Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of bladder cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary 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.

Some of the reference citations in the 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. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: A separate PDQ summary on Bladder and Other Urothelial Cancers Screening is also available. Information on bladder cancer in children is available in the PDQ summary on Unusual Cancers of Childhood.

Note: Estimated new cases and deaths from bladder cancer in the United States in 2008: ^[1]

• New cases: 68,810.
• Deaths: 14,100.

Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial bladder tumors (i.e., stage Ta, Tis, or T1). Those who do present with superficial, noninvasive bladder cancer can often be cured, and those with deeply invasive disease can sometimes be cured by surgery, radiation therapy, or a combination of modalities that include chemotherapy. Studies have demonstrated that some patients with distant metastases have achieved long-term complete response following treatment with combination chemotherapy regimens. There are clinical trials suitable for patients with all stages of bladder cancer; whenever possible, patients should be included in clinical trials designed to improve on standard therapy.

The major prognostic factors in carcinoma of the bladder are the depth of invasion into the bladder wall and the degree of differentiation of the tumor. 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 for recurrence and the development of invasive cancer. Such patients may be considered to have the entire urothelial surface at risk for the development of cancer. Tis may exist for variable durations. Adverse prognostic features associated with a greater risk of disease progression include the presence of multiple aneuploid cell lines, nuclear p53 overexpression, and expression of the Lewis-x blood group antigen.^[2][3][4][5] Patients with Tis who have a complete response to bacillus Calmette-Guérin have approximately a 20% risk of disease progression at 5 years; patients with incomplete response have approximately a 95% risk of disease progression.^[2] Several treatment methods (i.e., transurethral surgery, intravesical medications, and cystectomy) have been used in the management of patients with superficial tumors, and each method can be associated with 5-year survival in 55% to 80% of patients treated.^[2][3][6]

Invasive tumors that are confined to the bladder muscle on pathologic staging after radical cystectomy are associated with approximately a 75% 5-year progression-free survival rate. Patients with more deeply invasive tumors, which are also usually less well differentiated, and those with lymphovascular invasion experience 5-year survival rates of 30% to 50% following radical cystectomy.^[7] When the patient presents with locally extensive tumor that invades pelvic viscera or with metastases to lymph nodes or distant sites, 5-year survival is uncommon, but considerable symptomatic palliation can still be achieved.^[8]

Expression of the tumor suppressor gene p53 also has been associated with an adverse prognosis for patients with invasive bladder cancer. A retrospective study of 243 patients treated by radical cystectomy found that the presence of nuclear p53 was an independent predictor for recurrence among patients with stage T1, T2, or T3 tumors.^[9] Another retrospective study showed p53 expression to be of prognostic value when considered with stage or labeling index.^[10]

References

Cellular Classification

More than 90% of bladder carcinomas are transitional cell carcinomas derived from the uroepithelium. About 6% to 8% are squamous cell carcinomas, and 2% are adenocarcinomas.^[1] Adenocarcinomas may be either of urachal origin or of nonurachal origin; the latter type is generally thought to arise from metaplasia of chronically irritated transitional epithelium.^[2] Pathologic grade, which is based on cellular atypia, nuclear abnormalities, and the number of mitotic figures is of great prognostic importance.

References

Stage Information

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 size and mobility of palpable masses, the degree of induration of the bladder wall, and the presence of extravesical extension or invasion of adjacent organs. Clinical staging, even when computed tomographic and/or magnetic resonance imaging scans and other imaging modalities are used, often underestimates the extent of tumor, particularly in cancers that are less differentiated and more deeply invasive.^[1][2][3]

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define bladder cancer.^[4]

TNM Definitions

Primary tumor (T)
• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• Ta: Noninvasive papillary carcinoma
• Tis: Carcinoma in situ (i.e., flat tumor)
• T1: Tumor invades subepithelial connective tissue
• T2: Tumor invades muscle
  • pT2a: Tumor invades superficial muscle (inner half)
  • pT2b: Tumor invades deep muscle (outer half)
• T3: Tumor invades perivesical tissue
  • pT3a: Microscopically
  • pT3b: Macroscopically (extravesical mass)
• T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall
  • T4a: Tumor invades the prostate, uterus, vagina
  • T4b: Tumor invades the pelvic wall, abdominal wall

The suffix “m” should be added to the appropriate T category to indicate multiple lesions. The suffix “is” may be added to any T to indicate the presence of associated carcinoma in situ.

