrence after initial treatment of non-muscle invasive urothelial carcinoma of the bladder is 60% to 70%. Patients with non-muscle invasive urothelial carcinoma of the bladder have 20 to 30% risk of progression to a higher disease stage or pathologic grade.

Patients with low grade papillary tumors (Ta) commonly recur locally but rarely progress to muscle invasive disease. These patients have a survival similar to individuals without bladder cancer. Patients with tumors invading the submucosa (lamina propria) of the bladder wall (T1) are a heterogeneous group. Patients with low-grade tumors have an indolent clinical course characterized by local recurrence(s) without progression to a higher disease stage or grade. In contrast, patients with high grade T1 tumors have an aggressive clinical course with progression to muscle invasion or development of distant metastatic disease.

Clinical and pathologic characteristics of non-muscle invasive urothelial carcinoma of the bladder associated with an aggressive clinical course and progression to higher disease stages include:

  • Tumor invasion of the deep portion of the lamina propria (T1b).

  • High grade histology.

  • Presence of lymphovascular invasion (LVI).

  • Presence of extensive urothelial carcinoma in situ (Tis).

  • More than three bladder tumors at the time of TURBT.

  • Size of bladder tumor more than 3cm.

  • First local recurrence within three months after initial TURBT.

  • Two or more recurrences in less than 12 months after initial TURBT.

  • Incomplete resection of tumor due to diffuse involvement of the bladder urothelium or unfavorable location of tumor (near a ureteral orifice or in a bladder diverticulum).

  • Recurrence after intravesical chemotherapy or immunotherapy.

Muscle invasive bladder cancer

The ten-year recurrence-free survival after radical cystectomy for patients with muscle invasive bladder cancer depends on the pathologic staging at the time of radical cystectomy:

  • Patients with organ confined muscle invasive disease: 80% or higher.

  • Patients with muscle invasive disease and extension into perivesical fat tissue: 50%.

  • Patients with muscle invasive disease and regional metastases to pelvic lymph nodes: 30%.

Clinical, surgical, and pathologic factors influence the risk of recurrence after radical cystectomy:

  • Depth of tumor invasion into the bladder wall (T stage).

  • Primary tumor with high grade histology.

  • Presence of lymphovascular invasion (LVI) in the primary tumor is associated with overall survival in patients with regional node negative disease at the time of radical cystectomy.

  • Immunohistochemical expression of protein factors involved in cell cycle regulation in the primary bladder tumor: p53, p27, p21, retinoblastoma protein (pRb), and cyclin E. Altered expression of three or more protein factors is associated with an unfavorable risk of recurrence.

  • Surgical margin status: positive surgical margin is associated with a poor prognosis.

  • Presence or absence of regional lymph node metastasis (N stage).

  • Extent of lymph node dissection at the time of radical cystectomy: less than 10 resected lymph nodes is associated with a higher rate of recurrence.

  • Number of metastatic lymph nodes at the time of cystectomy.

  • Ratio of metastatic regional lymph nodes to total number of resected lymph nodes.

  • Presence of extracapsular invasion in metastatic lymph nodes.

  • Expertise of the urologist performing the radical cystectomy (better outcomes with experienced urologic oncologists).

  • Volume of cases of the institution where radical cystectomy is performed (better outcomes in high volume tertiary centers).

38% of patients who receive induction cisplatin-based combination chemotherapy do not have a residual tumor in the bladder (pathologic complete response) at the time of radical cystectomy. Pathologic complete response at the time of radical cystectomy is associated with improved overall survival and recurrence-free survival.

Metastatic or unresectable urothelial carcinoma of the bladder

The great majority of patients with metastatic or unresectable urothelial carcinoma of the bladder have incurable disease. The most common sites of metastatic spread include the lymphatic system, liver, lungs, and bones. Most metastases are diagnosed during the first two to three years after radical cystectomy. The median overall survival for patients with metastatic urothelial carcinoma of the bladder treated with cisplatin-based combination chemotherapy is 15 months. The five year survival rate is 13%. Established clinical prognostic factors in patients with metastatic or unresectable urothelial carcinoma of the bladder receiving cisplatin-based combination chemotherapy include:

  • Performance or functional status.

