Current Clinical Trials

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 ¹ for more information.)

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

• T4b, N0, M0
• Any T, N1, M0
• Any T, N2, M0
• Any T, 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.

Information about ongoing clinical trials is available from the NCI Web site ².

For patients with T4b, N0, M0; Any T, N1, M0; Any T, N2, M0; Any T, N3, M0 disease:

Treatment options:

1. Radical cystectomy with pelvic lymph node dissection.[2,11,12]
2. External-beam radiation therapy (EBRT).[13,14]
3. Urinary diversion or cystectomy for palliation.
4. Chemotherapy as an adjunct to local treatment (RTOG-8512 ³).[15-19]

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.[20-22][Level of evidence: 3iiiDiv] Information about ongoing clinical trials is available from the NCI Web site ⁴.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV bladder cancer ⁵. 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 ².

References

1. Vieweg J, Gschwend JE, Herr HW, et al.: The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol 161 (1): 72-6, 1999.  [PUBMED Abstract]
   
   
2. Konety BR, Joslyn SA, O'Donnell MA: Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the Surveillance, Epidemiology and End Results Program data base. J Urol 169 (3): 946-50, 2003.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
4. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al.: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 10 (7): 1066-73, 1992.  [PUBMED Abstract]
   
   
5. Vaughn DJ, Malkowicz SB, Zoltick B, et al.: Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: an active and tolerable outpatient regimen. J Clin Oncol 16 (1): 255-60, 1998.  [PUBMED Abstract]
   
   
6. Redman BG, Smith DC, Flaherty L, et al.: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol 16 (5): 1844-8, 1998.  [PUBMED Abstract]
   
   
7. Small EJ, Lew D, Redman BG, et al.: Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point. J Clin Oncol 18 (13): 2537-44, 2000.  [PUBMED Abstract]
   
   
8. Bajorin DF: Paclitaxel in the treatment of advanced urothelial cancer. Oncology (Huntingt) 14 (1): 43-52, 57; discussion 58, 61-2, 2000.  [PUBMED Abstract]
   
   
9. von der Maase H, Hansen SW, Roberts JT, et al.: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18 (17): 3068-77, 2000.  [PUBMED Abstract]
   
   
10. Sternberg CN, de Mulder P, Schornagel JH, et al.: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42 (1): 50-4, 2006.  [PUBMED Abstract]
    
    
11. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. J Urol 149 (5): 957-72, 1993.  [PUBMED Abstract]
    
    
12. Grossman HB, Natale RB, Tangen CM, et al.: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349 (9): 859-66, 2003.  [PUBMED Abstract]
    
    
13. Jahnson S, Pedersen J, Westman G: Bladder carcinoma--a 20-year review of radical irradiation therapy. Radiother Oncol 22 (2): 111-7, 1991.  [PUBMED Abstract]
    
    
14. Coppin CM, Gospodarowicz MK, James K, et al.: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (11): 2901-7, 1996.  [PUBMED Abstract]
    
    
15. Kachnic LA, Kaufman DS, Heney NM, et al.: Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 15 (3): 1022-9, 1997.  [PUBMED Abstract]
    
    
16. Tester W, Porter A, Asbell S, et al.: Combined modality program with possible organ preservation for invasive bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 25 (5): 783-90, 1993.  [PUBMED Abstract]
    
    
17. Logothetis CJ, Johnson DE, Chong C, et al.: Adjuvant chemotherapy of bladder cancer: a preliminary report. J Urol 139 (6): 1207-11, 1988.  [PUBMED Abstract]
    
    
18. Skinner DG, Daniels JR, Russell CA, et al.: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 145 (3): 459-64; discussion 464-7, 1991.  [PUBMED Abstract]
    
    
19. Scher HI: Chemotherapy for invasive bladder cancer: neoadjuvant versus adjuvant. Semin Oncol 17 (5): 555-65, 1990.  [PUBMED Abstract]
    
    
20. Raghavan D, Huben R: Management of bladder cancer. Curr Probl Cancer 19 (1): 1-64, 1995 Jan-Feb.  [PUBMED Abstract]
    
    
21. Vogelzang NJ, Stadler WM: Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer. Urology 53 (2): 243-50, 1999.  [PUBMED Abstract]
    
    
22. Sweeney CJ, Roth BJ, Kabbinavar FF, et al.: Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 24 (21): 3451-7, 2006.  [PUBMED Abstract]
    
    

Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.