National Cancer Institute


Expert-reviewed information summary about the treatment of bladder cancer.

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 who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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).

Bladder Cancer Treatment

General Information About Bladder Cancer

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 lymphoma. It is the third most common cancer in men but only the eleventh most common cancer in women. Of the roughly 70,000 new cases annually, about 53,000 are in men and about 18,000 are in women. Of the roughly 15,000 annual deaths, over 10,000 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 2017:

  • New cases: 79,030.
  • Deaths: 16,870.

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 referred to as urothelial carcinoma) can develop anywhere along this pathway.

Anatomy of the male urinary system (left panel) and female urinary system (right panel); two-panel drawing showing the right and left kidneys, the ureters, the bladder filled with urine, and the 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).Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. 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 the bladder, the renal pelvises, the ureters, and the proximal urethra are transitional cell carcinomas (also called urothelial carcinomas) that derive from transitional epithelium. (Refer to the PDQ summaries on Renal Cell Cancer Treatment and Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information.)

Transitional cell carcinoma of the bladder can be low-grade or high-grade:

  • Low-grade bladder cancer often recurs in the bladder after treatment but rarely invades the muscular wall of the bladder or spreads to other parts of the body. Patients rarely die from low-grade bladder cancer.
  • High-grade bladder cancer commonly recurs in the bladder and also has a strong tendency to invade the muscular wall of the bladder and spread to other parts of the body. High-grade bladder cancer is treated more aggressively than low-grade bladder cancer and is much more likely to result in death. Almost all deaths from bladder cancer are due to high-grade disease.

Bladder cancer is also divided into muscle-invasive and nonmuscle-invasive disease, based on invasion of the muscularis propria (also referred to as the detrusor muscle), which is the thick muscle deep in the bladder wall.

  • Muscle-invasive disease is much more likely to spread to other parts of the body and is generally treated by either removing the bladder or treating the bladder with radiation and chemotherapy. As noted above, high-grade cancers are much more likely to be muscle-invasive than low-grade cancers. Thus, muscle-invasive cancers are generally treated more aggressively than nonmuscle-invasive cancers.
  • Nonmuscle-invasive disease can often be treated by removing the tumor(s) via a transurethral approach, and sometimes chemotherapy or other treatments are introduced into the bladder with a catheter to help fight the cancer.

Under conditions of chronic inflammation, such as infection of the bladder with the 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 the vast majority (over 90%) of 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:

  • Use of tobacco, especially cigarettes.
  • Family history of bladder cancer.
  • Genetic mutations.
    • mutation (Costello Syndrome, Facio-Cutaneous-Skeletal Syndrome).
    • mutation.
    • mutation (Cowden Syndrome).
    • slow acetylator phenotype.
    • null phenotype.
  • Occupational exposure to chemicals in processed paint, dye, metal, and petroleum products that include:
    • Aluminum production (polycyclic aromatic hydrocarbons, fluorides).
    • Aminobiphenyl and its metabolites.
    • Aromatic amines, benzidine and its derivatives.
    • Certain aldehydes.
    • 2-Napthylamine, beta-napthylamine.
  • Treatment with cyclophosphamide, ifosfamide, or pelvic radiation for other malignancies.
  • Chinese herbs: (AA) extracted from species of .
  • Exposure to arsenic.
    • Arsenic in well water.
    • Inorganic arsenic compounds (gallium arsenide).
  • Chlorinated aliphatic hydrocarbons and chlorination by-products in treated water.
  • bladder infections (Bilharzial bladder cancer).
  • Neurogenic bladder and associated indwelling catheters.

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. Smokers with less functional polymorphisms of N-acetyltransferase-2 (known as slow acetylators) have a higher risk of bladder cancer than other smokers, presumably because of their reduced ability to detoxify carcinogens.

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 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 . Patients with upper urinary tract urothelial carcinomas may present with pain due to obstruction by the tumor.

It is important to note that 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 ) 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:

  • Depth of invasion into the bladder wall.
  • Pathologic grade of the tumor.
  • Presence versus absence of carcinoma .