Regional lymph nodes (N)
• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in a single lymph node 2 cm or smaller in largest dimension
• N2: Metastasis in a single lymph node larger than 2 cm but 5 cm or smaller in largest dimension; or multiple lymph nodes 5 cm or smaller in largest dimension
• N3: Metastasis in a lymph node larger than 5 cm in largest dimension

Distant metastasis (M)
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

AJCC Stage Groupings

Stage 0a
• Ta, N0, M0

Stage 0is
• Tis, N0, M0

Stage I
• T1, N0, M0

Stage II
• T2a, N0, M0
• T2b, N0, M0

Stage III
• T3a, N0, M0
• T3b, N0, M0
• T4a, N0, M0

Stage IV
• T4b, N0, M0
• Any T, N1, M0
• Any T, N2, M0
• Any T, N3, M0
• Any T, any N, M1

An older, less frequently used staging system was derived by comparing clinical estimates of stage with the pathologic stage of radical cystectomy specimens.^[2][3] To better ensure uniform staging and reporting of clinical results, the use of the modern TNM classification described above is recommended.

Treatment Option Overview

Prolonged survival in most patients with superficial cancers is achieved by transurethral resection (TUR) with or without intravesical chemotherapy. Cure is not possible for the majority of patients with deeply invasive tumors and for most patients with regional or distant metastases. In North America, the standard treatment of patients with invasive bladder cancers is radical cystectomy and urinary diversion. Other treatment approaches include TUR and segmental resection with or without radiation therapy, combined chemotherapy-radiation therapy, or either followed by salvage cystectomy, when needed, for local failure. Many newly diagnosed bladder cancer patients are candidates for participation in a clinical trial. Clinical trials include studies of chemoprevention of superficial disease, adjuvant chemotherapy for advanced local or regional disease, preservation of bladder function with chemotherapy-radiation therapy, and development of more effective systemic therapy and methods of palliation for metastatic tumors.^{[1][2][3][4][5][6]}

Reconstructive techniques that fashion low-pressure storage reservoirs from the reconfigured small and large bowel eliminate the need for external drainage devices and, in some male patients, allow voiding per urethra. These techniques are designed to improve the quality of life for patients who require cystectomy.^[7]

References

Stage 0 Bladder Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage 0 bladder cancer is defined by the following TNM classifications:
• Ta, N0, M0
• Tis, N0, M0

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 following initial resection was 80%.^[1] Patients at greatest risk of recurrent disease are those whose tumors are large, poorly differentiated, multiple, or associated with nuclear p53 overexpression. In addition, patients with carcinoma in situ (Tis) or dysplasia of grossly uninvolved bladder epithelium are at greater risk of recurrence and progression.^[1][2][3]

Transurethral resection (TUR) and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first.^[4][Level of evidence: 3iiDiv] A second TUR performed on 38 patients with Tis or Ta disease found 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 who require more aggressive forms of treatment are those with extensive multifocal recurrent disease and/or other unfavorable prognostic features. Segmental cystectomy 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.

Intravesical therapy with thiotepa, mitomycin, doxorubicin, or bacillus Calmette-Guérin (BCG) is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR. Administration of intravesical BCG plus subcutaneous BCG following TUR was compared with TUR alone in patients with Ta and T1 lesions. Treatment with BCG delayed progression to muscle-invasive and/or metastatic disease, improved bladder preservation, and decreased the risk of death from bladder cancer.^[5][6] Another randomized study of patients with superficial bladder cancer also reports a decrease in tumor recurrence in patients given intravesical and percutaneous BCG compared with controls.^[7] Two nonconsecutive 6-week treatment courses with BCG may be necessary to obtain optimal response.^[8] Patients with a T1 tumor at the 3-month evaluation after a 6-week course of BCG and patients with Tis that persists after a second 6-week BCG course have a high likelihood of developing muscle-invasive disease and should be considered for cystectomy.^[8][9][10] A randomized study that compared intravesical and subcutaneous BCG with intravesical doxorubicin showed better response rates and freedom from recurrence with the BCG regimen for recurrent papillary tumors as well as for Tis.^[11] A randomized trial from the Swedish-Norwegian Bladder Cancer Group compared 2 years of intravesical treatment with mitomycin C versus BCG. No difference was observed in tumor progression or overall survival (OS) between the two arms at 5 years.^[12][Level of evidence: 1iiDii] Although BCG may not prolong OS for Tis disease, it appears to afford complete response rates of about 70%, thereby decreasing the need for salvage cystectomy.^[13] Studies show that intravesical BCG delays tumor recurrence and tumor progression.^[6][14] Preliminary results from a prospective randomized trial suggest that maintenance BCG, when given to patients who are disease-free after a 6-week induction course, improves survival.^[15] One study that compared mitomycin with interferon-α-2b showed an improved outcome with mitomycin, even though interferon was better tolerated.^[16]

