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Bladder cancer


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TNM definitions
AJCC stage groupings
Stage 0a
Stage 0is
Stage I
Stage II
Stage III
Stage IV
TREATMENT OPTION OVERVIEW
STAGE 0 BLADDER CANCER
Tis or Ta, N0, M0
STAGE I BLADDER CANCER
T1, N0, M0
STAGE II BLADDER CANCER
T2a, N0, M0 or T2b, N0, M0
STAGE III BLADDER CANCER
T3a, N0, M0 or T3b, N0, M0 or T4a, N0, M0
STAGE IV BLADDER CANCER
T4b, N0, M0, any T, N1-N3, M0, or any T, any N, M1
RECURRENT BLADDER CANCER

GENERAL INFORMATION

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 are often curable, and those with deeply invasive disease can sometimes be cured by surgery, irradiation, 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.[1-4] Patients with Tis who have a complete response to bacillus Calmette-Guerin have approximately a 20% risk of disease progression at 5 years; patients with incomplete response have approximately a 95% risk of disease progression.[1] 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.[1,2,5]

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) experience 5-year survival rates of 20% to 40% following radical cystectomy. 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.[6]

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.[7] Another retrospective study showed p53 expression to be of prognostic value when considered with stage or labeling index.[8]

References:

  1. Hudson MA, Herr HW: Carcinoma in situ of the bladder. Journal of Urology 153(3, Part 1): 564-572, 1995.

  2. Torti FM, Lum BL: The biology and treatment of superficial bladder cancer. Journal of Clinical Oncology 2(5): 505-531, 1984.

  3. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. Journal of Clinical Oncology 14(10): 2646-2652, 1996.

  4. Stein JP, Grossfeld GD, Ginsberg DA, et al.: Prognostic markers in bladder cancer: a contemporary review of the literature. Journal of Urology 160(3 pt 1): 645-659, 1998.

  5. Witjes JA, Caris CT, Mungan NA, et al.: Results of a randomized phase III trial of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guerin versus mitomycin C alone in patients with superficial bladder cancer. Journal of Urology 160(5): 1668-1672, 1998.

  6. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. Journal of Urology 149(5): 957-972, 1993.

  7. Esrig D, Elmajian D, Groshen S, et al.: Accumulation of nuclear p53 and tumor progression in bladder cancer. New England Journal of Medicine 331(19): 1259-1264, 1994.

  8. Lipponen PK: Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. International Journal of Cancer 53: 365-370, 1993.


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:

  1. Mostofi FK, Davis CJ, Sesterhenn IA: Pathology of tumors of the urinary tract. In: Skinner DG, Lieskovsky G, Eds.: Diagnosis and Management of Genitourinary Cancer. Philadelphia, WB Saunders, 1988, pp 83-117.

  2. Wilson TG, Pritchett TR, Lieskovsky G, et al.: Primary adenocarcinoma of bladder. Urology 38(3): 223-226, 1991.


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.[1-3]

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


TNM definitions

Primary tumor (T)

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.

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Ta: Noninvasive papillary carcinoma
Tis: Carcinoma in situ: "flat tumor"
T1: Tumor invades subepithelial connective tissue
T2: Tumor invades muscle
T2a: Tumor invades superficial muscle (inner half)
T2b: Tumor invades deep muscle (outer half)
T3: Tumor invades perivesical tissue
T3a: microscopically
T3b: 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

Regional lymph nodes (N)

Regional lymph nodes are those within the true pelvis; all others are distant lymph nodes.

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension
N2: Metastasis in a single lymph node, more than 2 cm but not more than
5 cm in greatest dimension; or multiple lymph nodes, none more than
5 cm in greatest dimension
N3: Metastasis in a lymph node more than 5 cm in greatest 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.

References:

  1. National Institutes of Health: National Institutes of Health Consensus Development Conference: magnetic resonance imaging. Journal of the American Medical Association 259(14): 2132-2138, 1988.

  2. Marshall VF: The relationship of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. Journal of Urology 68(4): 714-723, 1952.

  3. Skinner DG: Current state of classification and staging of bladder cancer. Cancer Research 37(8, Part II): 2838-2842, 1977.

  4. Urinary bladder. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 241-246.


TREATMENT OPTION OVERVIEW

Prolonged survival in most patients with superficial cancers is achieved by transurethral resection (TUR) with or without intravesical chemotherapy. However, 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. Therefore, 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.[1-6]

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]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

  1. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. Journal of Urology 149(5): 957-972, 1993.