  • Presence or absence of visceral or skeletal metastases.

Patients with metastatic bladder cancer without visceral metastases treated with front line cisplatin- based combination chemotherapy have a median overall survival of 18 months and a five-year overall survival of 21%. In contrast, patients with visceral metastases treated with cisplatin-based combination chemotherapy have a median overall survival of 10 months and a five year survival of 7%. Patients with a baseline Karnofsky performance status of 80 to 100 treated with cisplatin-based combination chemotherapy have a median overall survival of 16 months compared to 8 months in patients with Karnofsky performance status of 70.

What if scenarios.

Management of micropapillary variant of urothelial carcinoma of the bladder

Micropapillary variant of urothelial carcinoma of the bladder (Figure 11) is an aggressive form of bladder cancer. It is associated with a rapid progression and development of widespread distant metastatic disease. Understaging is common. Contrast enhanced cross sectional imaging studies of the chest, abdomen, and pelvis should be obtained in all patients. A bone scan is indicated if the serum alkaline phosphatase is elevated. Induction cisplatin-based combination chemotherapy followed by radical cystectomy should be strongly considered in patients with muscle invasive micropapillary variant of urothelial carcinoma of the bladder.

Figure 11.

Micropapillary variant of urothelial carcinoma of the bladder. This is an aggressive form of bladder cancer associated with a rapid progression and development of widespread distant metastatic disease. Clinical understaging is a common problem seen in the management of micropapillaryvariant of urothelial carcinoma of the bladder.

Management of pure small cell carcinoma of the bladder

Pure small cell carcinoma of the bladder is a rare and aggressive type of bladder cancer. It represents less than 1% of all malignant bladder tumors. Small cell carcinoma of the bladder is associated with a rapid growth, progression to higher stages of disease, and development of distant metastases. There is no standard of care for patients with small cell carcinoma of the bladder. Small cell carcinoma of the bladder is a chemosensitive disease. Temporary responses to a combination of cisplatin plus etoposide can be seen. Some patients with organ-confined disease may have delay of recurrence or achieve a remission with three to four cycles of induction cisplatin plus etoposide followed by radical cystectomy.

Four to six cycles of first line platinum-based combination chemotherapy are prescribed to patients with metastatic or unresectable small cell carcinoma of the bladder. A commonly prescribed first line regimen is:

  • Cisplatin 80mg/m2 IV on day 1 plus etoposide 80mg/m2 IV on days 1, 2, and 3 every 21 days.

Management of pure squamous cell carcinoma of the bladder

Pure squamous cell carcinoma of the bladder represents less than 5% of bladder cancers in the U.S. In Western countries risk factors include long term catheterization, chronic or recurrent infection and non functional bladder. Squamous cell carcinoma of the bladder is an aggressive form of bladder cancer. Patients usually present with locally advanced or metastatic disease (extravesical extension of tumor, metastases to pelvic lymph nodes, viscera, or bones).

Management by a multidisciplinary team is needed. Treatment should be individualized. In patients with locally advanced but resectable squamous cell carcinoma of the bladder, induction (neoadjuvant) chemotherapy or concurrent chemoradiotherapy followed by radical cystectomy is a management option.

Combination chemotherapy for squamous cell carcinoma of the bladder:

  • Cisplatin 75mg/m2 IV on day 1 plus continuous intravenous infusion of 5FU 1000mg/m2/ day on days 1 to 4 (96 hour 5FU infusion) every 21 days.

Radiosensitizing chemotherapy administered concurrently with external beam radiotherapy (chemoradiotherapy) to the bladder:

  • Cisplatin 25mg/m2 IV on days 1 and 2 administered each week of external beam radiotherapy.

Follow-up surveillance and therapy/management of recurrences.

