An estimated 54,300 new cases of bladder carcinoma will be diagnosed in the United States in 2001, with 12,400 deaths attributable to this cancer. The majority of these tumors will be superficial, confined to the mucosa and lamina propria of the bladder. Although these superficial bladder cancers frequently recur and may be multifocal, survival is excellent. To decrease rates of recurrence and progression, these tumors are best approached with cystoscopic surgery and, in select cases, intravesical drug therapy with, for example, bacillus Calmette-Guérin or chemotherapeutic agents.
When a tumor invades the muscular wall of the bladder, the prognosis markedly worsens because of the increased risk of metastatic progression. For this reason, there is a clear need for effective systemic chemotherapy for bladder cancer. Systemic chemotherapy may be used for the palliation of metastatic disease, and in a select minority of these patients, to achieve long-term survival. In the earlier-disease, perioperative setting, chemotherapy may be considered to eradicate microscopic metastases and increase surgical cure rates. This article will discuss recent developments in chemotherapy for invasive bladder cancer.
Transitional cell carcinoma of the urothelium is a chemotherapy-sensitive tumor. Significant response rates have been demonstrated with the single agents cisplatin (Platinol), methotrexate, cyclophosphamide (Cytoxan, Neosar), doxorubicin, and vinblastine, among others. Cisplatin-based combination regimens, such as M-VAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) and CMV (cisplatin, methotrexate, vinblastine), have been studied extensively.
Investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) developed M-VAC in the 1980s, and a phase II investigation suggested response rates as high as 72%, with a 36% complete response rate. Randomized trials have demonstrated that M-VAC is superior to both single-agent cisplatin and CISCA (cisplatin, cyclophosphamide, Adriamycin).[3,4]
The Intergroup phase III trial in 246 evaluable, previously untreated patients with advanced urothelial carcinoma who had been randomized to single-agent cisplatin vs M-VAC revealed the combination to have a higher response rate (39% vs 12%; P = .0001) and improved overall survival (12.5 vs 8.2 months; P = .0002). When investigators at the M. D. Anderson Cancer Center randomized patients with advanced disease to M-VAC vs CISCA, M-VAC was shown to be superior with respect to response rate (65% vs 46%; P < .05) and overall survival (46 vs 36 weeks; P = .000315). Based on these randomized trials, M-VAC has emerged as the standard treatment for patients with metastatic urothelial carcinoma.
The most important limitation of M-VAC is toxicity and poor patient tolerance. In the Intergroup trial, the combination showed substantially more toxicity, including mucositis, myelosuppression, and treatment-related deaths, than single-agent cisplatin. Additionally, some patients with advanced urothelial carcinoma have age- and/or disease-related renal dysfunction that makes cisplatin-based regimens problematic. Nevertheless, M-VAC remains an important milestone in the development of chemotherapy for bladder cancer.
In an effort to improve the therapeutic index of M-VAC, studies have been conducted to find ways to improve the tolerability or increase the efficacy of the regimen. The addition of granulocyte colony-stimulating factor (G-CSF [Neupogen]) to M-VAC has been shown to abrogate some of the toxicities, including mucositis and granulocytopenia. Several studies have attempted dose intensification of M-VAC by using hematopoietic growth factors; however, the results have generally been disappointing.[6-8] At the 2000 meeting of the American Society of Clinical Oncology (ASCO), the European Organization for the Research and Treatment of Cancer (EORTC) reported the results of a phase III trial that failed to demonstrate a survival advantage for high-dose-intensity M-VAC and G-CSF, compared to standard M-VAC.
Early phase II trials of M-VAC suggested that this regimen had the potential to cure patients with advanced urothelial cancer. But the effectiveness of M-VAC with respect to long-term survival, and which patients were most likely to derive a long-term benefit, was unknown. A recent study by Bajorin et al from MSKCC addressed these issues. In this series, in which 203 patients with advanced bladder cancer were treated with M-VAC, the presence of visceral (lung, liver, or bone) metastases and a baseline Karnofsky performance status less than 80% predicted independently for a poor outcome. Patients with both of these risk factors had a 5-year survival of 0% (median survival: 9.3 months). However, if patients had neither risk factor, the probability of achieving 5-year survival jumped to 33% (median survival: 33 months).