  2. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

  3. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

  4. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. Journal of Urology 151(1): 21-26, 1994.

  5. Raghavan D, Huben R: Management of bladder cancer. Current Problems in Cancer 19(1): 1-64, 1995.

  6. Sauer R, Birkenhake S, Kuhn R, et al.: Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer. International Journal of Radiation Oncology, Biology, Physics 40(1): 121-127, 1998.

  7. Hautmann RE, Miller K, Steiner U, et al.: The ileal neobladder: 6 years of experience with more than 200 patients. Journal of Urology 150(1): 40-45, 1993.


STAGE 0 BLADDER CANCER


Tis or Ta, N0, M0

Stage 0 bladder tumors can be cured by a variety of forms of treatment, 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.[1-3]

Transurethral resection (TUR) and fulguration are the most common and conservative forms of management. 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. In series of patients who were followed for more than 10 years after management of superficial tumors, the risk of developing a transitional cell carcinoma of the upper urinary tract has been reported in the 2% to 13% range.[1,4]

Intravesical therapy with thiotepa, mitomycin, doxorubicin, or bacillus Calmette-Guerin (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.[4,5] 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.[6] Two nonconsecutive 6-week treatment courses with BCG may be necessary to obtain optimal response.[7] 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.[7-9] 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.[10] A randomized trial from the Swedish-Norwegian Bladder Cancer Group compared 2 years of intravesical treatment with mitomycin C versus BCG. However, no difference was observed in tumor progression or overall survival between the two arms at 5 years.[11][Level of evidence: 1iiD] 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.[12] Studies show that intravesical BCG delays tumor recurrence and tumor progression.[5,13] 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.[14] One study that compared mitomycin with interferon alfa-2b showed an improved outcome with mitomycin, although interferon was better tolerated.[15]

Treatment options:

Standard:

1. TUR with fulguration.[16]

2. TUR with fulguration followed by intravesical BCG. BCG is the treatment of choice for Tis.[4,6,8,12,13]

3. TUR with fulguration followed by intravesical chemotherapy.[2,10,16]

4. Segmental cystectomy (rarely indicated).[16]

5. Radical cystectomy in selected patients with extensive or refractory superficial tumor.[16,17]

Under clinical evaluation:
1. Photodynamic therapy after intravenous hematoporphyrin derivative appears capable of completely eradicating tumors in one half of the treated patients who were in a small study with minimal follow-up.[18] Further evaluation of this technique is needed.

2. Intravesical interferon alfa-2a has shown activity against papillary tumors and Tis both as primary treatment and as secondary treatment after failure of other intravesical agents.[19]

3. Use of chemoprevention agents after treatment to prevent recurrence.[20]

References:

  1. Holmang S, Hedelin H, Anderstrom C, et al.: The relationship among multiple recurrences, progression and prognosis of patients with stages TA and T1 transitional cell cancer of the bladder followed for at least 20 years. Journal of Urology 153(6): 1823-1827, 1995.

  2. Igawa M, Urakami S, Shirakawa H, et al.: Intravesical instillation of epirubicin: effect on tumour recurrence in patients with dysplastic epithelium after transurethral resection of superficial bladder tumour. British Journal of Urology 77(3): 358-362, 1996.

  3. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. Journal of Clinical Oncology 14(10): 2646-2652, 1996.

  4. Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical Bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. Journal of Clinical Oncology 13(6): 1404-1408, 1995.

  5. Lamm DL, Griffith JG: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Seminars in Urology 10(1): 39-44, 1992.

  6. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 142(3): 719-722, 1989.

  7. Coplen DE, Marcus MD, Myers JA, et al.: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. Journal of Urology 144(3): 652-657, 1990.

  8. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 137(2): 220-224, 1987.

  9. Herr HW: Progression of stage T1 bladder tumors after intravesical bacillus Calmette-Guerin. Journal of Urology 145(1): 40-44, 1991.

  10. Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New England Journal of Medicine 325(17): 1205-1209, 1991.

  11. Malmstrom PU, Wijkstrom H, Lundholm C, et al.: 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Journal of Urology 161(4): 1124-1127, 1999.

  12. De Jager R, Guinan P, Lamm D, et al.: Long-term complete remission in bladder carcinoma in situ with intravesical TICE bacillus Calmette Guerin: overview analysis of six phase II clinical trials. Urology 38(6): 507-513, 1991.