Surveillance after treatment of bladder cancer

Periodic office cystoscopy and urine cytology are the current standard surveillance tests after treatment for bladder cancer is completed.

1. Cystoscopy

Periodic office flexible cystoscopy is the "gold standard" surveillance test to detect recurrent or residual bladder tumors.

Disadvantages of cystoscopy:

  • Invasive.

  • Costly.

  • Flat high grade lesions and urothelial carcinoma in situ (Tis) can be missed.

  • Inability to detect urothelial carcinoma of the upper urinary tract.

2. Urine cytology

Urine cytology is one of standard surveillance tests for the detection of recurrent or residual bladder tumors.

Strengths of urine cytology:

  • Specificity more than 90%.

  • Non invasive.

  • Sample easy to obtain.

  • Best test to detect high risk bladder lesions including high grade tumors and urothelial carcinoma in situ (Tis).

  • High negative predictive value for high grade bladder tumors.

Disadvantages of urine cytology:

  • Low sensitivity to detect low grade bladder tumors.

  • Reliability depends on the level of expertise of the cytopathologist.

  • Need for experienced cytopathologist.

3. Cross-sectional imaging studies

Contrast enhanced cross-sectional imaging studies (CT scan or MRI) of the abdomen and pelvis should be obtained every three to six months during the first two years of surveillance for patients who have completed treatment for muscle invasive bladder cancer and who have adequate renal function. Patients with high risk of recurrence or progression to gross metastatic disease (T3 or T4 tumors, high grade histology, micropapillary variant, presence of regional nodal metastasis) need cross sectional imaging studies every three to four months during the first two years of surveillance.

In contrast, patients with low risk of recurrence or progression to gross metastatic disease (T1 or T2 tumors, no evidence of regional nodal metastasis, low grade histology) need cross-sectional imaging studies every six months during the first two years of surveillance.

After two years of surveillance, the frequency of cross-sectional imaging studies varies and depends on the specific risk of recurrence or progression to gross metastatic disease. In general, during the third and fourth years of surveillance, cross-sectional imaging studies should be obtained every six to twelve months. In patients with impaired renal function, cross-sectional imaging studies of the abdomen and pelvis without contrast enhancement should be obtained.

A dedicated evaluation of the upper urinary tract is mandatory each time surveillance cross-sectional imaging studies are obtained.

Surveillance after treatment of non-muscle invasive bladder cancer

After complete TURBT, 70% to 80% of patients with non-muscle invasive bladder cancer have recurrence of tumor involving the bladder urothelium. Surveillance is indicated after treatment of non-muscle invasive bladder. The goal of surveillance is to detect bladder tumor recurrence at an early stage. Standard tests used for surveillance are office cystoscopy, urine cytology, and imaging of the upper urinary tract. After treatment of non-muscle invasive bladder cancer, office cystoscopy should be performed every three months during the first two years of surveillance, at less frequent intervals during years three and four, and annually thereafter. Urothelial carcinoma in situ (Tis) are flat, high grade bladder tumors that are difficult to detect and commonly missed by cystoscopy. Urine cytology has a higher sensitivity and specificity in the detection of flat high grade Tis tumors compared to cystoscopy. Imaging of the upper urinary tract every one to two years is recommended after treatment of high grade bladder tumors.

Surveillance after radical cystectomy for muscle invasive bladder cancer

After treatment of muscle invasive bladder cancer the following tests are recommended every four to six months for two years and at increasing intervals thereafter:

  • Urine cytology

  • Serum electrolyte and creatinine levels

  • Contrast enhanced cross sectional imaging studies (CT scan or MRI) of the abdomen and pelvis

  • Chest X-ray

Cytology of urethral washing is recommended every six to twelve months for the first two years of surveillance and at increasing intervals thereafter.