Standard treatment options:

1. TUR with fulguration.^[17]
2. TUR with fulguration followed by intravesical BCG. BCG is the treatment of choice for Tis.^{[5][7][9][13][14]}
3. TUR with fulguration followed by intravesical chemotherapy.^[2][11][17]
4. Segmental cystectomy (rarely indicated).^[17]
5. Radical cystectomy in selected patients with extensive or refractory superficial tumor.^[17][18]

Treatment options under clinical evaluation:

1. Photodynamic therapy after intravenous hematoporphyrin derivative appears capable of completely eradicating tumors in 50% of the treated patients who were in a small study with minimal follow-up.^[19] Further evaluation of this technique is needed.
2. Intravesical interferon-alpha-2a has shown activity against papillary tumors and Tis both as primary treatment and as secondary treatment after failure of other intravesical agents.^[20]
3. Use of chemoprevention agents after treatment to prevent recurrence.^[21]

Information about ongoing clinical trials is available from the NCI Web site.

Stage I Bladder Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage I bladder cancer is defined by the following TNM classification:
• T1, N0, M0

Patients with stage I 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 recurrence following initial resection was 80%.^[1] Patients at greatest risk of recurrent disease are those whose tumors are large, poorly differentiated, multiple, or associated with nuclear p53 overexpression.^[2] In addition, patients with carcinoma in situ (Tis) or dysplasia of grossly uninvolved bladder epithelium are at greater risk of recurrence and progression.^[1][3][4]

Transurethral resection (TUR) and fulguration are the most common and conservative forms of management. Careful surveillance of subsequent bladder tumor progression is important. One retrospective series addressed the value of performing a second TUR within 2 to 6 weeks of the first.^[5][Level of evidence: 3iiDiv] A second TUR performed on 58 patients with T1 disease found that 14 patients (24%) had residual (T1) disease and 16 patients (28%) had muscle invasion (T2). Such information may change the definitive management options in these individuals. Patients who require more aggressive forms of treatment are those with extensive multifocal recurrent disease and/or other unfavorable prognostic features. Segmental cystectomy 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.

Intravesical therapy with thiotepa, mitomycin, doxorubicin, or bacillus Calmette Guérin (BCG) is most often used in patients with multiple tumors or recurrent tumors or as a prophylactic measure in high-risk patients after TUR. Administration of intravesical BCG combined with subcutaneous BCG following TUR was compared with TUR alone in patients with Ta and T1 lesions. Treatment with BCG delayed progression to muscle-invasive and/or metastatic disease, improved bladder preservation, and decreased the risk of death from bladder cancer.^[6] Another randomized study in patients with superficial bladder cancer also reports a decrease in tumor recurrence in patients given intravesical and percutaneous BCG compared with controls.^[7] Two nonconsecutive 6-week courses with BCG may be necessary to obtain optimal response.^[8] Patients with a T1 tumor at the 3-month evaluation after a 6-week course of BCG and patients with Tis that persists after a second 6-week BCG course have a high likelihood of developing muscle-invasive disease and should be considered for cystectomy.^[8][9][10] A randomized study that compared intravesical and subcutaneous BCG to intravesical doxorubicin showed better response rates and freedom from recurrence with the BCG regimen for recurrent papillary tumors as well as for Tis.^[11] Preliminary results of one study have shown a possible survival benefit with maintenance BCG after a 6-week induction course.^[12] Another study that compared alternating mitomycin and BCG with BCG alone, both given for 24 months, found that the efficacy was equal, but that the side effects of the combined regimen were slightly less.^[13][Level of evidence: 1iiDiii] A similar trial comparing sequential mitomycin and BCG to mitomycin alone also found no major differences in toxic effects or efficacy.^[14][Level of evidence: 1iiDiii] A randomized trial from the Swedish-Norwegian Bladder Cancer Group compared 2 years of intravesical treatment with mitomycin C versus BCG for patients at high risk for recurrence or progression. At 5 years, a significant improvement was noted in disease-free survival with BCG (P = .04); however, no difference was observed in tumor progression or overall survival between the two arms.^[15]

