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.[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. 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. 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).[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. 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.