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Incidence and Mortality
Bladder cancer is the sixth most common cancer in the United States after lung cancer, prostate cancer, breast cancer, colon cancer, and melanoma. It is the fourth most common cancer in men and the eleventh most common cancer in women. Of the roughly 82,000 new cases annually, about 62,000 are in men and about 20,000 are in women. Of the roughly 17,000 annual deaths, more than 12,000 are in men and fewer than 5,000 are in women. The reasons for this disparity between the sexes are not well understood.[
Estimated new cases and deaths from bladder cancer in the United States in 2023:[
Anatomy
The urinary tract consists of the kidneys, the ureters, the bladder, and the urethra. The urinary tract is lined with transitional cell urothelium from the renal pelvis to the proximal urethra. Transitional cell carcinoma (also known as urothelial carcinoma) can develop anywhere along this pathway.
Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel). Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.
Histopathology
Under normal conditions, the bladder, the lower part of the kidneys (the renal pelvises), the ureters, and the proximal urethra are lined with a specialized mucous membrane referred to as transitional epithelium (also called urothelium). Most cancers that form in these tissues are transitional cell carcinomas (also called urothelial carcinomas) that derive from transitional epithelium. For more information, see Renal Cell Cancer Treatment and Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment.
Transitional cell carcinoma of the bladder can be low-grade or high-grade:
Bladder cancer is also divided into muscle-invasive and nonmuscle-invasive disease, based on invasion of the muscularis propria (also known as the detrusor muscle), which is the thick muscle deep in the bladder wall.
Under conditions of chronic inflammation, such as infection of the bladder with the Schistosoma haematobium parasite, squamous metaplasia may occur in the bladder; the incidence of squamous cell carcinomas of the bladder is higher under conditions of chronic inflammation than is otherwise seen. In addition to transitional cell carcinomas and squamous cell carcinomas, adenocarcinomas, small cell carcinomas, and sarcomas can form in the bladder. In the United States, transitional cell carcinomas represent most (>90%) bladder cancers. However, a significant number of transitional cell carcinomas have areas of squamous or other differentiation.
Carcinogenesis and Risk Factors
Increasing age is the most important risk factor for most cancers. Other risk factors for bladder cancer include the following:
There is strong evidence linking exposure to carcinogens to bladder cancer. The most common risk factor for bladder cancer in the United States is cigarette smoking. It is estimated that up to half of all bladder cancers are caused by cigarette smoking and that smoking increases a person's risk of bladder cancer two to four times above baseline risk.[
Certain occupational exposures have also been linked to bladder cancer, and higher rates of bladder cancer have been reported in textile dye and rubber tire industries; among painters; leather workers; shoemakers; and aluminum-, iron-, and steelworkers. Specific chemicals linked to bladder carcinogenesis include beta-naphthylamine, 4-aminobiphenyl, and benzidine. Although these chemicals are now generally banned in Western countries, many other chemicals still in use are also suspected of causing bladder cancer.[
Exposure to the chemotherapy drug cyclophosphamide has also been associated with an increased risk of bladder cancer.
Chronic urinary tract infections and infection with the parasite S. haematobium have also been associated with an increased risk of bladder cancer, often squamous cell carcinomas. Chronic inflammation is thought to play a key role in carcinogenesis in these settings.
Clinical Features
Bladder cancer typically presents with gross or microscopic hematuria. Less commonly, patients may complain of urinary frequency, nocturia, and dysuria, symptoms that are more common in patients with carcinoma in situ. Patients with upper urinary tract urothelial carcinomas may present with pain resulting from obstruction by the tumor.
Urothelial carcinomas are often multifocal—the entire urothelium needs to be evaluated if a tumor is found. In patients with bladder cancer, upper urinary tract imaging is essential for staging and surveillance. This can be accomplished with ureteroscopy, retrograde pyelograms during cystoscopy, intravenous pyelograms, or computed tomography (CT) urograms. Similarly, patients with an upper urinary tract transitional cell carcinoma have a high risk of developing bladder cancer; these patients need periodic cystoscopy and surveillance of the contralateral upper urinary tract.
Diagnostics
When bladder cancer is suspected, the most useful diagnostic test is cystoscopy. Radiological studies such as CT scans or ultrasound do not have sufficient sensitivity to be useful for detecting bladder cancers. Cystoscopy can be performed in a urology clinic.
If cancer is seen on cystoscopy, the patient is typically scheduled for bimanual examination under anesthesia and a repeat cystoscopy in an operating room so that transurethral resection of the tumor(s) and/or biopsies can be performed. If a high-grade cancer (including carcinoma in situ) or invasive cancer is seen, the patient is staged with a CT scan of the abdomen and pelvis (or CT urogram) and either a chest x-ray or chest CT scan. Patients with a nonhepatic elevation of alkaline phosphatase or symptoms suggestive of bone metastases undergo a bone scan.