At 6-year follow-up of the previously described Intergroup trial comparing M-VAC and single-agent cisplatin in patients with advanced urothelial cancer, the chance of long-term, cancer-free survival in patients treated with M-VAC was only 3.7%. Predictors for poor outcome in this study included nontransitional histology, poor performance status, and/or bone/visceral metastasis. Thus, the probability of long-term survival for many patients treated with M-VAC is small. The identified poor prognostic factors are clinically useful in predicting the potential for a long-term benefit from combination chemotherapy regimens such as M-VAC. This information can also be used when evaluating reported trials of new chemotherapy regimens, since patient selection may significantly influence results.
In summary, M-VAC is an active—but toxic—regimen for advanced bladder cancer. Given the small chance for long-term survival for most patients treated with this regimen, efforts to identify new agents and combinations with improved efficacy or tolerability have been ongoing. Newer agents with significant activity include gemcitabine (Gemzar) and paclitaxel (Taxol).
Gemcitabine for Advanced Bladder Cancer
Gemcitabine (2´2´-difluorodeoxycytidine) is a cytosine analog with a structure that is similar to cytarabine. Gemcitabine is approved by the US Food and Drug Administration for the palliative treatment of patients with advanced pancreatic cancer, but it has broad antitumor activity, including activity in bladder cancer.
A review of gemcitabine in bladder cancer was recently published. In phase I studies of gemcitabine, responses were reported in patients with bladder cancer. Based on this activity, phase II studies were initiated in advanced urothelial cancer. Lorusso et al treated 31 evaluable patients who had previously received cisplatin with gemcitabine, 1,200 mg/m2 administered on days 1, 8, and 15 every 28 days. A response rate of 22.5% was demonstrated (95% confidence interval [CI] = 8%-37%). Stadler et al and Moore et al performed phase II trials in patients with advanced bladder cancer who were previously untreated with chemotherapy. Patients received gemcitabine, 1,200 mg/m2, on days 1, 8, and 15 every 28 days. Response rates in these trials were 28% (95% CI = 15%-45%) in the Stadler trial and 24% (95% CI = 12%-41%) in the Moore trial. Median survival was 12.5 and 8 months, respectively. In all these phase II trials, this therapy was well tolerated; toxicity was generally mild and reversible.
Gemcitabine/Cisplatin: Based on the significant single-agent activity and the acceptable toxicity profile of gemcitabine in patients with bladder cancer, combination trials with cisplatin were performed subsequently. Three phase II trials of the combination of gemcitabine/cisplatin have been reported (Table 1).[17-20]
Von der Masse et al treated 44 patients with gemcitabine, 1,000 mg/m2, and cisplatin, 35 mg/m2, on days 1, 8, and 15 every 28 days. A response rate of 41% (95% CI = 25%-58%) was reported. Toxicities included grade 3/4 granulocytopenia in 46% and thrombocytopenia in 71% of patients. Moore et al treated 31 patients with gemcitabine, 1,000 mg/m2, on days 1, 8, and 15, and cisplatin, 70 mg/m2, on day 2 every 28 days. An overall response rate of 57% was demonstrated in this study (95% CI = 37%-76%). Toxicity was principally hematologic with grade 3/4 granulocytopenia reported in 39% and grade 3/4 thrombocytopenia in 55% of patients. Median survival for all patients was 13.2 months. Kaufman et al reported the results of a multi-institutional phase II trial of the combination of gemcitabine/cisplatin. A total of 46 patients were treated in this study. Initial doses were gemcitabine, 1,000 mg/m2 on days 1, 8, and 15 every 28 days, with cisplatin, 100 mg/m2, on day 2. Due to excessive hematologic toxicity in the first cohort of 11 patients, the cisplatin dose was reduced to 75 mg/m2 for the duration of the trial. The objective response rate was 41% with a median survival of 14.3 months. Toxicity included grade 3/4 granulocytopenia in 74% and grade 3/4 thrombocytopenia in 65% of patients.
