In an effort to reduce the toxic effects of platinum-based regimens given in the perioperative setting, a German multicenter study randomly assigned 327 patients with pathologic T3a-T4a and/or N+ disease after radical cystectomy to 3 cycles of cisplatin and methotrexate (CM) or three cycles of methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC). The median progression-free survival was 43.4 months in the CM arm and 49.7 months in the M-VEC arm, yielding a hazard ratio [HR] for disease progression of 1.13 (90% confidence interval [CI], 0.86–1.48). The median overall survival (OS) was 47.1 months in the CM arm and 51.8 months in the M-VEC arm, yielding an HR for death of 1.10 (90% CI, 0.88–1.44). Leukopenia was more common with the four-drug regimen, but the rates of febrile neutropenia, infection, and treatment-related deaths were the same with both regimens. This study was powered to accept as much as a 50% increase in progression-free survival as being noninferior.[Level of evidence: 1iiA]
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%.[12,13,14] 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. [16,1,17]
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 OS.[Level of evidence: 1iiA] In some nonrandomized studies, 50% or more of patients who had bladder-preserving therapy (i.e., initial transurethral resection 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.[3,4,19] In a phase III study, the Radiation Therapy Oncology Group evaluated the potential benefit of adding two cycles of neoadjuvant methotrexate, cisplatin, and vinblastine administered 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 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.