Surveillance after bladder preservation treatment for muscle invasive bladder cancer

The following tests are recommended every four to six months for two years and at increasing intervals after bladder preservation treatment for muscle invasive bladder cancer:

  • Urine cytology

  • Serum electrolytes and creatinine levels

  • Contrast enhanced cross sectional imaging studies (CT scan or MRI) of the abdomen and pelvis

  • Chest X-ray

  • Cystoscopy

  • Random biopsies of the bladder is performed periodically in some centers

Management of local tumor recurrence after treatment of non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, and Tis)

Endoscopic resection is the first step in the management of recurrent or persistent non-muscle invasive bladder tumors. After TURBT, a course of induction intravesical BCG or mitomicyn C is indicated. Follow up cystoscopic evaluation at 12 weeks should be performed. A second consecutive course of intravesical BCG or mitomycin C may be prescribed to patients who respond to initial induction intravesical therapy. Maintenance intravesical BCG may be considered for patients who have a complete response after one or two courses of induction intravesical BCG or mitomycin C.

Patients with residual bladder tumor at a 12-week cystoscopic evaluation performed after a second consecutive course of induction intravesical therapy should undergo a TURBT. After endoscopic resection of the residual bladder tumor, intravesical therapy with a different chemotherapeutic agent (e.g. valrubicin) or combination intravesical immunotherapy with BCG plus interferon-2B may be considered.

Management of patients with positive urine cytology and no cystoscopic or radiologic evidence of identifiable recurrent bladder tumor

Patients with a positive urine cytology found during surveillance should undergo a cystoscopy. In the absence of identifiable tumor, biopsies of different regions of the bladder urothelium and the prostate gland should be obtained. In addition, bilateral ureteroscopy and cytology from both ureters should be obtained. Patients with urothelial carcinoma found on biopsy should receive induction intravesical BCG. Patients with a complete response at a 12 week cystoscopic evaluation may be considered for maintenance intravesical BCG. Patients with residual tumor or disease refractory to induction intravesical BCG at a 12-week cystoscopic evaluation may receive intravesical mitomycin C or may undergo a radical cystectomy.

Management of patients with progression to muscle invasive urothelial carcinoma of the bladder

All patients with non-muscle invasive urothelial carcinoma of the bladder who have progression to muscle invasive disease should undergo a radical cystectomy. Intravesical valrubicin is approved by the US Food and Drug Administration (FDA) for the treatment of BCG refractory Tis in patients who decline radical cystectomy.

Management of patients with recurrence of urothelial carcinoma of the bladder after radical cystectomy

The rate of local-regional recurrence after radical cystectomy in contemporary radical cystectomy series is 6% to 13%. Most local regional recurrences occur 8 to 18 months after radical cystectomy.

Clinical prognostic factors associated with recurrence after radical cystectomy include:

  • High pathologic stage of primary tumor (T stage)

  • High histologic grade

  • Regional lymph node involvement

  • Less extensive pelvic lymphadenectomy at the time of radical cystectomy (<12 resected lymph nodes is associated with a higher risk of recurrence)

  • Positive surgical margins at the time of radical cystectomy

  • Presence of lymphovascular invasion in the primary bladder tumor

  • Surgery performed by experienced urologic oncologists at large volume tertiary centers is associated with a lower rate of local and regional recurrence

Local-regional and systemic recurrence of urothelial carcinoma of the bladder after radical cystectomy is associated with a poor prognosis. The great majority of patients with local-regional and systemic recurrence of bladder cancer after radical cystectomy have incurable disease. The median survival of patients with local-regional recurrence of bladder cancer after radical cystectomy is 4 to 8 months. In the majority of patients, treatment of local-regional recurrence is palliative and not curative. Treatment options include radiotherapy, concurrent chemoradiotherapy, and systemic chemotherapy.

Most systemic recurrences of urothelial carcinoma of the bladder occur within the first 36 months after radical cystectomy. The most common sites of systemic recurrence are the lymphatic system (pelvic, retroperitoneal, and intrathoracic lymph nodes), liver, lungs, and bones. The goals of therapy for patients with systemic recurrence of bladder cancer are to improve symptoms, improve quality of life, and prolong survival.