Prognostic Factors
The major prognostic factors in carcinoma of the bladder are the following:
Among nonmuscle-invasive cancers, the following factors are also prognostic:[
Most superficial tumors are well differentiated. Patients in whom superficial tumors are less differentiated, large, multiple, or associated with carcinoma in situ (Tis) in other areas of the bladder mucosa are at greatest risk of recurrence and the development of invasive cancer. These patients may be considered to have the entire urothelial surface at risk of cancer development.
Survival
Patients who die of bladder cancer almost always have disease that has metastasized from the bladder to other organs. Low-grade bladder cancers rarely grow into the muscular wall of the bladder and rarely metastasize, so patients with low-grade (grade I) bladder cancers very rarely die of their cancer. Nonetheless, they may experience multiple relapses that need to be resected.
Almost all deaths from bladder cancer are among patients with high-grade disease, which has a much greater potential to invade deeply into the bladder's muscular wall and spread to other organs.
Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial bladder tumors (i.e., stage Ta, Tis, or T1). The prognosis of these patients depends largely on the grade of the tumor. Patients with high-grade tumors have a significant risk of dying of their cancer even if it is not muscle-invasive.[
There are clinical trials suitable for patients with all stages of bladder cancer; whenever possible, clinical trials designed to improve upon standard therapy should be considered.
General information about clinical trials is also available from the NCI website.
Follow-up
Bladder cancer tends to recur, even when it is noninvasive at the time of diagnosis; therefore, standard practice is to perform surveillance of the urinary tract after a diagnosis of bladder cancer. However, no trials have been conducted to assess whether surveillance affects rates of progression, survival, or quality of life; nor have clinical trials defined an optimal surveillance schedule. Urothelial carcinomas are thought to reflect a so-called field defect whereby the cancer emerges because of genetic mutations that are widely present in the patient's bladder or entire urothelium. Thus, people who have had a bladder tumor resected often subsequently have recurrent tumors in the bladder, often in different locations from the site of the initial tumor. Similarly, but less commonly, they may have tumors appear in the upper urinary tract (i.e., in the renal pelvises or ureters).
An alternative explanation for these patterns of recurrence is that cancer cells that are disrupted when a tumor is resected may reimplant elsewhere in the urothelium. Support for this second theory is that tumors are more likely to recur downstream than upstream from the initial cancer. Upper urinary tract cancers are more likely to recur in the bladder than bladder cancers are to recur in the upper urinary tract.[
References:
More than 90% of bladder cancers are transitional cell carcinomas derived from the uroepithelium. About 2% to 7% are squamous cell carcinomas, and 2% are adenocarcinomas.[
Pathological grade of transitional cell carcinomas, which is based on cellular atypia, nuclear abnormalities, and the number of mitotic figures, is of great prognostic importance.
References:
The clinical staging of carcinoma of the bladder is determined by the depth of invasion of the bladder wall by the tumor. This determination requires a cystoscopic examination that includes a biopsy and examination under anesthesia to assess the following:
Clinical staging, even when computed tomographic (CT) and/or magnetic resonance imaging (MRI) scans and other imaging modalities are used, often underestimates the extent of tumor, particularly in cancers that are less differentiated and more deeply invasive. CT imaging is the standard staging modality. A clinical benefit from obtaining MRI or positron emission tomography scans instead of CT imaging has not been demonstrated.[
AJCC Stage Groupings and TNM Definitions
The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define bladder cancer.[
Stage | TNM | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph node; M = distant metastasis. | |||
a Reprinted with permission from AJCC: Urinary bladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 757–65. | |||
0a | Ta, N0, M0 | Ta = Noninvasive papillary carcinoma. | ![]() |
N0 = No lymph node metastasis. | |||
M0 = No distant metastasis. | |||
0is | Tis, N0, M0 | Tis = Urothelial carcinomain situ:flat tumor. | |
N0 = No lymph node metastasis. | |||
M0 = No distant metastasis. |
Stage | TNM | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph node; M = distant metastasis. | |||
a Reprinted with permission from AJCC: Urinary bladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 757–65. | |||
I | T1, N0, M0 | T1 = Tumor invades lamina propria (subepithelial connective tissue). | ![]() |
N0 = No lymph node metastasis | |||
M0 = No distant metastasis. |
Stage | TNM | Description | Illustration | |
---|---|---|---|---|
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological. | ||||
a Reprinted with permission from AJCC: Urinary bladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 757–65. | ||||
II | T2a, N0, M0 | pT2a = Tumor invades superficial muscularis propria (inner half). | ![]() |
|
N0 = No lymph node metastasis. | ||||
M0 = No distant metastasis. | ||||
T2b, N0, M0 | pT2b = Tumor invades deep muscularis propria (outer half). | |||
N0 = No lymph node metastasis. | ||||
M0 = No distant metastasis. |
Stage | TNM | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological. | |||
a Reprinted with permission from AJCC: Urinary bladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 757–65. | |||
IIIA | T3a, T3b, T4a, N0, M0 | –pT3a = Microscopically. | ![]() |
–pT3b = Macroscopically (extravesical mass). | |||
