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Bladder Cancer Treatment (PDQ®)

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Last Modified: 02/21/2014

Stage IV Bladder Cancer Treatment

Standard Treatment Options for Stage IV Bladder Cancer
        Standard treatment options for patients with T4b, N0, M0 or any T, N1–N3, M0 disease
        Standard treatment options for patients with any T, any N, M1 disease
Treatment Options Under Clinical Evaluation for Patients With Any T, Any N, M1 Disease
Current Clinical Trials

Currently, only a small fraction of patients with stage IV bladder cancer can be cured and for many patients, the emphasis is on palliation of symptoms. 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]

Standard Treatment Options for Stage IV Bladder Cancer

Standard treatment options for patients with T4b, N0, M0 or any T, N1–N3, M0 disease

Treatment options for patients with T4b, N0, M0 or any T, N1–N3, M0 disease include the following:

  1. Chemotherapy alone.
  2. Radical cystectomy.
  3. Radical cystectomy followed by chemotherapy.
  4. Radical cystectomy alone.
  5. External-beam radiation therapy (EBRT) with or without concomitant chemotherapy.
  6. Urinary diversion or cystectomy for palliation.
Chemotherapy alone

Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer.[2-6] The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); high-dose MVAC; and cisplatin, methotrexate, and vinblastine (CMV). Gemcitabine plus cisplatin (GC) was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. Of note, patients with good performance status and lymph node-only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. In the large randomized controlled trial that compared MVAC with GC, for example, 5-year overall survival (OS) in patients with lymph node-only disease was 20.9%.[7]

Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. Thus, there is no regimen that has been shown to prolong survival in patients who are not candidates for cisplatin-based multiagent chemotherapy regimens. Many regimens have been shown to be active, however, with regard to producing radiologically measurable responses:

These include carboplatin plus paclitaxel,[8] carboplatin plus gemcitabine,[9-11] paclitaxel plus gemcitabine,[12-14] single-agent gemcitabine,[15,16] and single-agent paclitaxel.[17-19] Regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.[20-23]

Evidence (chemotherapy alone):

  1. Results from a randomized controlled trial that compared MVAC with docetaxel plus cisplatin in 220 patients reported that MVAC was associated with longer OS (median survival, 14.2 months vs. 9.3 months; P = .026).[24]

  2. A randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks; P = .003) with the MVAC regimen.[25]

  3. Results from a randomized trial that compared MVAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with MVAC in both response rate and median survival (12.5 months vs. 8.2 months; P = .002).[26]

  4. A multicenter randomized controlled trial compared CMV with methotrexate plus vinblastine without cisplatin in 214 patients. The relative risk of dying was 0.68 (95% confidence interval [CI], 0.51–0.90; P = .0065) in favor of CMV. The median survival was 7 months with CMV and 4.5 months with methotrexate plus vinblastine .[27]

  5. The European Organisation for Research and Treatment of Cancer (EORTC) conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose intensity MVAC regimen administered every 2 weeks with granulocyte colony-stimulating factor (G-CSF) versus a classic MVAC regimen administered every 4 weeks.[28]
    • Although there was no significant difference in OS at a median follow-up of 3.2 years (hazard ratio [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 MVAC 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 with 14% in patients treated with the classic MVAC regimen.

    • The high-dose intensity MVAC 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), although only 19% of patients treated with a classic MVAC regimen ever received G-CSF.[28][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 MVAC regimen and 47 patients assigned to the classic MVAC regimen) may account, in part, for these results.

  6. Gemcitabine plus cisplatin.
    • In a multicenter randomized phase III trial that compared GC with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR, 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC.

    • 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 MVAC regimen.[29][Level of evidence: 1iiA]

Radical cystectomy

Patients with stage IV disease with involvement of pelvic organs by direct extension or metastases to regional lymph nodes may undergo radical cystectomy with pelvic lymph node dissection.[30-32] The extent of lymph node dissection during cystectomy is controversial [30] because there are no data from prospective trials demonstrating improved outcomes with lymph node dissection. Because T4b tumors cannot generally be completely resected and because lymph node metastases usually signal distant micrometastases, patients with locally advanced bladder cancer are usually given chemotherapy before surgery with the goal of facilitating resection and eliminating micrometastatic disease. While there are data supporting preoperative chemotherapy for clinical stage II and stage III disease, patients with stage IV disease were excluded from most clinical trials investigating the role or preoperative chemotherapy.

External-beam radiation therapy (EBRT) with or without concomitant chemotherapy

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.[33,34] Patients with evidence of lymph node metastases have therefore generally been excluded from phase III trials of radiation therapy.[35,36]

Urinary diversion or cystectomy for palliation

Urinary diversion may be indicated, not only for palliation of urinary symptoms but also for preservation of renal function in candidates for chemotherapy.

Standard treatment options for patients with any T, any N, M1 disease

Standard treatment options for patients with any T, any N, M1 disease include the following:

  1. Chemotherapy alone or as an adjunct to local treatment.
  2. EBRT for palliation.
  3. Urinary diversion or cystectomy for palliation.
Chemotherapy alone or as an adjunct to local treatment

Cisplatin-based combination chemotherapy regimens are the standard of care for stage IV bladder cancer.[2-6] The only chemotherapy regimens that have been shown to result in longer survival in randomized controlled trials are MVAC, high-dose MVAC, and CMV. GC was compared with MVAC in a randomized controlled trial and no difference in response rate or survival was reported. Of note, patients with good performance status and lymph node-only disease have a low but significant rate of achieving a durable complete remission with MVAC or GC. In the large randomized controlled trial comparing MVAC with GC, for example, 5-year OS in patients with lymph node-only disease was 20.9%.[7]

Single-agent cisplatin and multiagent regimens that do not include cisplatin have never been shown to improve survival in a randomized controlled trial. Thus, for patients who are not candidates for cisplatin-based multiagent chemotherapy regimens, there is no regimen that has been shown to prolong their survival. Many regimens have been shown to be active, however, with regard to producing radiologically-measurable responses.