Standard treatment options:

1. TUR with fulguration.^[16][17]
2. TUR with fulguration followed by intravesical BCG.^{[6][7][9][10][13]}
3. TUR with fulguration followed by intravesical chemotherapy.^[3][13]
4. Segmental cystectomy (rarely indicated).^[16]
5. Radical cystectomy in selected patients with extensive or refractory superficial tumor.^[18]
6. Interstitial implantation of radioisotopes with or without external-beam radiation therapy.^[19][20]

Treatment options under clinical evaluation:

1. Use of chemoprevention agents after treatment to prevent recurrence.^[21]
2. Intravesical therapies.

Information about ongoing clinical trials is available from the NCI Web site.

Stage II Bladder Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage II bladder cancer is defined by the following TNM classifications:
• T2a, N0, M0
• T2b, N0, M0

Stage II bladder cancer may be controlled in some patients by transurethral resection (TUR), but often more aggressive forms of treatment are dictated by recurrent tumor or by the large size, multiple foci, or undifferentiated grade of the neoplasm. Segmental cystectomy is appropriate only in very selected patients.

Radical cystectomy is considered standard treatment. Radical cystectomy includes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and the uterus, tubes, ovaries, anterior vaginal wall, and urethra in women and may or may not be accompanied by pelvic lymph node dissection.^[1] Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men and that new forms of urinary diversion can obviate the need for an external urinary appliance.^[2][3][4][5] In a retrospective analysis from a single institution, elderly patients (≥70 years) in good general health were found to have similar clinical and functional results following radical cystectomy when compared with younger patients.^[6]

After radical cystectomy, however, an approximate 50% risk of recurrence still exists for patients with muscle-invasive disease. 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.^[7] Because the disease 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) 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. A randomized study conducted by the Southwest Oncology Group compared three cycles of neoadjuvant cisplatin, methotrexate, vinblastine, and doxorubicin administered prior to cystectomy with cystectomy alone in 317 patients with stage T2 to stage T4a bladder cancer and showed that 5-year survival was 57% in the group receiving neoadjuvant chemotherapy and 43% in the group treated with cystectomy alone, which is a difference of borderline statistical significance (P = .06 by stratified log-rank test).^[8] No deaths or postoperative complications were associated with neoadjuvant chemotherapy. In addition, 38% of patients who received neoadjuvant chemotherapy had a pathologic complete response at the time of surgery, and 85% of those achieving a pathologic complete response were alive at 5 years.^[8][Level of evidence: 1iiA]

A larger, randomized study, conducted by the Medical Research Council and the European Organization for Research and Treatment of Cancer, evaluated three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate administered prior to cystectomy or radiation therapy in 976 patients with stage T2 grade 3, stage T3, or stage T4a disease. Although this study demonstrated an improvement in 3-year survival from 50% in patients who received no neoadjuvant chemotherapy to 55.5% in those who had, this difference was not statistically significant (P = .075) because the study had been originally powered to detect a 10% absolute difference in survival.^[9][Level of evidence: 1iiA] A meta-analysis of 10 randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that platinum-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in an improvement in 5-year survival from 45% to 50% (P = .016). Neoadjuvant single-agent cisplatin was not associated with any such survival benefit in the meta-analysis.^[10] Based on these findings, it is reasonable to offer neoadjuvant platinum-based combination chemotherapy prior to cystectomy in patients with muscle-invasive bladder cancer.