–T4a = Extravesical tumor invades directly into prostatic stroma, uterus, vagina. | |||
N0 = No lymph node metastasis. | |||
M0 = No distant metastasis. | |||
T1–T4a, N1, M0 | T1 = Tumor invades lamina propria (subepithelial connective tissue). | ||
T2 = Tumor invades muscularis propria. | |||
–pT2a = Tumor invades superficial muscularis propria (inner half). | |||
–pT2b = Tumor invades deep muscularis propria (outer half). | |||
T3 = Tumor invades perivesical soft tissue. | |||
–pT3a = Microscopically. | |||
–pT3b = Macroscopically (extravesical mass). | |||
T4 = Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall. | |||
–T4a = Extravesical tumor invades directly into prostatic stroma, uterus, vagina. | |||
N1 = Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node). | |||
M0 = No distant metastasis. | |||
IIIB | T1–4a, N2, N3, M0 | T1 = Tumor invades lamina propria (subepithelial connective tissue). | ![]() |
T2 = Tumor invades muscularis propria. | |||
–pT2a = Tumor invades superficial muscularis propria (inner half). | |||
–pT2b = Tumor invades deep muscularis propria (outer half). | |||
T3 = Tumor invades perivesical soft tissue. | |||
–pT3a = Microscopically. | |||
pT3b = Macroscopically (extravesical mass). | |||
T4 = Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall. | |||
–T4a = Extravesical tumor invades directly into prostatic stroma, uterus, vagina. | |||
N2 = Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node metastasis). | |||
N3 = Lymph node metastasis to the common iliac lymph nodes. | |||
M0 = No distant metastasis. |
Stage | TNM | Description | Illustration |
---|---|---|---|
T = primary tumor; N = regional lymph node; M = distant metastasis; p = pathological. | |||
a Reprinted with permission from AJCC: Urinary bladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 757–65. | |||
IVA | T4b, N0, M0 | –T4b = Extravesical tumor invades pelvic wall, abdominal wall. | ![]() |
N0 = No lymph node metastasis. | |||
M0 = No distant metastasis. | |||
Any T, Any N, M1a | TX = Primary tumor cannot be assessed. | ||
T0 = No evidence of primary tumor. | |||
–Ta = Noninvasive papillary carcinoma. | |||
Tis = Urothelial carcinomain situ:flat tumor. | |||
T1 = Tumor invades lamina propria (subepithelial connective tissue). | |||
T2 = Tumor invades muscularis propria. | |||
–pT2a = Tumor invades superficial muscularis propria (inner half). | |||
–pT2b = Tumor invades deep muscularis propria (outer half). | |||
T3 = Tumor invades perivesical soft tissue. | |||
–pT3a = Microscopically. | |||
–pT3b = Macroscopically (extravesical mass). | |||
T4 = Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall. | |||
–T4a = Extravesical tumor invades directly into prostatic stroma, uterus, vagina. | |||
–T4b = Extravesical tumor invades pelvic wall, abdominal wall. | |||
NX = Lymph nodes cannot be assessed. | |||
N0 = No lymph node metastasis. | |||
N1 = Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node). | |||
N2 = Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node metastasis). | |||
N3 = Lymph node metastasis to the common iliac lymph nodes. | |||
M0 = No distant metastasis. | |||
–M1a = Distant metastasis limited to lymph nodes beyond the common iliacs. | |||
IVB | Any T, Any N, M1b | TX = Primary tumor cannot be assessed. | |
T0 = No evidence of primary tumor. | |||
–Ta = Noninvasive papillary carcinoma. | |||
Tis = Urothelial carcinomain situ:flat tumor. | |||
T1 = Tumor invades lamina propria (subepithelial connective tissue). | |||
T2 = Tumor invades muscularis propria. | |||
–pT2a = Tumor invades superficial muscularis propria (inner half). | |||
–pT2b = Tumor invades deep muscularis propria (outer half). | |||
T3 = Tumor invades perivesical soft tissue. | |||
–pT3a = Microscopically. | |||
–pT3b = Macroscopically (extravesical mass). | |||
T4 = Extravesical tumor directly invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall. | |||
–T4a = Extravesical tumor invades directly into prostatic stroma, uterus, vagina. | |||
–T4b = Extravesical tumor invades pelvic wall, abdominal wall. | |||
NX = Lymph nodes cannot be assessed. | |||
N0 = No lymph node metastasis. | |||
N1 = Single regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node). | |||
N2 = Multiple regional lymph node metastasis in the true pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node metastasis). | |||
N3 = Lymph node metastasis to the common iliac lymph nodes. | |||
M1b = Non-lymph node distant metastases. |
For urothelial histologies, a low- and high-grade designation is used to match the current World Health Organization/International Society of Urologic Pathology recommended grading system.[
For squamous cell carcinoma and adenocarcinoma, the grading schema in Table is recommended.[
G | G Definition |
---|---|
a Reprinted with permission from AJCC: Urinary bladder. In: Amin MB, Edge SB, Greene FL, et al., eds.:AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 757–65. | |
GX | Grade cannot be assessed. |
G1 | Well differentiated. |
G2 | Moderately differentiated. |
G3 | Poorly differentiated. |
References:
Nonmuscle-Invasive Bladder Cancer
Treatment of nonmuscle-invasive bladder cancers (Ta, Tis, T1) is based on risk stratification. Essentially all patients are initially treated with a transurethral resection (TUR) of the bladder tumor followed by a single immediate instillation of intravesical chemotherapy (mitomycin is typically used in the United States).[
Subsequent therapy after the treatment above is based on risk and typically consists of one of the following:[
Muscle-Invasive Bladder Cancer
Standard treatment for patients with muscle-invasive bladder cancers whose goal is cure is either neoadjuvant multiagent cisplatin–based chemotherapy followed by radical cystectomy and urinary diversion or radiation therapy with concomitant chemotherapy.[
Many patients newly diagnosed with bladder cancer are candidates for participation in clinical trials.