  13. Herr HW, Wartinger DD, Fair WR, et al.: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. Journal of Urology 147(4): 1020-1023, 1992.

  14. Lamm DL, Crawford ED, Blumenstein B, et al.: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group study. Proceedings of the American Society of Clinical Oncology 11: A-627, 203, 1992.

  15. Boccardo F, Cannata D, Rubagotti A, et al.: Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. Journal of Clinical Oncology 12(1): 7-13, 1994.

  16. Soloway MS: The management of superficial bladder cancer. In: Javadpour N, Ed.: Principles and Management of Urologic Cancer. Baltimore: Williams and Wilkins, 2nd ed., 1983, pp 446-466.

  17. Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages TA, TIS, and T1 transitional cell carcinoma of the bladder. Journal of Urology 151(1): 31-36, 1994.

  18. Prout GR, Lin CW, Benson RC, et al.: Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder. New England Journal of Medicine 317(20): 1251-1255, 1987.

  19. Torti FM, Shortliffe LD, Williams RD, et al.: Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group study. Journal of Clinical Oncology 6(3): 476-483, 1988.

  20. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. Journal of Urology 151(1): 21-26, 1994.


STAGE I BLADDER CANCER

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 levels of evidence summary for more information.


T1, N0, M0

Stage I bladder tumors can be cured by a variety of forms of treatment, 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. 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. In series of patients who were followed for more than 10 years after management of superficial tumors, the risk of developing a transitional cell carcinoma of the upper urinary tract has been reported in the 2% to 13% range.[1,5]

Intravesical therapy with thiotepa, mitomycin, doxorubicin, or BCG (bacillus Calmette-Guerin) 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.[5] 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.[6] Two nonconsecutive 6-week courses with BCG may be necessary to obtain optimal response.[7] 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.[7-9] 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.[10] Preliminary results of one study have shown a possible survival benefit with maintenance BCG after a 6-week induction course.[11] 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.[12][Level of evidence: 1iiDii] A similar trial comparing sequential mitomycin and BCG to mitomycin alone also found no major differences in toxic effects or efficacy.[13][Level of evidence: 1iiDii] 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=0.04); however, no difference was observed in tumor progression or overall survival between the two arms.[14]

Treatment options:

Standard:

1. TUR with fulguration.[15,16]

2. TUR with fulguration followed by intravesical BCG.[5,6,8,9,12]

3. TUR with fulguration followed by intravesical chemotherapy.[3,12]

4. Segmental cystectomy (rarely indicated).[15]

5. Radical cystectomy in selected patients with extensive or refractory superficial tumor.[17]

6. Interstitial implantation of radioisotopes with or without external-beam irradiation.[18,19]

Under clinical evaluation:
1. Use of chemoprevention agents after treatment to prevent recurrence.[20]

2. Intravesical therapies.

References:

  1. Holmang S, Hedelin H, Anderstrom C, et al.: The relationship among multiple recurrences, progression and prognosis of patients with stages TA and T1 transitional cell cancer of the bladder followed for at least 20 years. Journal of Urology 153(6): 1823-1827, 1995.

  2. Smits G, Schaafsma E, Kiemeney L, et al.: Microstaging of pT1 transitional cell carcinoma of the bladder: identification of subgroups with distinct risks of progression. Urology 52(6): 1009-1014, 1998.

  3. Igawa M, Urakami S, Shirakawa H, et al.: Intravesical instillation of epirubicin: effect on tumour recurrence in patients with dysplastic epithelium after transurethral resection of superficial bladder tumour. British Journal of Urology 77(3): 358-362, 1996.

  4. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. Journal of Clinical Oncology 14(10): 2646-2652, 1996.

  5. Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical Bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. Journal of Clinical Oncology 13(6): 1404-1408, 1995.

  6. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 142(3): 719-722, 1989.

  7. Coplen DE, Marcus MD, Myers JA, et al.: Long-term follow-up of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. Journal of Urology 144(3): 652-657, 1990.

  8. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. Journal of Urology 137(2): 220-224, 1987.

  9. Herr HW: Progression of stage T1 bladder tumors after intravesical bacillus Calmette-Guerin. Journal of Urology 145(1): 40-44, 1991.

  10. Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New England Journal of Medicine 325(17): 1205-1209, 1991.

  11. Lamm DL, Crawford ED, Blumenstein B, et al.: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group study. Proceedings of the American Society of Clinical Oncology 11: A-627, 203, 1992.