Cisplatin-based combination chemotherapy is the treatment of choice for chemotherapy naive patients. Cisplatin-based combination chemotherapy is a treatment option for patients who responded previously to induction cisplatin-based combination chemotherapy or for patients who had systemic relapse more than six months after completion of adjuvant cisplatin-based combination chemotherapy.

Single agent paclitaxel or pemetrexed may be considered for patients who had disease refractory to induction cisplatin-based combination chemotherapy or for patients with systemic relapse within six months of completion of adjuvant cisplatin-based combination chemotherapy. Timely recognition and management of chemotherapy-related side effects is fundamental. Best supportive care is crucial.

Pathophysiology

Ta and Tis have distinct molecular pathways and clinical course. Two distinct molecular pathways of oncogenesis and tumor progression are recognized in urothelial carcinoma of the bladder (Ta).

Non-muscle invasive papillary urothelial carcinoma oncogenesis molecular pathway

Seventy percent of Ta have activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3). Activating mutations of the HRAS gene are also frequent in Ta tumors (30% to 40%). Activation of FGFR3 leads to activation of the Ras-mitogen activated protein kinase (MAPK) signaling transduction pathway.

Urothelial carcinoma in situ and muscle invasive urothelial carcinoma of the bladder oncogenesis molecular pathway

Alterations of the p53 and the retinoblatoma (RB) cell cycle regulation pathways are frequent in urothelial carcinoma in situ (Tis). More than half of patients with Tis have mutations of the TP53 and the RB genes. Mutation of the TP53 tumor suppressor gene leads to functional and structural alteration of the p53 protein.

Mutation of the RB gene leads to functional alteration of cell cycle regulatory nuclear phosphoprotein Rb. Alterations of the p53 and RB cell cycle regulation pathways lead to cell proliferation, angiogenesis, and metastasis. Activation and overexpression of the epidermal growth factor receptor (EGFR) and Her 2 are common in muscle invasive urothelial carcinoma of the bladder. Overexpression of EGFR and Her 2 is associated with an aggressive clinical behavior and poor outcome.

Angiogenesis

Tumor angiogenesis is fundamental in invasive urothelial carcinoma of the bladder. Angiogenesis allows the maintenance of oxygen and nutrient supply to proliferating urothelial carcinoma cells. Regulation of angiogenesis is complex. It involves the interaction of multiple stimulatory and inhibitory proteins and interaction with other signal trasnduction pathways.

Downstream activation of the MAPK-ERK signal transduction pathway leads to up-regulation and expression of vascular endothelial growth factor (VEGF). VEGF is a key pro-angiogenic stimulatory ligand of the vascular endothelial growth factor receptor (VGFR). Estimation of microvessel density in the primary bladder tumor is a histologic measurement of angiogenesis. Tumor microvessel density is an independent prognostic factor of disease-free and overall survival in invasive urothelial carcinoma of the bladder.

Epigenetic changes

Epigenetic alteration of genes is important in urothelial carcinoma of the bladder. Epigenetic changes involve reversible alteration in gene function without changes in the genetic sequence. Aberrant methylation of CpG islands in the promoter regions of tumor suppressor genes leads to silencing of transcription. Epigenetic alteration of genes involved in cell cycle regulation, proliferation, angiogenesis, and apoptosis are increasingly recognized in urothelial carcinoma of the bladder.

Concomitant epigenetic silencing of whole chromosomal regions in a subset of urothelial carcinomas of the bladder has been recently reported. Silencing of whole chromosomal regions occurred in association with histone H3K9 and K27 hypermethylation and H3K9 hypoacetylation. Bladder tumors with epigenetic silencing of whole chromosomal regions showed a urothelial carcinoma in situ-associated gene expression signature, had a higher grade and stage, and usually did not have mutations of the FGFR3 gene. It is anticipated that silencing of multiple chromosomal regions leads to concomitant inactivation of tumor suppressor genes and plays an important role in the oncogenesis of urothelial carcinoma in situ and muscle invasive urothelial carcinoma of the bladder.

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