Reconstructive techniques that fashion low-pressure storage reservoirs from the reconfigured small and large bowel eliminate the need for external drainage devices and, in many patients, allow voiding per urethra. These techniques are designed to improve the quality of life for patients who require cystectomy.[
Stage ( TNM Staging Criteria) | Standard Treatment Options | |
---|---|---|
BCG = bacillus Calmette-Guérin; EBRT = external-beam radiation therapy; TNM = T, size of tumor and any spread of cancer into nearby tissue; N, spread of cancer to nearby lymph nodes; M, metastasis or spread of cancer to other parts of body; TUR = transurethral resection. | ||
Stage 0 Bladder Cancer | TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy | |
TUR with fulguration | ||
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of BCG | ||
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by intravesical chemotherapy | ||
Segmental cystectomy(rarely indicated) | ||
Radical cystectomy(in rare, highly selected patients with extensive or refractory superficial high-grade tumors) | ||
Stage I Bladder Cancer | TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy | |
TUR with fulguration | ||
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of BCG | ||
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by intravesical chemotherapy | ||
Segmental cystectomy(rarely indicated) | ||
Radical cystectomyin selected patients with extensive or refractory superficial tumors | ||
Stages II and III Bladder Cancer | Radical cystectomy | |
Neoadjuvant combination chemotherapy followed by radical cystectomy | ||
Radical cystectomy followed by adjuvant chemotherapy or immunotherapy | ||
EBRT with or without concomitant chemotherapy | ||
Segmental cystectomy(in selected patients) | ||
TUR with fulguration(in selected patients) | ||
Stage IV Bladder Cancer | T4b, N0, M0 | Chemotherapy alone |
Radical cystectomy | ||
Radical cystectomy followed by chemotherapy | ||
Radical cystectomy alone | ||
EBRT with or without concomitant chemotherapy | ||
Urinary diversion or cystectomyfor palliation | ||
Any T, any N, M1 | Chemotherapyalone or as an adjunct to local treatment | |
Immunotherapy | ||
EBRTfor palliation | ||
Urinary diversion or cystectomyfor palliation | ||
Recurrent Bladder Cancer | Combination chemotherapy | |
Immunotherapy | ||
Targeted therapy | ||
Surgeryfor new superficial or localized tumors | ||
Palliative therapy | ||
Clinical trials |
References:
Standard Treatment Options for Stage 0 Bladder Cancer
Patients with stage 0 bladder tumors can be cured by a variety of treatments, even though the tendency for new tumor formation is high. In a series of patients with Ta or T1 tumors who were followed for a minimum of 20 years or until death, the risk of bladder cancer recurrence after initial resection was 80%.[
One series of 125 patients with TaG3 cancers followed for 15 to 20 years reported that 39% progressed to more advanced-stage disease while 26% died of urothelial cancer. In comparison, among 23 patients with TaG1 tumors, none died and 5% progressed.[
Standard treatment options for stage 0 bladder cancer include the following:
Transurethral resection (TUR) with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy
TUR and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. Because most bladder cancers recur after TUR, one immediate intravesical instillation of chemotherapy after TUR is often administered. Numerous randomized controlled trials have evaluated this practice, and a meta-analysis of seven trials reported that a single intravesical treatment with chemotherapy reduced the odds of recurrence by 39% (odds ratio, [OR] 0.61; P < .0001).[
One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first TUR.[
Such information may change the definitive management options in these individuals. Patients with extensive multifocal recurrent disease and/or other unfavorable prognostic features require more aggressive forms of treatment.
