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 IV bladder cancer is defined by the following TNM classifications:
In its early stages, bladder cancer may not have obvious symptoms. In the later stages, symptoms of bladder cancer may include:
Bloody urine, most often painless, is the most common symptom. The urine color ranges from faintly rusty to deep red, sometimes containing blood clots. Blood traces, invisible to the naked eye, may show up in tests of urine samples.
Frequent urinary tract infections, painful urination, a need to urinate often, and difficulty holding in urine.
Currently, only a small fraction of patients with stage IV bladder carcinoma can be cured. The potential for cure is restricted to patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes. These patients may undergo radical cystectomy with pelvic lymph node dissection. The extent of lymph node dissection during cystectomy is controversial  as there are no data from prospective trials demonstrating improved outcomes with lymph node dissection. Definitive radiation therapy with or without concurrent chemotherapy, evaluated mainly in patients with locally advanced (T2-T4) disease, appears to have minimal curative potential in patients with regional lymph node metastases.
Prognosis is so poor in patients with stage IV disease that consideration of entry into a clinical trial is appropriate. The focus of care for many stage IV patients is on palliation of symptoms from bladder tumor that is often massive. Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy. Platinum-based combination chemotherapy regimens are the standard of care. A prospective, randomized trial of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) compared with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks, P = .003) with the former regimen. Results from a randomized trial that compared M-VAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with M-VAC in both response rate and median survival (12.5 months vs. 8.2 months, P = .002). The (outpatient) regimen of paclitaxel and carboplatin achieved response rates in the range of 50% in single-institution phase II trials.[5,6][Level of evidence: 3iiiDiv] However, when this regimen was evaluated in a multicenter phase II study conducted by the Southwest Oncology Group, the response rate was only 21%.[Level of evidence: 3iiiDiv] Gemcitabine has shown activity in phase II trials of patients with metastatic bladder cancer. In a multicenter, randomized, phase III trial comparing the combination of gemcitabine/cisplatin (GC) with the M-VAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded similar response rates, time-to-progression, and overall survival (OS) (hazard ratio [HR] = 1.04; 95% confidence interval [CI], 0.82-1.32; P = .75) compared with M-VAC, but GC had a better safety profile and was better tolerated than M-VAC. Although this study was not designed to show the equivalence of the two regimens, the similar efficacy and reduced toxic effects of GC make it a reasonable alternative in patients who may not tolerate the M-VAC regimen.[Level of evidence: 1iiA]