These include carboplatin plus paclitaxel,[8] carboplatin plus gemcitabine,[9-11] paclitaxel plus gemcitabine,[12-14] single-agent gemcitabine,[15,16] and single-agent paclitaxel.[17-19] The regimens of carboplatin, methotrexate, and vinblastine; carboplatin, epirubicin, methotrexate, and vinblastine; and paclitaxel, gemcitabine, and carboplatin have been studied but are not widely used.[20-23]

Ongoing studies are evaluating new chemotherapy combinations.

Evidence (chemotherapy):

  1. A prospective randomized trial that compared MVAC with cisplatin, cyclophosphamide, and doxorubicin demonstrated improved response and median survival rates (48 weeks vs. 36 weeks; P = .003) with the MVAC regimen.[25]

  2. Results from a randomized trial that compared MVAC with single-agent cisplatin in advanced bladder cancer also showed a significant advantage with MVAC in both response rate and median survival (12.5 months vs. 8.2 months; P = .002).[26]

  3. A multicenter randomized controlled trial compared CMV with methotrexate plus vinblastine without cisplatin in 214 patients. The relative risk of dying was 0.68 (95% CI, 0.51–0.90; P = .0065) in favor of CMV. The median survival was 7 months with CMV compared with 4.5 months for methotrexate plus vinblastine.[27]

  4. The EORTC conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose intensity MVAC regimen given every 2 weeks with G-CSF compared with a classic MVAC regimen given every 4 weeks.[28]
    • 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 MVAC 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 with 14% in patients treated with the classic MVAC regimen.

    • The high-dose intensity MVAC 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), although only 19% of patients treated with a classic MVAC regimen ever received G-CSF.[28][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 MVAC regimen and 47 patients assigned to the classic MVAC regimen) may account, in part, for these results.

  5. Gemcitabine plus cisplatin:
    • In a multicenter randomized phase III trial that compared GC with the MVAC regimen in 405 patients with advanced or metastatic bladder cancer, GC yielded response rates, time-to-progression, and OS (HR = 1.04; 95% CI, 0.82–1.32; P = .75) similar to MVAC, but GC had a better safety profile and was better tolerated than MVAC.

    • 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 MVAC regimen.[29][Level of evidence: 1iiA]

Ongoing studies are evaluating new chemotherapy combinations.

EBRT for palliation

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.

Urinary diversion or cystectomy for palliation

Urinary diversion may be indicated, not only for palliation of urinary symptoms, but also for preservation of renal function in candidates for chemotherapy.

Treatment Options Under Clinical Evaluation for Patients With Any T, Any N, M1 Disease

Prognosis is poor in patients with stage IV disease and consideration of entry into a clinical trial is appropriate.

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, and pemetrexed.[37,38][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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  11. De Santis M, Bellmunt J, Mead G, et al.: Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol 27 (33): 5634-9, 2009.  [PUBMED Abstract]

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  16. Lorusso V, Pollera CF, Antimi M, et al.: A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. Eur J Cancer 34 (8): 1208-12, 1998.  [PUBMED Abstract]

  17. Roth BJ, Dreicer R, Einhorn LH, et al.: Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol 12 (11): 2264-70, 1994.  [PUBMED Abstract]

  18. Dreicer R, Gustin DM, See WA, et al.: Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. J Urol 156 (5): 1606-8, 1996.  [PUBMED Abstract]

  19. Vaughn DJ, Broome CM, Hussain M, et al.: Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 20 (4): 937-40, 2002.  [PUBMED Abstract]

  20. Bellmunt J, Albanell J, Gallego OS, et al.: Carboplatin, methotrexate, and vinblastine in patients with bladder cancer who were ineligible for cisplatin-based chemotherapy. Cancer 70 (7): 1974-9, 1992.  [PUBMED Abstract]

  21. Bellmunt J, Ribas A, Albanell J, et al.: M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder. Am J Clin Oncol 19 (4): 344-8, 1996.  [PUBMED Abstract]

  22. Skarlos DV, Aravantinos G, Linardou E, et al.: Chemotherapy with methotrexate, vinblastine, epirubicin and carboplatin (Carbo-MVE) in transitional cell urothelial cancer. A Hellenic Co-Operative Oncology Group study. Eur Urol 31 (4): 420-7, 1997.  [PUBMED Abstract]

  23. Hainsworth JD, Meluch AA, Litchy S, et al.: Paclitaxel, carboplatin, and gemcitabine in the treatment of patients with advanced transitional cell carcinoma of the urothelium. Cancer 103 (11): 2298-303, 2005.  [PUBMED Abstract]

  24. Bamias A, Aravantinos G, Deliveliotis C, et al.: Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol 22 (2): 220-8, 2004.  [PUBMED Abstract]

  25. 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]

  26. 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]

  27. Mead GM, Russell M, Clark P, et al.: A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party. Br J Cancer 78 (8): 1067-75, 1998.  [PUBMED Abstract]

  28. 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]

  29. 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]

  30. 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]

  31. 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]

  32. 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]

  33. 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]

  34. 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]

  35. Shipley WU, Winter KA, Kaufman DS, et al.: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 16 (11): 3576-83, 1998.  [PUBMED Abstract]

  36. James ND, Hussain SA, Hall E, et al.: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 366 (16): 1477-88, 2012.  [PUBMED Abstract]

  37. Raghavan D, Huben R: Management of bladder cancer. Curr Probl Cancer 19 (1): 1-64, 1995 Jan-Feb.  [PUBMED Abstract]

  38. 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]