Evidence (TUR with fulguration followed by immediate postoperative instillation of intravesical chemotherapy):
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of BCG
Intravesical BCG is the treatment of choice for reducing the risk of cancer progression and is mainly used for cancers with an intermediate or high risk of progressing.[
Intravesical therapy with thiotepa, MMC, doxorubicin, or BCG is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR.[
Evidence (TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of BCG):
Intravesical chemotherapy
Intravesical BCG with maintenance BCG treatments
BCG is associated with a risk of significant toxicity, including rare deaths from BCG sepsis. Compared with MMC, BCG produces more local toxicity (44% with BCG vs. 30% with MMC) and systemic side effects (19% with BCG vs. 12% with MMC). Because of concerns about side effects and toxicity, BCG is not generally used for patients with a low risk of progression to advanced-stage disease.[
Segmental cystectomy (rarely indicated)
Segmental cystectomy is rarely indicated.[
Radical cystectomy (in rare, highly selected patients with extensive or refractory superficial high-grade tumors)
Radical cystectomy is used in selected patients with extensive or refractory superficial tumor,[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Standard Treatment Options for Stage I Bladder Cancer
Patients with stage I bladder tumors are unlikely to die of bladder cancer, but the tendency for new tumor formation is high. In a series of patients with Ta or T1 tumors who were followed for a minimum of 20 years or until death, the risk of bladder recurrence after initial resection was 80%.[
One series of 125 patients with TaG3 cancers followed for 15 to 20 years reported that 39% progressed to more advanced stage disease, while 26% died of urothelial cancer. In comparison, among 23 patients with TaG1 tumors, none died and 5% progressed.[
Standard treatment options for stage I bladder cancer include the following:
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy
TUR and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. Because most bladder cancers recur after TUR, one immediate intravesical instillation of chemotherapy after TUR is widely used. Numerous randomized, controlled trials have evaluated this practice, and a meta-analysis of seven trials reported that a single intravesical treatment with chemotherapy reduced the odds of recurrence by 39% (odds ratio [OR], 0.61; P < .0001).[
TUR with fulguration
Staging a bladder cancer via TUR is based on the extent of invasion. To assess whether cancer has invaded the muscle, muscularis propria must be present in the resected tissue. While a repeat TUR is generally considered mandatory for T1 and high-grade noninvasive bladder cancers if no muscularis propria is present in the resected tissue from the first TUR, many experts recommend that a second TUR be routinely performed within 2 to 6 weeks of the first TUR to confirm staging and achieve a more complete resection. The rationale for this derives from numerous findings, including the following:
Evidence (routine repeat TUR):
Repeat TUR has not been shown to reduce relapse rates or prolong survival, but there is a clear rationale for seeking accurate staging information on which to base treatment decisions. Such information may change the definitive management options for patients and identify patients who are more likely to benefit from more aggressive treatment.
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by periodic intravesical instillations of BCG
Intravesical BCG is the treatment of choice for reducing the risk of cancer progression and is mainly used for cancers with an intermediate or high risk of progressing.[
Evidence (immediate intravesical chemotherapy after transurethral resection):
Evidence (intravesical BCG with maintenance BCG treatments):
BCG is associated with a risk of significant toxicity, including rare deaths from BCG sepsis. Compared with MMC, BCG produces more local toxicity (44% with BCG vs. 30% with MMC) and systemic side effects (19% with BCG vs. 12% with MMC). Because of concerns about side effects and toxicity, BCG is not generally used for patients with a low risk of progression to more-advanced–stage disease.[
Evidence (two treatment courses of intravesical BCG):
TUR with fulguration followed by an immediate postoperative instillation of intravesical chemotherapy followed by intravesical chemotherapy
Intravesical therapy with thiotepa, mitomycin, doxorubicin, or BCG is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR.[
Evidence (intravesical chemotherapy):
Segmental cystectomy (rarely indicated)
Segmental cystectomy is rarely indicated.[
Radical cystectomy in selected patients with extensive or refractory superficial tumors
Radical cystectomy is used in selected patients with extensive or refractory superficial tumor.[
Certain patients with nonmuscle-invasive bladder cancer face a substantial risk of progression and death from their cancers.
Evidence (radical cystectomy):
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Standard Treatment Options for Stages II and III Bladder Cancer
Standard treatment options for stage II bladder cancer and stage III bladder cancer include the following:
The most common treatments for muscle-invasive bladder cancer are radical cystectomy and radiation therapy. There is no strong evidence from randomized controlled trials to determine whether surgery or radiation therapy is more effective. There is strong evidence that both therapies become more effective when combined with chemotherapy. The treatments with the highest level of evidence supporting their effectiveness are radical cystectomy preceded by multiagent cisplatin-based chemotherapy and radiation therapy with concomitant chemotherapy.