In patients who are not willing or able to undergo radical cystectomy, definitive radiation therapy is an option that yields a 5-year survival of approximately 30%.^[11][12][13] 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. In addition, compared with patients treated with radical cystectomy, those treated with definitive radiation therapy report less sexual dysfunction.^[14] Randomized trials, conducted from the 1950s through the 1980s, of definitive radiation therapy (with salvage cystectomy only for incomplete response or failure) versus preoperative radiation therapy followed by cystectomy have found similar or worse survival in patients who received definitive radiation therapy.^[15][16][17]

Systemic chemotherapy has been incorporated with definitive radiation therapy to develop a more effective bladder-sparing approach for patients with locally advanced disease. The utility of this multimodality approach was confirmed in a prospective, randomized comparison of radiation therapy and chemoradiation therapy, which reported an improved rate of local control when cisplatin was given in conjunction with radiation therapy, even though there was no improvement in the rate of distant metastases or overall survival (OS).^[18][Level of evidence: 1iiA] In some nonrandomized studies, 50% or more of the patients who had bladder-preserving therapy (i.e., initial TUR of as much tumor as possible followed by concurrent chemoradiation therapy) were alive at 5 years, and 75% of those survivors had an intact bladder.^[19][20][21] In a phase III study (RTOG-8903), the Radiation Therapy Oncology Group evaluated the potential benefit of adding two cycles of neoadjuvant methotrexate, cisplatin, and vinblastine prior to concurrent cisplatin and radiation therapy, but neoadjuvant chemotherapy was associated with increased hematologic toxic effects and yielded no improvement in response rate, freedom from distant metastases, or OS when compared with chemoradiation therapy alone.^[22] Because no randomized trials have directly compared the bladder-preserving chemoradiation therapy approach with radical cystectomy, it is not clear if the former is as effective as the latter. Choice of treatment should be guided by a patient’s overall medical condition and by consideration of the adverse effects of therapy.

Treatment options:

1. Radical cystectomy with or without pelvic lymph node dissection.^[23]
2. Neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy.^[8]
3. External-beam radiation therapy (EBRT) with or without concurrent chemotherapy .^{[11][12][13][18][19][20][21]}
4. Interstitial implantation of radioisotopes before or after EBRT.^[24][25]
5. TUR with fulguration (in selected patients).
6. Segmental cystectomy (in selected patients).^[23]

Stage III Bladder Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage III bladder cancer is defined by the following TNM classifications:
• T3a, N0, M0
• T3b, N0, M0
• T4a, N0, M0

A few highly selected patients with stage III bladder cancer may be suitable for segmental cystectomy or interstitial radiation therapy.

For most patients, radical cystectomy is considered standard treatment. Radical cystectomy includes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and the uterus, tubes, ovaries, anterior vaginal wall, and urethra in women and may or may not be accompanied by pelvic lymph node dissection.^[1] Studies (RTOG-8512) suggest that radical cystectomy with preservation of sexual function can be performed in some men, and new forms of urinary diversion can obviate the need for an external urinary appliance.^[2][3][4][5] In a retrospective analysis (RTOG-8903) from a single institution, elderly patients (≥70 years) in good general health were found to have similar clinical and functional results following radical cystectomy when compared with younger patients.^[6]

After radical cystectomy, however, an approximate 50% risk of recurrence still exists for patients with muscle-invasive disease. 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.^[7] Because the disease 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) may be preferable to postoperative treatment since tumor downstaging from chemotherapy may enhance resectability, occult metastatic disease may be treated as early as possible, and chemotherapy may be better tolerated. A randomized study conducted by the Southwest Oncology Group compared three cycles of neoadjuvant cisplatin, methotrexate, vinblastine, and doxorubicin administered prior to cystectomy with cystectomy alone in 317 patients with stage T2 to stage T4a bladder cancer, and showed that 5-year survival was 57% in the group receiving neoadjuvant chemotherapy and 43% in the group treated with cystectomy alone, which is a difference of borderline statistical significance (P = .06 by stratified log-rank test).^[8] No deaths or postoperative complications were associated with neoadjuvant chemotherapy. In addition, 38% of patients who received neoadjuvant chemotherapy had a pathologic complete response at the time of surgery, and 85% of those achieving a pathologic complete response were alive at 5 years.^[8][Level of evidence: 1iiA]

A larger, randomized study, conducted by the Medical Research Council and the European Organization for Research and Treatment of Cancer, evaluated three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate administered prior to cystectomy or radiation therapy in 976 patients with stage T2 grade 3, stage T3, or stage T4a disease. Although this study demonstrated an improvement in 3-year survival from 50% in patients who received no neoadjuvant chemotherapy to 55.5% in those who had, this difference was not statistically significant (P = .075) because the study had been originally powered to detect a 10% absolute difference in survival.^[9][Level of evidence: 1iiA] A meta-analysis of 10 randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that platinum-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in an improvement in 5-year survival from 45% to 50% (P = .016). Neoadjuvant single-agent cisplatin was not associated with any such survival benefit in the meta-analysis.^[10] Based on these findings, it is reasonable to offer neoadjuvant platinum-based combination chemotherapy prior to cystectomy in patients with muscle-invasive bladder cancer.