  12. Rintala E, Jauhiainen K, Kaasinen E, et al.: Alternating mitomycin C and bacillus Calmette-Guerin instillation prophylaxis for recurrent papillary (stages Ta to T1) superficial bladder cancer. Journal of Urology 156(1): 56-60, 1996.

  13. Witjes JA, Caris CT, Mungan NA, et al.: Results of a randomized phase III trial of sequential intravesical therapy with mitomycin C and bacillus Calmette-Guerin versus mitomycin C alone in patients with superficial bladder cancer. Journal of Urology 160(5): 1668-1672, 1998.

  14. Malmstrom PU, Wijkstrom H, Lundholm C, et al.: 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Journal of Urology 161(4): 1124-1127, 1999.

  15. Soloway MS: The management of superficial bladder cancer. In: Javadpour N, Ed.: Principles and Management of Urologic Cancer. Baltimore: Williams and Wilkins, 2nd ed., 1983, pp 446-466.

  16. Herr HW, Reuter VE: Evaluation of new resectoscope loop for transurethral resection of bladder tumors. Journal of Urology 159(6): 2067-2068, 1998.

  17. Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages TA, TIS, and T1 transitional cell carcinoma of the bladder. Journal of Urology 151(1): 31-36, 1994.

  18. Goffinet DR, Schneider MJ, Glatstein EJ, et al.: Bladder cancer: results of radiation therapy in 384 patients. Radiology 117(1): 149-153, 1975.

  19. Vanderwerf-Messing B, Hop WC: Carcinoma of the urinary bladder, category T1 NX M0 treated either by radium implant or by transurethral resection only. International Journal of Radiation Oncology, Biology, Physics 7(3): 299-303, 1981.

  20. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. Journal of Urology 151(1): 21-26, 1994.


STAGE II BLADDER CANCER

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 levels of evidence summary for more information.


T2a, N0, M0 or T2b, N0, M0

Stage II bladder cancer may be controlled in some cases 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. In some reports, bladder-sparing radiation therapy with salvage cystectomy when indicated yields similar therapeutic results to those of radical cystectomy and can be delivered to patients who are not candidates for surgery. In some studies, one half or more of patients who had bladder-preserving therapy (initial TUR of as much tumor as possible with chemotherapy and concomitant radiation therapy) were disease-free 3 to 4 years after treatment;[1-3] radical cystectomy was reserved for patients who did not achieve a complete response. Some investigators think that the prognosis is worse for patients with hydronephrosis on the initial intravenous pyelogram, and therefore, they are not candidates for this approach.[1,3] Choice of treatment is affected by a patient's overall medical condition and consideration of the adverse effects of therapy. 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.[4] 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.[5-8] In a retrospective analysis from a single institution, elderly patients (70 years of age or older) in good general health were found to have similar clinical and functional results following radical cystectomy when compared to younger patients.[9] The only prospective, randomized trial reported to date did not show any survival advantage for preoperative radiation therapy and radical cystectomy compared with radical cystectomy alone.[10] Treatment with concurrent chemotherapy and radiation therapy has been associated with improved rates of local control compared with historical series of patients treated with radiation therapy alone. The only prospective, randomized comparison of radiation therapy and chemoradiotherapy reported an improved rate of local control when cisplatin was given in conjunction with radiation therapy.[11]

Treatment options:

Standard:

1. Radical cystectomy with or without pelvic lymph node dissection.[12]

2. External-beam irradiation (nonsurgical candidates and selected cases).[13-15]

3. Interstitial implantation of radioisotopes before or after external-beam irradiation.[16]

4. TUR with fulguration (in selected patients).

5. Segmental cystectomy (in selected patients).[12]

Under clinical evaluation:
Multiple clinical trials are evaluating the potential of chemotherapy
administered prior to cystectomy, following cystectomy, or in conjunction
with external-beam radiation therapy to improve local tumor control, prevent
distant metastases, or allow preservation of the bladder.[1-3,17-21]
The combination regimen methotrexate, vinblastine, doxorubicin, and
cisplatin produced a pathologic complete response in approximately 20% of
patients treated prior to definitive surgery.[19] However, there is no
evidence to date that the use of neoadjuvant cisplatin or cisplatin-based
regimens will improve the survival of patients with locally advanced bladder
cancer.[22][Level of evidence: 1iiA] In a bladder-sparing clinical trial of
external radiation therapy with chemotherapy, initial results from the
Radiation Therapy Oncology Group have shown that 2 cycles of neoadjuvant
methotrexate, cisplatin, and vinblastine do not improve down staging to
a complete response, patient survival, or freedom from metastatic disease
over radiation and concurrent cisplatin alone.[3][Level of evidence: 1iiA]

References:

  1. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

  2. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

  3. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: inital results of Radiation Therapy Oncology Group 89-03. Journal of Clinical Oncology 16(11): 3576-3583, 1998.

