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

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

• T3a, N0, M0
• T3b, N0, M0
• T4a, N0, M0

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

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

After radical cystectomy, however, an approximate 50% risk of recurrence still exists for patients with muscle-invasive disease. The addition of preoperative radiation therapy to radical cystectomy did not result in any survival advantage when compared with radical cystectomy alone in a prospective, randomized trial.[7] Because the disease commonly recurs with distant metastases, systemic chemotherapy administered before or after cystectomy has been evaluated as a means of improving outcome. Administration of chemotherapy before cystectomy (i.e., neoadjuvant) may be preferable to postoperative treatment since tumor downstaging from chemotherapy may enhance resectability, occult metastatic disease may be treated as early as possible, and chemotherapy may be better tolerated. A randomized study conducted by the Southwest Oncology Group compared three cycles of neoadjuvant cisplatin, methotrexate, vinblastine, and doxorubicin administered prior to cystectomy with cystectomy alone in 317 patients with stage T2 to stage T4a bladder cancer, and showed that 5-year survival was 57% in the group receiving neoadjuvant chemotherapy and 43% in the group treated with cystectomy alone, which is a difference of borderline statistical significance (P = .06 by stratified log-rank test).[8] No deaths or postoperative complications were associated with neoadjuvant chemotherapy. In addition, 38% of patients who received neoadjuvant chemotherapy had a pathologic complete response at the time of surgery, and 85% of those achieving a pathologic complete response were alive at 5 years.[8][Level of evidence: 1iiA]

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