Radical cystectomy
Radical cystectomy is a standard treatment option for stage II and stage III bladder cancer, and its effectiveness at prolonging survival increases if it is preceded by cisplatin-based multiagent chemotherapy.[
Radical cystectomy is a major operation with a perioperative mortality rate of 2% to 3% when performed at centers of excellence.[
One study of 27 women who underwent radical cystectomy reported diminished ability to have orgasm in 45%, decreased lubrication in 41%, decreased sexual desire in 37%, and pain with vaginal intercourse in 22%. Fewer than one-half were able to have successful vaginal intercourse and most reported decreased satisfaction with their sexual lives after surgery.[
In a retrospective analysis from a single institution, older patients (≥70 years) in good general health were found to have clinical and functional results after radical cystectomy similar to younger patients.[
After radical cystectomy, however, an approximate 30% to 40% risk of recurrence still exists for patients with muscle-invasive disease, even at centers of excellence.[
Neoadjuvant combination chemotherapy followed by radical cystectomy
Because bladder cancer commonly recurs with distant metastases, systemic chemotherapy administered before or after cystectomy has been evaluated as a means of improving outcome. Administration of chemotherapy before cystectomy (i.e., neoadjuvant chemotherapy) may be preferable to postoperative treatment because tumor downstaging from chemotherapy may enhance resectability; occult metastatic disease may be treated as early as possible; and chemotherapy may be better tolerated. Currently, the body of evidence supporting preoperative chemotherapy is much stronger than the evidence supporting postoperative chemotherapy.
Evidence (neoadjuvant combination chemotherapy followed by radical cystectomy):
Most patients included in these studies received cisplatin, methotrexate, and vinblastine with or without doxorubicin. It is not known whether the doublet regimen of cisplatin plus gemcitabine offers any benefit when administered in the preoperative setting, nor is there any evidence of benefit for carboplatin-based chemotherapy regimens.
On the basis of these findings, preoperative cisplatin-based combination chemotherapy followed by radical cystectomy represents a standard therapeutic option for patients with muscle-invasive bladder cancer who are fit for chemotherapy and for whom the priority is to maximize survival.
Radical cystectomy followed by adjuvant chemotherapy or immunotherapy
Adjuvant chemotherapy
Numerous trials have investigated whether giving chemotherapy after radical cystectomy can improve progression-free survival (PFS) and OS. Although several trials showed a PFS benefit from postoperative cisplatin-based chemotherapy, the trials tended to be small and underpowered, and no trial demonstrated a persuasive benefit in OS.
Evidence (adjuvant chemotherapy):
Adjuvant immunotherapy
Evidence (adjuvant immunotherapy):
EBRT with or without concomitant chemotherapy
Definitive radiation therapy is a standard option that yields 5-year survival rates of approximately 30% to 40%.[
Most protocols for bladder preservation that use combined chemotherapy and radiation therapy have followed a relatively complex algorithm. After the initial stage TUR of the bladder tumor, patients undergo a repeat TUR to maximally resect the tumor. The patient is then treated with synchronous chemoradiation therapy to a dose of roughly 40 Gy followed by a repeat cystoscopy with biopsies to assess for residual cancer. If residual cancer is detected histopathologically, then the chemoradiation therapy is judged to have failed and the patient is advised to undergo a radical cystectomy. If the biopsies at 40 Gy are benign, then chemoradiation therapy is completed to a dose of about 65 Gy.
With definitive radiation therapy, best results are seen in patients with solitary lesions and without carcinoma in situ or hydronephrosis
After radiation therapy, approximately 50% of patients have dysuria and urinary frequency during treatment, which resolves several weeks after treatment, and 15% report acute toxic effects of the bowel.
Randomized trials that directly compare the bladder-preserving chemoradiation therapy approach with radical cystectomy have not been performed; the relative effectiveness of these two treatments is thus unknown.
Evidence (EBRT with or without concomitant chemotherapy):
TUR followed by chemoradiation therapy
TUR followed by chemoradiation therapy
Radiation therapy and chemotherapy
Neoadjuvant chemotherapy followed by chemoradiation therapy
Segmental cystectomy (in selected patients)
Segmental cystectomy is appropriate only in very selected patients.[
TUR with fulguration (in selected patients)
Stage II bladder cancer may be controlled in some patients by TUR, but more aggressive forms of treatment are often dictated by recurrent tumor or by the large size, multiple foci, or undifferentiated grade of the neoplasm.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
Only a small fraction of patients with stage IV bladder cancer can be cured, and for many patients, the emphasis is on palliation of symptoms. The potential for cure is restricted to patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes.[
Standard Treatment Options for Stage IV Bladder Cancer
Standard treatment options for patients with T4b, N0, M0 disease
Treatment options for patients with T4b, N0, M0 disease include the following:
Chemotherapy alone
Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer.[
Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.
These include carboplatin plus paclitaxel,[
Evidence (chemotherapy alone):
Radical cystectomy
Patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes may undergo radical cystectomy with pelvic lymph node dissection.[
External-beam radiation therapy (EBRT) with or without concomitant chemotherapy
Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2–T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases.[
Urinary diversion or cystectomy for palliation
Urinary diversion may be indicated, not only for palliation of urinary symptoms but also for preservation of renal function in candidates for chemotherapy.
Standard treatment options for patients with any T, any N, M1 disease
Standard treatment options for patients with any T, any N, M1 disease include the following:
Chemotherapy alone or as an adjunct to local treatment
Cisplatin-based combination chemotherapy regimens are the standard of care for first-line therapy for stage IV bladder cancer in patients who can tolerate it.[
Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.