  4. Olsson CA: Management of invasive carcinoma of the bladder. In: deKernion JB, Paulson DF, Eds.: Genitourinary Cancer Management. Philadelphia: Lea and Febiger, 1987, pp 59-94.

  5. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. Journal of Urology 144(5): 1137-1141, 1990.

  6. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. Journal of Urology 132(6): 1101-1107, 1984.

  7. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part I. Monographs in Urology 8(2): 1987.

  8. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part II. Monographs in Urology 8(3): 1987.

  9. Figueroa AJ, Stein JP, Dickinson M, et al.: Radical cystectomy for elderly patients with bladder carcinoma: an updated experience with 404 patients. Cancer 83(1): 141-147, 1998.

  10. Smith JA, Crawford ED, Blumenstein B, et al.: A randomized prospective trial of pre-operative irradiation plus radical cystectomy versus surgery alone for transitional cell carcinoma of the bladder: a Southwest Oncology Group study. Journal of Urology 139(4, Part 2): 266A, 1988.

  11. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. Journal of Clinical Oncology 14(11): 2901-2907, 1996.

  12. Richie JP: Surgery for invasive bladder cancer. Hematology/Oncology Clinics of North America 6(1): 129-145, 1992.

  13. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al.: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. Journal of Urology 142(6): 1448-1454, 1989.

  14. Yu WS, Sagerman RH, Chung CT, et al.: Bladder carcinoma: experience with radical and preoperative radiotherapy in 421 patients. Cancer 56(6): 1293-1299, 1985.

  15. Jahnson S, Pedersen J, Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiotherapy and Oncology 22(2): 111-117, 1991.

  16. van der Werf-Messing BH, van Putten WL: Carcinoma of the urinary bladder category T2,3 NX M0 treated by 40 Gy external irradiation followed by cesium-137 implant at reduced dose (50%). International Journal of Radiation Oncology, Biology, Physics 16(2): 369-371, 1989.

  17. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. International Journal of Radiation Oncology, Biology, Physics 25(5): 783-790, 1993.

  18. Natale RB, Southwest Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Cystectomy Alone vs Neoadjuvant MVAC (MTX/VBL/DOX/CDDP) plus Cystectomy in Patients with Locally Advanced Transitional Cell Carcinoma of the Bladder (Summary Last Modified 09/98), SWOG-8710, clinical trial, closed, 07/01/1998.

  19. Scher H, Herr H, Sternberg C, et al.: Neo-adjuvant chemotherapy for invasive bladder cancer: experience with the M-VAC regimen. British Journal of Urology 64(3): 250-256, 1989.

  20. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Journal of Urology 145(3): 459-467, 1991.

  21. Tester W, Caplan R, Heaney J, et al.: Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. Journal of Clinical Oncology 14(1): 119-126, 1996.

  22. Advanced Bladder Cancer Overview Collaboration: Does neoadjuvant cisplatin-based chemotherapy improve the survival of patients with locally advanced bladder cancer: a meta-analysis of individual patient data from randomized clinical trials. British Journal of Urology 75(2): 206-213, 1995.


STAGE III BLADDER CANCER

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 levels of evidence summary for more information.


T3a, N0, M0 or T3b, N0, M0 or T4a, N0, M0

A few highly selected patients with stage III bladder cancer may be suitable for segmental cystectomy or interstitial irradiation. The relatively high frequency of extensive intramural tumor spread and lymph node involvement make radical cystectomy and external-beam irradiation more logical forms of treatment in most patients. Because of the relatively poor results of either of these modalities when used alone, preoperative irradiation followed by radical cystectomy has been widely used during the past decade. This combined modality treatment appears to reduce the rate of local recurrence and is associated with especially good results in patients whose resected bladders contain no pathologic evidence of cancer. However, similar results achieved with radical cystectomy alone in some series have brought this issue under scrutiny. The only prospective, randomized trial reported to date did not show any survival advantage for preoperative radiation therapy and radical cystectomy compared with radical cystectomy alone.[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.[2-5]