In an effort to reduce the toxic effects of platinum-based regimens given in the perioperative setting, a German multicenter study randomized 327 patients with pathologic T3a-T4a and/or N+ disease after radical cystectomy to 3 cycles of cisplatin and methotrexate (CM) or three cycles of methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC).^[11] The median progression-free survival was 43.4 months in the CM arm and 49.7 months in the M-VEC arm, yielding a hazard ratio [HR] for disease progression of 1.13 (90% confidence interval [CI], 0.86–1.48). The median overall survival (OS) was 47.1 months in the CM arm and 51.8 months in the M-VEC arm, yielding an HR for death of 1.10 (90% CI, 0.88–1.44). Leukopenia was more common with the four-drug regimen, but the rates of febrile neutropenia, infection, and treatment-related deaths were the same with both regimens. This study was powered to accept as much as a 50% increase in progression-free survival as being noninferior.^[11][Level of evidence: 1iiA]

In patients who are not willing or able to undergo radical cystectomy, definitive radiation therapy is an option that yields a 5-year survival of approximately 30%.^[12][13][14] 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. In addition, compared with patients treated with radical cystectomy, those treated with definitive radiation therapy report less sexual dysfunction.^[15] Randomized trials, conducted from the 1950s through the 1980s, of definitive radiation therapy (with salvage cystectomy only for incomplete response or failure) versus preoperative radiation therapy followed by cystectomy have found similar or worse survival in patients who received definitive radiation therapy. ^{[16] [1][17]}

Systemic chemotherapy has been incorporated with definitive radiation therapy to develop a more effective bladder-sparing approach for patients with locally advanced disease. The utility of this multimodality approach was confirmed in a prospective, randomized comparison of radiation therapy and chemoradiation therapy, which reported an improved rate of local control when cisplatin was given in conjunction with radiation therapy, even though there was no improvement in the rate of distant metastases or OS.^[18][Level of evidence: 1iiA] In some nonrandomized studies, 50% or more of patients who had bladder-preserving therapy (i.e., initial transurethral resection of as much tumor as possible followed by concurrent chemoradiation therapy) were alive at 5 years, and 75% of those survivors had an intact bladder.^[3][4][19] In a phase III study, the Radiation Therapy Oncology Group evaluated the potential benefit of adding two cycles of neoadjuvant methotrexate, cisplatin, and vinblastine administered prior to concurrent cisplatin and radiation therapy, but neoadjuvant chemotherapy was associated with increased hematologic toxic effects and yielded no improvement in response rate, freedom from distant metastases, or OS compared with chemoradiation therapy alone.^[6] Because no randomized trials have directly compared the bladder-preserving chemoradiation therapy approach with radical cystectomy, it is not clear if the former is as effective as the latter. Choice of treatment should be guided by a patient’s overall medical condition and by consideration of the adverse effects of therapy.

Treatment options:

1. Radical cystectomy with or without pelvic lymph node dissection.^[7]
2. Neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy.^[8]
3. External-beam radiation therapy (EBRT) with or without concurrent chemotherapy.^{[3][4][5][6][12][13][14][18]}
4. EBRT with interstitial implantation of radioisotopes.^[20]
5. Segmental cystectomy (in highly selected cases).^[21]

Stage IV Bladder Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IV bladder cancer is defined by the following TNM classifications:
• T4b, N0, M0
• Any T, N1, M0
• Any T, N2, M0
• Any T, N3, M0
• Any T, Any N, M1

Currently, only a small fraction of patients with stage IV bladder carcinoma can be cured. 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.^[1] These patients may undergo radical cystectomy with pelvic lymph node dissection. The extent of lymph node dissection during cystectomy is controversial ^[2] as there are no data from prospective trials demonstrating improved outcomes with lymph node dissection. 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.