Among nonmuscle-invasive cancers, the following factors are also prognostic:

  • Number of tumors.
  • Tumor size (e.g., >3 cm or <3 cm).
  • Invasion of the lamina propria (Ta vs. T1).
  • Whether the tumor is the primary tumor or a recurrence.

Most superficial tumors are well differentiated. Patients in whom superficial tumors are less differentiated, large, multiple, or associated with carcinoma (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 from 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 from 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. Among patients with high-grade tumors, those who present with superficial, nonmuscle-invasive bladder cancer can usually be cured, and those with muscle-invasive disease can sometimes be cured. Studies have demonstrated that some patients with distant metastases have achieved long-term complete response after being treated with combination chemotherapy regimens, although most such patients have metastases limited to their lymph nodes and have a near-normal performance status.

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 due to 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.

Related Summaries

Other PDQ summaries containing information related to bladder cancer include the following:

  • Bladder and Other Urothelial Cancers Screening.
  • Renal Cell Cancer Treatment.
  • Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment.
  • Unusual Cancers of Childhood Treatment.

Cellular Classification of Bladder Cancer

More than 90% of bladder carcinomas are transitional cell carcinomas derived from the uroepithelium. About 2% to 7% are squamous cell carcinomas, and 2% are adenocarcinomas. Adenocarcinomas may be of urachal origin or nonurachal origin; the latter type is generally thought to arise from metaplasia of chronically irritated transitional epithelium. Small cell carcinomas also may develop in the bladder. Sarcomas of the bladder are very rare.

Pathologic grade of transitional cell carcinomas, which is based on cellular atypia, nuclear abnormalities, and the number of mitotic figures, is of great prognostic importance.

Stage Information for Bladder Cancer

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:

  • Size and mobility of palpable masses.
  • Degree of induration of the bladder wall.
  • Presence of extravesical extension or invasion of adjacent organs.

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 rather than CT imaging has not been demonstrated.

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define bladder cancer.

Treatment Option Overview for Bladder Cancer

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 C 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:

  • Surveillance for relapse or recurrence (typically used for tumors with low risk of recurrence or progression).
  • A minimum of 1 year of intravesical treatments with bacillus Calmette-Guérin (BCG) plus surveillance for relapse (typically used for tumors at intermediate or high risk of progression to muscle-invasive disease).
  • Additional intravesical chemotherapy (typically used for tumors with a high risk of recurrence but low risk of progression to muscle-invasive disease).

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. Other treatment approaches include the following:

  • Radical cystectomy followed by multiagent cisplatin–based chemotherapy.
  • Radical cystectomy without perioperative chemotherapy.
  • Radiation therapy without concomitant chemotherapy.
  • Partial cystectomy with or without perioperative 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 0 Bladder Cancer Treatment

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%. Of greater concern than recurrence is the risk of progression to muscle-invasive, locally-advanced, or metastatic bladder cancer. While progression is rare for patients with low-grade tumors, it is common among patients with high-grade cancers.

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 only 5% progressed. Risk factors for recurrence and progression are the following:

  • High-grade disease.
  • Presence of carcinoma .
  • Tumor larger than 3 cm.
  • Multiple tumors.
  • History of prior bladder cancer.

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; < .0001). However, although a single instillation of chemotherapy lowers the relapse rate in patients with multiple tumors, the majority still relapse. Such treatment is thus not sufficient by itself for these patients.

One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first TUR.[] A second TUR performed on 38 patients with Tis or Ta disease revealed that nine patients (24%) had lamina propria invasion (T1) and three patients (8%) had muscle invasion (T2).

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. An individual patient meta-analysis of randomized trials comparing intravesical BCG with intravesical MMC reported that there was a 32% reduction in risk of recurrence with BCG but only when the BCG treatment included a maintenance phase whereby BCG was given periodically for at least 1 year (typically an induction phase of six weekly treatments followed by three weekly treatment every 3 months). Intravesical chemotherapy is tolerated better than intravesical BCG. Although BCG may not prolong overall survival for Tis disease, it appears to afford complete response rates of about 70%, thereby decreasing the need for salvage cystectomy. Studies show that intravesical BCG delays tumor recurrence and tumor progression.

