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NCI/PDQ^® Health professionals: Bladder Cancer Treatment (PDQ®)

National Cancer Institute
Last Modified: July 12, 2012

TABLE OF CONTENTS

• General Information About Bladder Cancer
  • Incidence and Mortality
  • Prognosis
  • Related Summaries

• Cellular Classification of Bladder Cancer

• Stage Information for Bladder Cancer
  • Definitions of TNM

• Treatment Option Overview

• Stage 0 Bladder Cancer
  • Current Clinical Trials

• Stage I Bladder Cancer
  • Current Clinical Trials

• Stage II Bladder Cancer
  • Current Clinical Trials

• Stage III Bladder Cancer
  • Current Clinical Trials

• Stage IV Bladder Cancer
  • Chemotherapy for patients not eligible for cisplatin

• Current Clinical Trials

• Recurrent Bladder Cancer
  • Current Clinical Trials

• Changes to This Summary (07/12/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Bladder Cancer

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Incidence and Mortality

Estimated new cases and deaths from bladder cancer in the United States in 2012: 1

• New cases: 73,510.
• Deaths: 14,880.

Prognosis

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

Related Summaries

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

• Bladder and Other Urothelial Cancers Screening
• Unusual Cancers of Childhood (bladder cancer in children)

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. Hudson MA, Herr HW: Carcinoma in situ of the bladder. J Urol 153 (3 Pt 1): 564-72, 1995. [PUBMED Abstract]
3. Torti FM, Lum BL: The biology and treatment of superficial bladder cancer. J Clin Oncol 2 (5): 505-31, 1984. [PUBMED Abstract]
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-Guérin therapy: correlation to clinical outcome. J Clin Oncol 14 (10): 2646-52, 1996. [PUBMED Abstract]
5. Stein JP, Grossfeld GD, Ginsberg DA, et al.: Prognostic markers in bladder cancer: a contemporary review of the literature. J Urol 160 (3 Pt 1): 645-59, 1998. [PUBMED Abstract]
6. 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. J Urol 160 (5): 1668-71; discussion 1671-2, 1998. [PUBMED Abstract]
7. Quek ML, Stein JP, Nichols PW, et al.: Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy. J Urol 174 (1): 103-6, 2005. [PUBMED Abstract]
8. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. J Urol 149 (5): 957-72, 1993. [PUBMED Abstract]
9. Esrig D, Elmajian D, Groshen S, et al.: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331 (19): 1259-64, 1994. [PUBMED Abstract]
10. Lipponen PK: Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. Int J Cancer 53 (3): 365-70, 1993. [PUBMED Abstract]

Cellular Classification of Bladder Cancer

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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, Pa: WB Saunders, 1988, pp 83-117. [PUBMED Abstract]
2. Wilson TG, Pritchett TR, Lieskovsky G, et al.: Primary adenocarcinoma of bladder. Urology 38 (3): 223-6, 1991. [PUBMED Abstract]

Stage Information for Bladder Cancer

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Note: This Stage Information section has been updated to include information from the seventh edition (2010) of the American Joint Committee on Cancer's AJCC Cancer Staging Manual. The PDQ® Adult Treatment Editorial Board, which is responsible for maintaining this summary, is currently reviewing the new staging categories to determine whether additional changes need to be made to other parts of the summary. Any necessary changes will be made as soon as possible.

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

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define bladder cancer. 4

Table 1. Primary Tumor (T)^a

^aReprinted with permission from AJCC: Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 497505.

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 muscularis propria.
pT2a	Tumor invades superficial muscularis propria (inner half).
pT2b	Tumor invades deep muscularis propria (outer half).
T3	Tumor invades perivesical tissue.
pT3a	Microscopically.
pT3b	Macroscopically (extravesical mass).
T4	Tumor invades any of the following: prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall.
T4a	Tumor invades prostatic stroma, uterus, vagina.
T4b	Tumor invades pelvic wall, abdominal wall.

Table 2. Regional Lymph Nodes (N)^a,b

^aReprinted with permission from AJCC: Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 497505.^bRegional lymph nodes include both primary and secondary drainage regions. All other nodes above the aortic bifurcation are considered distant lymph nodes.

NX	Lymph nodes cannot be assessed.
N0	No lymph node metastasis.
N1	Single regional lymph node metastasis in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node).
N2	Multiple regional lymph node metastases in the true pelvis (hypogastric, obturator, external iliac, or presacral lymph node).
N3	Lymph node metastases to the common iliac lymph nodes.

Table 3. Distant Metastasis (M)^a

^aReprinted with permission from AJCC: Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 497505.

M0	No distant metastasis.
M1	Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groups^a

^aReprinted with permission from AJCC: Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 497505.