These include carboplatin plus paclitaxel,[
Ongoing studies are evaluating new chemotherapy combinations.
Evidence (chemotherapy):
Ongoing studies are evaluating new chemotherapy combinations.
Immunotherapy
Immunotherapy has emerged as a treatment alternative for patients with stage IV bladder cancer. Immune checkpoint inhibitors that have anti−programmed death-1 (PD-1) or anti−programmed death-ligand 1 (PD-L1) activity have been shown in clinical trials to have activity against urothelial carcinoma in patients who have previously been treated with or who are ineligible for platinum-based chemotherapy.[
Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that binds to PD-1. In patients previously treated with platinum-based chemotherapy, pembrolizumab has been shown to prolong OS compared with second-line chemotherapy. As a result, pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) for patients with locally advanced or metastatic urothelial carcinoma who fall into one of the following three categories:
It is important to note that in 2018, the FDA issued an alert about preliminary data from two ongoing first-line therapy trials comparing pembrolizumab or atezolizumab with cisplatin- or carboplatin-based therapy. The data showed that immunotherapy was associated with shorter survival in patients with low expression of PD-L1. As a result, the labels were amended to restrict use of both agents to the three categories above.
Evidence (pembrolizumab):
Atezolizumab
Atezolizumab is a humanized monoclonal antibody that binds to PD-L1 and prevents it from binding to its receptors, PD-1 or B7-1. Clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged OS or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.
Atezolizumab has been approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma who fall into one of the following three categories:
It is important to note that in 2018, the FDA issued an alert about preliminary data from two ongoing first-line therapy trials comparing pembrolizumab or atezolizumab with cisplatin- or carboplatin-based therapy. The data showed that immunotherapy was associated with shorter survival in patients with low expression of PD-L1. As a result, the labels were amended to restrict use of both agents to the three categories above.
Evidence (atezolizumab):
Nivolumab
Nivolumab is a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody that blocks interaction between PD-L1 and PD-L2 with PD-1. There are no published controlled trials and thus no data regarding whether nivolumab results in longer survival or improved quality of life.
Evidence (nivolumab):
Avelumab
Avelumab is a monoclonal anti–PD-L1 antibody that has shown activity against urothelial carcinoma. A randomized controlled trial reported an OS benefit from maintenance avelumab when given after platinum-based chemotherapy in patients whose cancer did not progress during chemotherapy.
Evidence (avelumab):
Durvalumab
Durvalumab is an anti–PD-L1 monoclonal antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.
Evidence (durvalumab):
EBRT for palliation
Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2–T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases.
Urinary diversion or cystectomy for palliation
Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy.
Treatment Options Under Clinical Evaluation for Patients With Any T, Any N, M1 Disease
Prognosis is poor in patients with stage IV disease and consideration of entry into a clinical trial is appropriate.
Other chemotherapy regimens appear to be active in the treatment of metastatic disease. Chemotherapy agents that have shown activity in metastatic bladder cancer include paclitaxel, docetaxel, ifosfamide, gallium nitrate, and pemetrexed.[
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
The prognosis for any patient with progressive or recurrent invasive bladder cancer is generally poor. Management of recurrence depends on previous therapy, sites of recurrence, and individual patient considerations.
Treatment Options for Recurrent Bladder Cancer
Treatment options for patients with recurrent bladder cancer include the following:
Combination chemotherapy
Patients who have not received previous chemotherapy for urothelial carcinoma should be considered for chemotherapy as described above for stage IV disease.
In patients with recurrent transitional cell carcinoma, combination chemotherapy has produced high response rates, with occasional complete responses seen.[
Cisplatin-based combination chemotherapy regimens are the standard of care for first-line therapy for stage IV bladder cancer in patients who can tolerate it.[
GC (gemcitabine and cisplatin) was compared with MVAC in a randomized controlled trial, and neither regimen was associated with a statistically significant difference in response rate or survival. The two regimens are generally considered equivalent, but they have never been compared in a noninferiority trial. Of note, patients with good performance status and lymph node–only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. In the large, randomized, controlled trial comparing MVAC with GC, for example, the 5-year overall survival (OS) rate in patients with lymph node–only disease was 20.9%.[
Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. For patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong survival; however, many regimens have demonstrated radiologically measurable responses.
These regimens include carboplatin plus paclitaxel,[
Evidence (combination chemotherapy):
Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the MVAC regimen.[
Immunotherapy
Immunotherapy has emerged as a treatment alternative for patients with recurrent bladder cancer. Immune checkpoint inhibitors that have anti−programmed death-1 (PD-1) or anti−programmed death-ligand 1 (PD-L1) activity have been shown in clinical trials to have activity against urothelial carcinoma in patients who have previously been treated with or who are ineligible for cisplatin-based chemotherapy.[
Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that binds to PD-1. In patients previously treated with platinum-based chemotherapy, pembrolizumab has been shown to prolong OS compared with second-line chemotherapy. As a result, pembrolizumab has been approved by the U.S. Food and Drug Administration (FDA) for patients with locally advanced or metastatic urothelial carcinoma who fall into one of the following three categories:
It is important to note that in 2018, the FDA issued an alert that preliminary data from two ongoing trials showed shorter survival in first-line therapy trials comparing pembrolizumab or atezolizumab with cisplatin- or carboplatin-based therapy. As a result, the labels were amended to restrict use of both agents to the three categories above.