In the United States, external-beam irradiation has been generally reserved for patients who are poor medical candidates for radical cystectomy. However, selected patients have been treated with transurethral resection (TUR) and definitive radiation therapy, with salvage cystectomy reserved for those whose treatment fails.[6,7] One series suggests that patients treated with preoperative radiation therapy and immediate cystectomy had an outcome similar to those treated with radical irradiation alone, with salvage cystectomy reserved for local recurrence.[6] In combined modality studies, one half or more of patients who had bladder-preserving therapy were disease-free 3 to 4 years after treatment,[8-11] with salvage cystectomy reserved for patients who did not achieve a complete response. Some investigators think that the prognosis is worse for patients with hydronephrosis on the initial intravenous pyelogram, and therefore, they are not candidates for this approach.[8,11]

Because the frequency of distant metastases is becoming apparent with improved local control of advanced bladder cancer, systemic preoperative or postoperative adjuvant chemotherapy is now under evaluation in clinical trials. Treatment with concurrent chemotherapy and radiation therapy has been associated with improved rates of local control compared with radiation therapy alone. The only prospective, randomized trial reported to date resulted in an improved rate of local control when cisplatin was given in conjunction with radiation therapy.[12]

All patients with this stage should be considered candidates for clinical trials.

Treatment options:

Standard:

1. Radical cystectomy.[1]

2. External-beam irradiation.[13-15]

3. External-beam irradiation with interstitial implantation of radioisotopes.[16]

4. Segmental cystectomy (in highly selected cases).[17]

5. Combined external-beam irradiation and cisplatin.[8-12]

Under clinical evaluation:
Multiple trials are evaluating the potential of chemotherapy administered
prior to cystectomy, following cystectomy, or in conjunction with
external-beam radiation therapy to improve local tumor control, prevent
distant metastases, or allow preservation of the
bladder.[8-11,18-21] The combination regimen methotrexate,
vinblastine, doxorubicin, and cisplatin produced a pathologic complete
response in approximately 20% of patients treated prior to definitive
surgery.[22] Results from two clinical studies suggest that a combined
modality treatment with neoadjuvant methotrexate, cisplatin, and vinblastine
(MCV) followed by radiation therapy and concurrent cisplatin can result in
high rates of tumor clearance and can allow bladder preservation in some
patients.[8,11,21] However, there is no evidence to date that the use of
neoadjuvant cisplatin or cisplatin-based regimens will improve the survival
of patients with locally advanced bladder cancer.[23][Level of evidence:
1iiA] In a bladder-sparing clinical trial of external radiation therapy
with chemotherapy, initial results from the Radiation Therapy Oncology Group
have shown that 2 cycles of neoadjuvant MCV do not improve down staging to a
complete response, patient survival, or freedom from metastatic disease over
radiation and concurrent cisplatin alone.[11][Level of evidence: 1iiA]

References:

  1. Smith JA, Crawford ED, Blumenstein B, et al.: A randomized prospective trial of pre-operative irradiation plus radical cystectomy versus surgery alone for transitional cell carcinoma of the bladder: a Southwest Oncology Group study. Journal of Urology 139(4, Part 2): 266A, 1988.

  2. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. Journal of Urology 144(5): 1137-1141, 1990.

  3. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. Journal of Urology 132(6): 1101-1107, 1984.

  4. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part I. Monographs in Urology 8(2): 1987.

  5. Fowler JE: Continent urinary reservoirs and bladder substitutes in the adult: part II. Monographs in Urology 8(3): 1987.

  6. Sell A, Jakobsen A, Nerstrom B, et al.: Treatment of advanced bladder cancer category T2 T3 and T4a: a randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor: DAVECA protocol 8201. Scandinavian Journal of Urology and Nephrology 138(Suppl): 193-201, 1991.

  7. Jenkins BJ, Caulfield MJ, Fowler CG, et al.: Reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive (T2/T3) bladder cancer. Journal of Urology 62(4): 343-346, 1988.

  8. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

  9. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

  10. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. International Journal of Radiation Oncology, Biology, Physics 25(5): 783-790, 1993.

  11. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: inital results of Radiation Therapy Oncology Group 89-03. Journal of Clinical Oncology 16(11): 3576-3583, 1998.

  12. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. Journal of Clinical Oncology 14(11): 2901-2907, 1996.