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. It is applicable to only a small minority of patients because of the tendency of bladder carcinoma to involve multiple regions of the bladder mucosa and to occur in areas that cannot be segmentally resected. Moreover, cystectomy (whether segmental or radical) is generally not indicated for T0 bladder cancer (see radical cystectomy below).

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, based on reports that up to 20% of patients with Tis will die of bladder cancer. However, cystectomy (whether segmental or radical) is generally not indicated for patients with Ta or Tis bladder cancer. Patients at high risk of progression, typically those with recurrent high-grade tumors with carcinoma after intravesical therapy with BCG, should be considered for radical cystectomy.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage 0 bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage I Bladder Cancer Treatment

Standard Treatment Options for Stage I Bladder Cancer

Patients with stage I bladder tumors are unlikely to die from 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%. Of greater concern than recurrence is the risk of progression to muscle-invasive, locally-advanced, or metastatic bladder cancer. While progression is rare for low-grade tumors, it is common among high-grade cancers.

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 only 5% progressed. Risk factors for recurrence and progression include the following:

  • High-grade disease.
  • Presence of carcinoma .
  • Tumor larger than 3 cm.
  • Multiple tumors.
  • History of prior bladder cancer.

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; < .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:

  • The risk of local recurrence after TUR is high.
  • Residual cancer is often found when a repeat TUR is performed.
  • More-advanced–stage cancer is sometimes found with repeat TUR.
  • Patients undergoing radical cystectomy for nonmuscle-invasive bladder cancer are often found to have T2 or greater disease when the cystectomy specimen is examined.
  • A substantial number of patients with high-grade nonmuscle-invasive bladder cancer subsequently die from their disease.

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 bacillus Calmette-Guérin (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. An individual patient meta-analysis of randomized trials that compared intravesical BCG with intravesical mitomycin C (MMC) reported that there was a 32% reduction in risk of recurrence with BCG but only when the BCG treatment included a maintenance phase whereby BCG was given periodically for at least 1 year (typically an induction phase of six weekly treatments followed by three weekly treatments every 3 months). Intravesical chemotherapy is tolerated better than intravesical BCG. Although BCG may not prolong overall survival for Tis disease, it appears to afford complete response rates of about 70%, thereby decreasing the need for salvage cystectomy. Studies show that intravesical BCG delays tumor recurrence and tumor progression.

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. It is applicable to only a small minority of patients because of the tendency of bladder carcinoma to involve multiple regions of the bladder mucosa and to occur in areas that cannot be segmentally resected. Moreover, cystectomy (whether segmental or radical) is generally not indicated for patients with T0 bladder cancer.

Radical cystectomy in selected patients with extensive or refractory superficial tumors

Radical cystectomy is used in selected patients with extensive or refractory superficial tumor. Patients at high risk of progression, typically those with recurrent high-grade tumors with carcinoma after intravesical therapy with BCG, should be considered for radical cystectomy. Other risk factors include multiple tumors and tumors larger than 3 cm.

Certain patients with nonmuscle-invasive bladder cancer face a substantial risk of progression and death from their cancers.

Evidence (radical cystectomy):

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stages II and III Bladder Cancer Treatment

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. At the present time, 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 accompanied by pelvic lymph node dissection and includes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and removal of the uterus, tubes, ovaries, anterior vaginal wall, and urethra in women. Studies of outcomes after radical cystectomy report increased survival in patients who had more, rather than fewer, lymph nodes resected; whether this represents a therapeutic benefit of resecting additional nodes or stage migration is unknown. There are no randomized controlled trials evaluating the therapeutic benefit of lymph node dissection in this setting.

Radical cystectomy is a major operation with a perioperative mortality rate of 2% to 3% when performed at centers of excellence. Postoperative complications include ileus. Most men have erectile dysfunction after radical cystectomy; sexual dysfunction after this operation is also common in women.