Stage	T	N	M
0a	Ta	N0	M0
0is	Tis	N0	M0
I	T1	N0	M0
II	T2a	N0	M0
	T2b	N0	M0
III	T3a	N0	M0
	T3b	N0	M0
	T4a	N0	M0
IV	T4b	N0	M0
	Any T	N13	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. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988. [PUBMED Abstract]
2. Marshall VF: The relationship of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J Urol 68(4): 714-723, 1952. [PUBMED Abstract]
3. Skinner DG: Current state of classification and staging of bladder cancer. Cancer Res 37 (8 Pt 2): 2838-42, 1977. [PUBMED Abstract]
4. Urinary bladder. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 497-505. [PUBMED Abstract]

Treatment Option Overview

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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:

1. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. J Urol 149 (5): 957-72, 1993. [PUBMED Abstract]
2. Housset M, Maulard C, Chretien Y, et al.: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. J Clin Oncol 11 (11): 2150-7, 1993. [PUBMED Abstract]
3. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 15 (3): 1022-9, 1997. [PUBMED Abstract]
4. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 151 (1): 21-6, 1994. [PUBMED Abstract]
5. Raghavan D, Huben R: Management of bladder cancer. Curr Probl Cancer 19 (1): 1-64, 1995 Jan-Feb. [PUBMED Abstract]
6. Sauer R, Birkenhake S, Kí¼hn R, et al.: Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer. Int J Radiat Oncol Biol Phys 40 (1): 121-7, 1998. [PUBMED Abstract]
7. Hautmann RE, Miller K, Steiner U, et al.: The ileal neobladder: 6 years of experience with more than 200 patients. J Urol 150 (1): 40-5, 1993. [PUBMED Abstract]

Stage 0 Bladder Cancer

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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

A randomized study of patients with superficial bladder cancer also reported 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

Another 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--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

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

References:

1. Holmíng S, Hedelin H, Anderstrím 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. J Urol 153 (6): 1823-6; discussion 1826-7, 1995. [PUBMED Abstract]
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. Br J Urol 77 (3): 358-62, 1996. [PUBMED Abstract]
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-Guérin therapy: correlation to clinical outcome. J Clin Oncol 14 (10): 2646-52, 1996. [PUBMED Abstract]
4. Herr HW: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 162 (1): 74-6, 1999. [PUBMED Abstract]
5. Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 13 (6): 1404-8, 1995. [PUBMED Abstract]
6. Lamm DL, Griffith JG: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Semin Urol 10 (1): 39-44, 1992. [PUBMED Abstract]
7. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 142 (3): 719-22, 1989. [PUBMED Abstract]
8. Coplen DE, Marcus MD, Myers JA, et al.: Long-term followup of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. J Urol 144 (3): 652-7, 1990. [PUBMED Abstract]
9. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 137 (2): 220-4, 1987. [PUBMED Abstract]
10. Herr HW: Progression of stage T1 bladder tumors after intravesical bacillus Calmette-Guerin. J Urol 145 (1): 40-3; discussion 43-4, 1991. [PUBMED Abstract]
11. Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med 325 (17): 1205-9, 1991. [PUBMED Abstract]
12. Malmstrím PU, Wijkstrím 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. Swedish-Norwegian Bladder Cancer Study Group. J Urol 161 (4): 1124-7, 1999. [PUBMED Abstract]
13. 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): 507-13, 1991. [PUBMED Abstract]
14. Herr HW, Wartinger DD, Fair WR, et al.: Bacillus Calmette-Guerin therapy for superficial bladder cancer: a 10-year followup. J Urol 147 (4): 1020-3, 1992. [PUBMED Abstract]
15. Lamm DL, Crawford ED, Blumenstein B, et al.: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group study. [Abstract] Proceedings of the American Society of Clinical Oncology 11: A-627, 203, 1992. [PUBMED Abstract]
16. 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. J Clin Oncol 12 (1): 7-13, 1994. [PUBMED Abstract]
17. Soloway MS: The management of superficial bladder cancer. In: Javadpour N, ed.: Principles and Management of Urologic Cancer. 2nd ed. Baltimore, Md: Williams and Wilkins, 1983, pp 446-467. [PUBMED Abstract]
18. Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 151 (1): 31-5; discussion 35-6, 1994. [PUBMED Abstract]
19. Prout GR Jr, Lin CW, Benson R Jr, et al.: Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder. N Engl J Med 317 (20): 1251-5, 1987. [PUBMED Abstract]
20. Torti FM, Shortliffe LD, Williams RD, et al.: Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study. J Clin Oncol 6 (3): 476-83, 1988. [PUBMED Abstract]
21. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 151 (1): 21-6, 1994. [PUBMED Abstract]

Stage I Bladder Cancer

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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 7

A randomized study of patients with superficial bladder cancer also reported a decrease in tumor recurrence in patients given intravesical and percutaneous BCG compared with controls. 8 Two, nonconsecutive, 6-week courses with BCG may be necessary to obtain optimal response. 9 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. 9 10 11 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. 12 Preliminary results of one study have shown a possible survival benefit with maintenance BCG after a 6-week induction course. 13 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. 14[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. 15[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. 16

