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

• T4b, N0, M0
• Any T, N1–N3, M0
• Any T, Any N, M1

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.[1] These patients may undergo radical cystectomy with pelvic lymph node dissection. The extent of lymph node dissection during cystectomy is controversial [2] 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.[3] 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).[4] 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%.[7][Level of evidence: 3iiiDiv] Gemcitabine has shown activity in phase II trials of patients with metastatic bladder cancer.[8] 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.[9][Level of evidence: 1iiA]

The European Organisation for Research and Treatment of Cancer Group conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose-intensity M-VAC regimen given every 2 weeks with granulocyte colony-stimulating factor (G-CSF) compared to a classic M-VAC regimen given every 4 weeks.[10] Although there was no significant difference in OS at a median follow-up of 3.2 years (HR = 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity M-VAC regimen was associated with improved OS (HR = 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22%, compared to 14% in patients treated with the classic M-VAC regimen. The high-dose intensity M-VAC regimen was also associated with higher response rates (72% vs. 58%, P = .016), improved median progression-free survival (9.5 months vs. 8.1 months, P = .017), and decreased neutropenic fever (10% vs. 26%, P < .001), though only 19% of patients treated with a classic M-VAC regimen ever received G-CSF.[10][Level of evidence: 1iiA] An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose M-VAC regimen and 47 patients assigned to the classic M-VAC regimen) may account, in part, for these results. Ongoing studies are evaluating new chemotherapy combinations.

Chemotherapy for patients not eligible for cisplatin

The only regimens that have shown a survival benefit in randomized controlled trials have been the cisplatin-based multiagent regimens MVAC, high-dose MVAC, and CMV; gemcitabine plus cisplatin is generally accepted as equivalent to MVAC based on the data discussed above.[3,4,10,11,12] Optimal treatment of patients who are not eligible for cisplatin-based chemotherapy caused by renal insufficiency or poor performance status is thus unknown. One common practice has been to substitute carboplatin for cisplatin to reduce nephrotoxicity and gastrointestinal toxicity. Two small randomized trials comparing cisplatin-based regimens to carboplatin-based regimens have been published.[13,14] One trial reported a lower complete response rate, while the other trial reported shorter disease-specific survival with the carboplatin-based regimen. However, these studies were underpowered, and the one that showed a disease-specific survival difference included an anthracycline in the cisplatin arm but not in the carboplatin arm. If carboplatin-based regimens are less effective than cisplatin regimens, which only prolong survival by several months, then carboplatin-based regimens may have no survival benefit.

Several less nephrotoxic regimens have been studied in clinical trials, but most of these trials have not focused on patients with renal impairment or poor performance status. Published regimens that have been studied in trials limited to patients with a medical contraindication to cisplatin include gemcitabine plus carboplatin, single-agent docetaxel, and single-agent paclitaxel.[15,16,17,18,19,20] In general, outcomes of studies in patients unfit for cisplatin have been inferior to those of cisplatin-based regimens with reported median survival times of less than 1 year. A randomized phase II/III trial comparing gemcitabine plus carboplatin (GCa) to methotrexate, carboplatin and vinblastine (M-CAVI) reported that in the phase II portion of the trial, the response rate was 42% with GCa compared to 30% with M-CAVI.[16] However, patients with a performance status of 2 and a creatinine clearance less than 60 mL/min had a response rate of only 26% and 20%, respectively and a severe acute toxicity rate of 26% and 25%, respectively. These regimens were judged to be nonbeneficial for patients meeting both those criteria.

Many other doublet and singlet noncisplatin chemotherapy regimens, such as gemcitabine plus paclitaxel, have been studied in healthier subjects with advanced-stage urothelial carcinoma.[21,22,23,24] Studies of these regimens have reported longer survival in unselected subjects than in subjects selected on the basis of impaired renal function and/or poor performance status. In the absence of any published randomized controlled trials showing improved outcomes with a noncisplatin regimen, it is impossible to know whether any of those regimens benefit patients.

For patients with T4b, N0, M0 and Any T, N1–N3, M0 disease:

Treatment options:

1. Radical cystectomy with pelvic lymph node dissection.[2,25,26]
2. External-beam radiation therapy (EBRT).[27,28]
3. Urinary diversion or cystectomy for palliation.
4. Chemotherapy as an adjunct to local treatment as seen in the RTOG-8512 trial, for example.[29,30,31,32,33]

For patients with Any T, Any N, M1 disease:

Standard treatment options:

1. Chemotherapy alone or as an adjunct to local treatment.[3,4,9]
2. EBRT for palliation.
3. Urinary diversion or cystectomy for palliation.

Treatment options under clinical evaluation:

• Other chemotherapy regimens appear active in the treatment of metastatic disease. Chemotherapy agents that have shown activity in metastatic bladder cancer include paclitaxel, docetaxel, ifosfamide, gallium nitrate, gemcitabine, and pemetrexed.[34,35,36][Level of evidence: 3iiiDiv]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV 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:

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3. Logothetis CJ, Dexeus FH, Finn L, et al.: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 8 (6): 1050-5, 1990.
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