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. Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men. In addition, new forms of urinary diversion can obviate the need for an external urinary appliance.

In a retrospective analysis from a single institution, elderly 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. Five-year overall survival (OS) has generally been reported to be in the range of 50% to 60% but varies by stage. The addition of preoperative radiation therapy to radical cystectomy did not result in any survival advantage when compared with radical cystectomy alone in a prospective randomized trial.

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):

Of note, the vast majority of 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.

External-beam radiation therapy (EBRT) with or without concomitant chemotherapy

Definitive radiation therapy is a standard option that yields a 5-year survival of approximately 30% to 40%. When radiation therapy and chemotherapy are administered concomitantly, the results are better. However, while the addition of chemotherapy to radiation therapy has been shown to reduce local relapse rates, it has not been shown to result in increased survival, decreased mortality, or improved quality of life.

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 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. There are no randomized controlled trials comparing segmental cystectomy with radical cystectomy. Only patients with adenocarcinomas of the urachus are routinely treated with segmental cystectomy. These tumors typically are mucinous adenocarcinomas occurring at the dome of the bladder and are treated with an en bloc resection of the bladder dome and urachal remnant, including the umbilicus.

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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage II bladder cancer and stage III bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage IV Bladder Cancer Treatment

Currently, 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 or any T, N1–N3, M0 disease

Treatment options for patients with T4b, N0, M0 or any T, N1–N3, M0 disease include the following:

Chemotherapy alone

Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer. The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); high-dose MVAC; and cisplatin, methotrexate, and vinblastine (CMV). Gemcitabine plus cisplatin (GC) was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. 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 that compared MVAC with GC, for example, 5-year overall survival (OS) 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. Thus, there is no regimen that has been shown to prolong survival in patients who are not candidates for cisplatin-based multiagent chemotherapy regimens. Many regimens have been shown to be active, however, with regard to producing radiologically measurable responses:

These include carboplatin plus paclitaxel, carboplatin plus gemcitabine, paclitaxel plus gemcitabine, single-agent gemcitabine, and single-agent paclitaxel. Regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.

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. The extent of lymph node dissection during cystectomy is controversial because there are no data from prospective trials demonstrating improved outcomes with lymph node dissection. Because T4b tumors cannot generally be completely resected and because lymph node metastases usually signal distant micrometastases, patients with locally advanced bladder cancer are usually given chemotherapy before surgery with the goal of facilitating resection and eliminating micrometastatic disease. While there are data supporting preoperative chemotherapy for clinical stage II and stage III disease, patients with stage IV disease were excluded from most clinical trials investigating the role or preoperative chemotherapy.

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. Patients with evidence of lymph node metastases have therefore generally been excluded from phase III trials of radiation therapy.

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 stage IV bladder cancer. The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are MVAC, high-dose MVAC, and CMV. GC was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. 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, 5-year OS 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. Thus, for patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong their survival. Many regimens have been shown to be active, however, with regard to producing radiologically measurable responses.

These include carboplatin plus paclitaxel, carboplatin plus gemcitabine, paclitaxel plus gemcitabine, single-agent gemcitabine, and single-agent paclitaxel. The regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.

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 platinum-based chemotherapy.

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. There are no published controlled trials and thus no data regarding whether atezolizumab results in longer survival or improved quality of life.

Evidence (atezolizumab):

Nivolumab

Nivolumab is a fully human IgG4 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):

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 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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IV bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Recurrent Bladder Cancer Treatment

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.

Evidence (combination chemotherapy):

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 cisplatin-based chemotherapy.

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. There are no published controlled trials and thus no data regarding whether atezolizumab results in longer survival or improved quality of life.

Evidence (atezolizumab):

Nivolumab

Nivolumab is a fully human IgG4 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):

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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Changes to This Summary (06/05/2017)

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.

Recurrent Bladder Cancer Treatment

An editorial change was made to this section.

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® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

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 who care for cancer 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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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:

  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)

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 . Available at: https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq. Accessed . [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.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.


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