Stage II Bladder Cancer

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

Stage II bladder cancer is defined by the following TNM classifications:

• T2a, N0, M0
• T2b, N0, M0

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

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

After radical cystectomy, however, an approximate 50% risk of recurrence still exists for patients with muscle-invasive disease. The addition of preoperative radiation therapy to radical cystectomy did not result in any survival advantage when compared with radical cystectomy alone in a prospective, randomized trial.[7] Because the disease commonly recurs with distant metastases, systemic chemotherapy administered before or after cystectomy has been evaluated as a means of improving outcome. Administration of chemotherapy before cystectomy (i.e., neoadjuvant) may be preferable to postoperative treatment because tumor downstaging from chemotherapy may enhance resectability, occult metastatic disease may be treated as early as possible, and chemotherapy may be better tolerated. A randomized study conducted by the Southwest Oncology Group compared three cycles of neoadjuvant cisplatin, methotrexate, vinblastine, and doxorubicin (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 .[11,12,13,18,19,20,21]
4. Interstitial implantation of radioisotopes before or after EBRT.[24,25]
5. TUR with fulguration (in selected patients).
6. Segmental cystectomy (in selected patients).[23]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II 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. Olsson CA: Management of invasive carcinoma of the bladder. In: deKernion JB, Paulson DF, eds.: Genitourinary Cancer Management. Philadelphia, Pa: Lea and Febiger, 1987, pp 59-94.
2. Brendler CB, Steinberg GD, Marshall FF, et al.: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. J Urol 144 (5): 1137-40; discussion 1140-1, 1990.
3. Skinner DG, Boyd SD, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. J Urol 132 (6): 1101-7, 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. 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): 141-7, 1998.
7. 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. [Abstract] J Urol 139(4, Part 2): 266A, 1988.
8. Grossman HB, Natale RB, Tangen CM, et al.: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349 (9): 859-66, 2003.
9. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet 354 (9178): 533-40, 1999.
10. Advanced Bladder Cancer Meta-analysis Collaboration.: Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 361 (9373): 1927-34, 2003.
11. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al.: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 142 (6): 1448-53; discussion 1453-4, 1989.
12. Yu WS, Sagerman RH, Chung CT, et al.: Bladder carcinoma. Experience with radical and preoperative radiotherapy in 421 patients. Cancer 56 (6): 1293-9, 1985.
13. Jahnson S, Pedersen J, Westman G: Bladder carcinoma--a 20-year review of radical irradiation therapy. Radiother Oncol 22 (2): 111-7, 1991.
14. Henningsohn L, Wijkström H, Dickman PW, et al.: Distressful symptoms after radical radiotherapy for urinary bladder cancer. Radiother Oncol 62 (2): 215-25, 2002.
15. Miller LS: Bladder cancer: superiority of preoperative irradiation and cystectomy in clinical stages B2 and C. Cancer 39 (2 Suppl): 973-80, 1977.
16. Horwich A, Pendlebury S, Dearnaley DP, et al.: Organ conservation in bladder cancer. Eur J Cancer 31 (Suppl 6): S208-9, 1995.
17. Sell A, Jakobsen A, Nerstrøm 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. Danish Vesical Cancer Group. Scand J Urol Nephrol Suppl 138: 193-201, 1991.
18. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (11): 2901-7, 1996.
19. 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.
20. 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.
21. Rödel C, Grabenbauer GG, Kühn R, et al.: Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 20 (14): 3061-71, 2002.
22. 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: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 16 (11): 3576-83, 1998.
23. Richie JP: Surgery for invasive bladder cancer. Hematol Oncol Clin North Am 6 (1): 129-45, 1992.
24. van der Werf-Messing BH, van Putten WL: Carcinoma of the urinary bladder category T2,3NXM0 treated by 40 Gy external irradiation followed by cesium137 implant at reduced dose (50%). Int J Radiat Oncol Biol Phys 16 (2): 369-71, 1989.
25. Pos F, Horenblas S, Dom P, et al.: Organ preservation in invasive bladder cancer: brachytherapy, an alternative to cystectomy and combined modality treatment? Int J Radiat Oncol Biol Phys 61 (3): 678-86, 2005.