  13. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al.: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. Journal of Urology 142(6): 1448-1454, 1989.

  14. Yu WS, Sagerman RH, Chung CT, et al.: Bladder carcinoma: experience with radical and preoperative radiotherapy in 421 patients. Cancer 56(6): 1293-1299, 1985.

  15. Jahnson S, Pedersen J, Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiotherapy and Oncology 22(2): 111-117, 1991.

  16. van der Werf-Messing BH, van Putten WL: Carcinoma of the urinary bladder category T2,3 NX M0 treated by 40 Gy external irradiation followed by cesium-137 implant at reduced dose (50%). International Journal of Radiation Oncology, Biology, Physics 16(2): 369-371, 1989.

  17. Skinner DG: Current perspectives in the management of high-grade invasive bladder cancer. Cancer 45(7): 1866-1874, 1980.

  18. Logothetis CJ, Johnson DE, Chong C, et al.: Adjuvant chemotherapy of bladder cancer: a preliminary report. Journal of Urology 139(6): 1207-1211, 1988.

  19. Natale RB, Southwest Oncology Group: NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Comparison of Cystectomy Alone vs Neoadjuvant MVAC (MTX/VBL/DOX/CDDP) plus Cystectomy in Patients with Locally Advanced Transitional Cell Carcinoma of the Bladder (Summary Last Modified 09/98), SWOG-8710, clinical trial, closed, 07/01/1998.

  20. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Journal of Urology 145(3): 459-467, 1991.

  21. Tester W, Caplan R, Heaney J, et al.: Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. Journal of Clinical Oncology 14(1): 119-126, 1996.

  22. Scher H, Herr H, Sternberg C, et al.: Neo-adjuvant chemotherapy for invasive bladder cancer: experience with the M-VAC regimen. British Journal of Urology 64(3): 250-256, 1989.

  23. Advanced Bladder Cancer Overview Collaboration: Does neoadjuvant cisplatin-based chemotherapy improve the survival of patients with locally advanced bladder cancer: a meta-analysis of individual patient data from randomized clinical trials. British Journal of Urology 75(2): 206-213, 1995.


STAGE IV BLADDER CANCER

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 levels of evidence summary for more information.


T4b, N0, M0, any T, N1-N3, M0, or 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 small volume metastases to regional lymph nodes.[1] These patients can receive radical cystectomy with or without preoperative irradiation. 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.[2-4] The prognosis of patients with T4 tumors is generally poor with either radical cystectomy or radiation therapy.

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. Combination chemotherapy regimens that include methotrexate, cisplatin, and vinblastine, with or without doxorubicin are encouraging and have induced some pathological complete responses.[5,6] 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 with the former regimen.[7] Results from a randomized trial that compared M-VAC to single-agent cisplatin in advanced bladder cancer show a significant advantage with M-VAC in both response rate and median survival.[8] The (outpatient) regimen of paclitaxel and carboplatin has been shown to be active and well tolerated. Partial responses in the range of 50% have been reported in phase II trials.[9,10][Level of evidence: 3iiiDiii] Phase III trials further evaluating the role of this regimen are in progress.[11] Gemcitabine has shown activity in phase II trials of patients with metastatic bladder cancer. Phase III trials comparing the gemcitabine/cisplatin combination with the M-VAC regimen are also in progress. Patients should be encouraged to participate in clinical trials whenever possible.

Treatment options:

For T4b, N0, M0 or any T, N1-N3, M0 patients:

Standard:

1. Radical cystectomy alone (in node-negative patients).[12]

2. External-beam irradiation.[13]

3. Urinary diversion or cystectomy for palliation.

4. Chemotherapy as an adjunct to local treatment.[14-18]

Under clinical evaluation:
Multiple trials are evaluating the potential of chemotherapy administered
prior to cystectomy, following cystectomy, or in conjunction with
external-beam radiation therapy to improve local tumor control, prevent
distant metastases, or allow preservation of the bladder.[12,14-17,19,20]

For any T, any N, M1 patients:

Standard:

1. Chemotherapy alone or as an adjunct to local treatment.[5,6]

2. External-beam irradiation (palliative).

3. Urinary diversion or cystectomy for palliation.

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, ifosfamide, gallium nitrate, and gemcitabine.[21]
Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for a listing of
clinical trials.