Standard treatment options:

1. TUR with fulguration. 17 18
2. TUR with fulguration followed by intravesical BCG. 6 8 10 11 14
3. TUR with fulguration followed by intravesical chemotherapy. 3 14
4. Segmental cystectomy (rarely indicated). 17
5. Radical cystectomy in selected patients with extensive or refractory superficial tumor. 19
6. Interstitial implantation of radioisotopes with or without external-beam radiation therapy. 20 21

Treatment options under clinical evaluation:

1. Use of chemoprevention agents after treatment to prevent recurrence. 22
2. Intravesical therapies.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

References:

1. Holmíng S, Hedelin H, Anderstrím 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. J Urol 153 (6): 1823-6; discussion 1826-7, 1995. [PUBMED Abstract]
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): 1009-13; discussion 1013-4, 1998. [PUBMED Abstract]
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. Br J Urol 77 (3): 358-62, 1996. [PUBMED Abstract]
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-Guérin therapy: correlation to clinical outcome. J Clin Oncol 14 (10): 2646-52, 1996. [PUBMED Abstract]
5. Herr HW: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 162 (1): 74-6, 1999. [PUBMED Abstract]
6. Herr HW, Schwalb DM, Zhang ZF, et al.: Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 13 (6): 1404-8, 1995. [PUBMED Abstract]
7. Lamm DL, Griffith JG: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Semin Urol 10 (1): 39-44, 1992. [PUBMED Abstract]
8. Sarosdy MF, Lamm DL: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 142 (3): 719-22, 1989. [PUBMED Abstract]
9. Coplen DE, Marcus MD, Myers JA, et al.: Long-term followup of patients treated with 1 or 2, 6-week courses of intravesical bacillus Calmette-Guerin: analysis of possible predictors of response free of tumor. J Urol 144 (3): 652-7, 1990. [PUBMED Abstract]
10. Catalona WJ, Hudson MA, Gillen DP, et al.: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 137 (2): 220-4, 1987. [PUBMED Abstract]
11. Herr HW: Progression of stage T1 bladder tumors after intravesical bacillus Calmette-Guerin. J Urol 145 (1): 40-3; discussion 43-4, 1991. [PUBMED Abstract]
12. Lamm DL, Blumenstein BA, Crawford ED, et al.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med 325 (17): 1205-9, 1991. [PUBMED Abstract]
13. Lamm DL, Crawford ED, Blumenstein B, et al.: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group study. [Abstract] Proceedings of the American Society of Clinical Oncology 11: A-627, 203, 1992. [PUBMED Abstract]
14. 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. Finnbladder Group. J Urol 156 (1): 56-9; discussion 59-60, 1996. [PUBMED Abstract]
15. 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. J Urol 160 (5): 1668-71; discussion 1671-2, 1998. [PUBMED Abstract]
16. Malmstrím PU, Wijkstrím 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. Swedish-Norwegian Bladder Cancer Study Group. J Urol 161 (4): 1124-7, 1999. [PUBMED Abstract]
17. Soloway MS: The management of superficial bladder cancer. In: Javadpour N, ed.: Principles and Management of Urologic Cancer. 2nd ed. Baltimore, Md: Williams and Wilkins, 1983, pp 446-467. [PUBMED Abstract]
18. Herr HW, Reuter VE: Evaluation of new resectoscope loop for transurethral resection of bladder tumors. J Urol 159 (6): 2067-8, 1998. [PUBMED Abstract]
19. Amling CL, Thrasher JB, Frazier HA, et al.: Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 151 (1): 31-5; discussion 35-6, 1994. [PUBMED Abstract]
20. Goffinet DR, Schneider MJ, Glatstein EJ, et al.: Bladder cancer: results of radiation therapy in 384 patients. Radiology 117 (1): 149-53, 1975. [PUBMED Abstract]
21. van der Werf-Messing B, Hop WC: Carcinoma of the urinary bladder (category T1NxM0) treated either by radium implant or by transurethral resection only. Int J Radiat Oncol Biol Phys 7 (3): 299-303, 1981. [PUBMED Abstract]
22. Lamm DL, Riggs DR, Shriver JS, et al.: Megadose vitamins in bladder cancer: a double-blind clinical trial. J Urol 151 (1): 21-6, 1994. [PUBMED Abstract]

Stage II Bladder Cancer

Back Up

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 (MVAC) 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 (CMV) 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. The two regimens that have been most extensively studied and show the strongest evidence of benefit in this setting are MVAC and CMV. There is no data from clinical trials demonstrating equivalent effectiveness with newer regimens such as gemcitabine and cisplatin or high-dose MVAC.

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
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