Prognosis is so poor in patients with stage IV disease that consideration of entry into a clinical trial is appropriate. The focus of care for many stage IV patients is on palliation of symptoms from bladder tumor that is often massive. Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy. Platinum-based combination chemotherapy regimens are the standard of care. A prospective, randomized trial of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) compared with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks, P = .003) with the former regimen.^[3] Results from a randomized trial that compared M-VAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with M-VAC in both response rate and median survival (12.5 months vs. 8.2 months, P = .002).^[4] The (outpatient) regimen of paclitaxel and carboplatin achieved response rates in the range of 50% in single-institution phase II trials.^[5][6][Level of evidence: 3iiiDiv] However, when this regimen was evaluated in a multicenter phase II study conducted by the Southwest Oncology Group, the response rate was only 21%.^[7][Level of evidence: 3iiiDiv] Gemcitabine has shown activity in phase II trials of patients with metastatic bladder cancer.^[8] In a multicenter, randomized, phase III trial comparing the combination of gemcitabine/cisplatin (GC) with the M-VAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded similar response rates, time-to-progression, and overall survival (OS) (hazard ratio [HR] = 1.04; 95% confidence interval [CI], 0.82–1.32; P = .75) compared with M-VAC, but GC had a better safety profile and was better tolerated than M-VAC. 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 M-VAC regimen.^[9][Level of evidence: 1iiA]

The European Organisation for Research and Treatment of Cancer Group conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose-intensity M-VAC regimen given every 2 weeks with granulocyte colony-stimulating factor (G-CSF) compared to a classic M-VAC regimen given every 4 weeks.^[10] Although there was no significant difference in OS at a median follow-up of 3.2 years (HR = 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity M-VAC regimen was associated with improved OS (HR = 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22%, compared to 14% in patients treated with the classic M-VAC regimen. The high-dose intensity M-VAC regimen was also associated with higher response rates (72% vs. 58%, P = .016), improved median progression-free survival (9.5 months vs. 8.1 months, P = .017), and decreased neutropenic fever (10% vs. 26%, P < .001), though only 19% of patients treated with a classic M-VAC regimen ever received G-CSF.^[10][Level of evidence: 1iiA] An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose M-VAC regimen and 47 patients assigned to the classic M-VAC regimen) may account, in part, for these results. Ongoing studies are evaluating new chemotherapy combinations.

Information about ongoing clinical trials is available from the NCI Web site.

For patients with T4b, N0, M0; Any T, N1, M0; Any T, N2, M0; Any T, N3, M0 disease:

Treatment options:

1. Radical cystectomy with pelvic lymph node dissection.^[2][11][12]
2. External-beam radiation therapy (EBRT).^[13][14]
3. Urinary diversion or cystectomy for palliation.
4. Chemotherapy as an adjunct to local treatment (RTOG-8512).^{[15][16][17][18][19]}

For patients with Any T, Any N, M1 disease:

Standard treatment options:

1. Chemotherapy alone or as an adjunct to local treatment.^[3][4][9]
2. EBRT for palliation.
3. Urinary diversion or cystectomy for palliation.

Treatment options under clinical evaluation:

• 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, gemcitabine, and pemetrexed.^[20][21][22][Level of evidence: 3iiiDiv] Information about ongoing clinical trials is available from the NCI Web site.

Recurrent Bladder Cancer

The prognosis for any patient with progressive or recurrent invasive bladder cancer is generally poor. Management of recurrence depends on prior therapy, sites of recurrence, and individual patient considerations. 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 this summary. 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.

In patients with recurrent transitional cell carcinoma, combination chemotherapy has produced high response rates with occasional complete responses seen.^[1][2] Results from a randomized trial that compared M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) with single-agent cisplatin in advanced bladder cancer show a significant advantage with M-VAC in both response rate and median survival.^[3] The overall response rate with M-VAC in this cooperative group trial was 39%. Other chemotherapy agents that have shown activity in metastatic bladder cancer include: paclitaxel, ifosfamide, gallium nitrate, gemcitabine, and pemetrexed. Ifosfamide, gallium, and pemetrexed have shown limited activity in patients previously treated with cisplatin.^{[4][5][6][7][8][9][10][11]} Information about ongoing clinical trials is available from the NCI Web site.

References

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