References:

  1. Vieweg J, Gschwend JE, Herr HW, et al.: The impact of primary stage on survival in patients with lymph node positive bladder cancer. Journal of Urology 161(1): 72-76, 1999.

  2. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. Journal of Urology 144(5): 1137-1141, 1990.

  3. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. Journal of Urology 132(6): 1101-1107, 1984.

  4. Richie JP: Surgery for invasive bladder cancer. Hematology/Oncology Clinics of North America 6(1): 129-145, 1992.

  5. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer 64(12): 2448-2458, 1989.

  6. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract, a Northern California Oncology Group study. Journal of Clinical Oncology 3(11): 1463-1470, 1985.

  7. Logothetis CJ, Dexeus FH, Finn L, et al.: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. Journal of Clinical Oncology 8(6): 1050-1055, 1990.

  8. Loehrer PJ, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Journal of Clinical Oncology 10(7): 1066-1073, 1992.

  9. Vaughn DJ, Malkowicz SB, Zoltick B, et al.: Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen. Journal of Clinical Oncology 16(1): 255-260, 1998.

  10. Redman BG, Smith DC, Flaherty L, et al.: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. Journal of Clinical Oncology 16(5): 1844-1848, 1998.

  11. Roth BJ, Eastern Cooperative Oncology Group: Phase III Randomized Study of Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (M-VAC) Versus Carboplatin and Paclitaxel for the Treatment of Advanced Carcinoma of the Urothelium (Summary Last Modified 01/1999), E-4897, clinical trial, active, 09/03/1998.

  12. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. Journal of Urology 149(5): 957-972, 1993.

  13. Jahnson S, Pedersen J, Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiotherapy and Oncology 22(2): 111-117, 1991.

  14. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. Journal of Clinical Oncology 15(3): 1022-1029, 1997.

  15. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. International Journal of Radiation Oncology, Biology, Physics 25(5): 783-790, 1993.

  16. Logothetis CJ, Johnson DE, Chong C, et al.: Adjuvant chemotherapy of bladder cancer: a preliminary report. Journal of Urology 139(6): 1207-1211, 1988.

  17. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. Journal of Urology 145(3): 459-467, 1991.

  18. Scher HI: Chemotherapy for invasive bladder cancer: neoadjuvant versus adjuvant. Seminars in Oncology 17(5): 555-565, 1990.

  19. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. Journal of Clinical Oncology 11(11): 2150-2157, 1993.

  20. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: inital results of Radiation Therapy Oncology Group 89-03. Journal of Clinical Oncology 16(11): 3576-3583, 1998.

  21. Raghavan D, Huben R: Management of bladder cancer. Current Problems in Cancer 19(1): 1-64, 1995.

  22. Vogelzang NJ, Stadler WM: Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer. Urology 53(2): 243-250, 1999.


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) to 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%.[3] Other chemotherapy agents that have shown activity in metastatic bladder cancer include: paclitaxel, ifosfamide, gallium nitrate, and gemcitabine. Ifosfamide and gallium have shown limited activity in patients previously treated with cisplatin.[4-9] Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for a listing of clinical trials.

References:

  1. Sternberg CN, Yagoda A, Scher HI, et al.: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Cancer 64(12): 2448-2458, 1989.

  2. Harker WG, Meyers FJ, Freiha FS, et al.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract, a Northern California Oncology Group study. Journal of Clinical Oncology 3(11): 1463-1470, 1985.

  3. Loehrer PJ, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. Journal of Clinical Oncology 10(7): 1066-1073, 1992.

  4. Roth BJ: Preliminary experience with paclitaxel in advanced bladder cancer. Seminars in Oncology 22(3, Suppl 6): 1-5, 1995.

  5. Witte RS, Elson P, Bono B, et al.: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. Journal of Clinical Oncology 15(2): 589-593, 1997.

  6. Einhorn LH, Roth BJ, Ansari R, et al.: Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma. Journal of Clinical Oncology 12(11): 2271-2276, 1994.

  7. Pollera CF, Ceribelli A, Crecco M, et al.: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Annals of Oncology 5(2): 182-184, 1994.

  8. Seidman AD, Scher HI, Heinemann MH, et al.: Continuous infusion gallium nitrate for patients with advanced refractory urothelial tract tumors. Cancer 68(12): 2561-2565, 1991.

  9. Roth BJ: Ifosfamide in the treatment of bladder cancer. Seminars in Oncology 23(3, Suppl 6): 50-55, 1996.

Date Last Modified: 11/1999



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