Evidence (pembrolizumab):
Atezolizumab
Atezolizumab is a humanized monoclonal antibody that binds to PD-L1 and prevents it from binding to its receptors PD-1 or B7-1. Clinical trials have reported that atezolizumab acts against urothelial carcinoma, but it has not shown prolonged OS or improved quality of life. The only randomized controlled trial testing atezolizumab reported no significant difference in OS compared with second-line chemotherapy.
Atezolizumab has been approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma who fall into one of the following three categories:
It is important to note that in 2018, the FDA issued an alert that preliminary data from two ongoing trials showed shorter survival in first-line therapy trials comparing pembrolizumab or atezolizumab with cisplatin or carboplatin-based therapy. As a result, the labels were amended to restrict use of both agents to the three categories above.
Evidence (atezolizumab):
Nivolumab
Nivolumab is a fully human immunoglobulin G4 PD-1 immune checkpoint inhibitor antibody that blocks interaction between PD-L1 and PD-L2 with PD-1. There are no published controlled trials and thus no data regarding whether nivolumab results in longer survival or improved quality of life.
Evidence (nivolumab):
Avelumab
Avelumab is a monoclonal anti–PD-L1 antibody that has shown activity against urothelial carcinoma. A randomized controlled trial reported an OS benefit from maintenance avelumab when given after platinum-based chemotherapy in patients whose cancer did not progress during chemotherapy.
Evidence (avelumab):
Durvalumab
Durvalumab is an anti–PD-L1 monoclonal antibody that has shown activity against urothelial carcinoma. There are no published controlled trials and no data demonstrating either longer survival or improved quality of life with this agent.
Evidence (durvalumab):
Targeted therapy
Ramucirumab
Ramucirumab is an immunoglobulin G1 monoclonal antibody that blocks the vascular endothelial growth factor receptor-2 (VEGFR-2). It is approved by the FDA for patients with gastric carcinoma and gastroesophageal junction adenocarcinoma, but not for patients with bladder cancer.
Evidence (ramucirumab):
Enfortumab vedotin
Enfortumab vedotin is a type of targeted therapy called an antibody-drug conjugate. Antibody-drug conjugates consist of a monoclonal antibody chemically linked to a drug. The monoclonal antibody part of enfortumab vedotin binds to a protein called nectin-4, which is found on the surface of most bladder cancer cells. The antibody is chemically linked to monomethyl auristatin E, or MMAE, a type of chemotherapy drug called a microtubule inhibitor. Once the conjugate is taken up by cells, the drug stops them from dividing and leads to their death.
Enfortumab vedotin has been approved by the FDA for patients with metastatic urothelial carcinoma that has progressed after treatment with both platinum-based first-line chemotherapy and second-line therapy with an immune checkpoint inhibitor. The approval was based on a single-arm trial of 125 patients with metastatic urothelial carcinoma.[
Evidence (enfortumab vedotin):
Because there was no control arm, this study could not demonstrate an improvement in OS or quality of life. A follow-up phase III trial is under way to assess the benefits of this medication.
Erdafitinib
Erdafitinib (JNJ-42756493) is a potent tyrosine kinase inhibitor of fibroblast growth factor receptors 1–4. It has been approved by the FDA for patients with urothelial carcinoma that has a mutation in one of the four fibroblast growth factor receptor genes and that has progressed after receiving chemotherapy.
Roughly 20% of metastatic urothelial carcinomas of the bladder have mutations of FGFR, as do 35% of urothelial carcinomas of the ureters and renal pelvis.
Evidence (erdafitinib):
Surgery for new superficial or localized tumors
Treatment of new superficial or locally invasive tumors that develop in the setting of previous conservative therapy for superficial bladder neoplasia has been discussed earlier in stage I in this summary.
Palliative therapy
Palliative radiation therapy should be considered for patients with symptomatic tumors.
Clinical trials
Recurrent or progressive disease in distant sites or after definitive local therapy has an extremely poor prognosis, and clinical trials should be considered whenever possible.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References:
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Bladder Cancer
Revised text to state that bladder cancer is the fourth most common cancer in men and the eleventh most common cancer in women, and of the roughly 82,000 new cases annually, about 62,000 are in men and about 20,000 are in women (cited American Cancer Society as reference 2).
Updated statistics with estimated new cases and deaths for 2023.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of bladder cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Bladder Cancer Treatment is:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Bladder Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389399]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2023-01-18
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