Gemcitabine/Cisplatin vs M-VAC: Given the promising results noted in the phase II trials of gemcitabine/cisplatin, an industry-sponsored phase III trial comparing combination gemcitabine/cisplatin with the standard M-VAC regimen in patients with previously untreated, advanced bladder cancer has been performed in Europe and the United States. This trial was initiated in 1996 and reached its accrual goal of 405 patients in 1998. Patients with previously untreated, locally advanced disease (T4b, N2, N3) or metastatic transitional cell carcinoma of the urothelium were randomized to receive gemcitabine, 1,000 mg/m2, on days 1, 8, and 15, and cisplatin 70 mg/m2, on day 2 every 28 days vs M-VAC. The primary end point was overall survival, and the study was sufficiently powered to detect a 4-month improvement in survival. Secondary end points included response rate, time to tumor progression, toxicity, quality of life, and resource utilization. The median age of the study population was 63 years, and the arms were well balanced with respect to prognostic risk factors, performance status, and presence of visceral metastases.
The overall survival for the group treated with gemcitabine/cisplatin was 13.8 months vs 14.8 months for those treated with M-VAC (not a statistically significant difference). The response rate (49% for gemcitabine/cisplatin vs 46% for M-VAC) and complete response rates (12% for gemcitabine/cisplatin vs 12% for M-VAC) were also not significantly different. The M-VAC regimen was associated with significantly more grade 3/4 mucositis and granulocytopenic fever and sepsis. Gemcitabine/cisplatin was associated with significantly more grade 3/4 anemia and thrombocytopenia. Quality-of-life measures demonstrated that more patients in the gemcitabine/cisplatin arm fared well with respect to weight, performance status, and fatigue. Use of supportive measures (eg, G-CSF, antibiotics, antifungals, and number of days of hospitalization) was greater with M-VAC. Thus, this trial demonstrates that gemcitabine/cisplatin is associated with similar survival to M-VAC. (The study was not sufficiently powered to demonstrate equivalent survival between the two arms.) In addition, gemcitabine/cisplatin showed a more favorable toxicity profile than M-VAC. This trial establishes gemcitabine/cisplatin as an alternative to M-VAC for the treatment of patients with advanced urothelial carcinoma.
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001.
2. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium: Efficacy and patterns of response and relapse. Cancer 64:2448-2458, 1989.
3. 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 10:1066-1073, 1992.
4. Logothetis CJ, Dexeus FH, Finn L, et al: A prospective randomized trial comparing M-VAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 8:1050-1055, 1990.
5. Gabrilove JL, Jakubowski A, Scher H, et al: Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of the urothelium. N Engl J Med 318:1414-1422, 1988.
6. Seidman AD, Scher H, Gabrilove JL, et al: Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial carcinoma. J Clin Oncol 11:408-414, 1993.
7. Loehrer PJ Sr, Elson P, Drecier R, et al: Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced bladder carcinoma: An Eastern Cooperative Oncology Group trial. J Clin Oncol 12: 483-488, 1994.
8. Logothetis CJ, Finn LD, Smith T, et al: Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: Results of a randomized trial. J Clin Oncol 13: 2272-2277, 1995.
9. Sternberg C, de Mulder PH, Schornagel J, et al: Randomized phase III trial in advanced urothelial tract tumors of high dose-intensity M-VAC chemotherapy and G-CSF vs classic M-VAC (abstract). Proc Am Soc Clin Oncol 19:329a, 2000.
10. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome to chemotherapy. J Clin Oncol 17:3173-3181, 1999.
11. Saxman SB, Propert KJ, Einhorn LH, et al: Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A Cooperative Group study. J Clin Oncol 15:2564-2569, 1997.
12. Vogelzang NJ, Stadler WM: Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer. Urology 53:243-250, 1999.
13. Pollera CF, Cetibelli A, Crecco M, et al: Weekly gemcitabine in advanced bladder cancer: A preliminary report from phase I study. Ann Oncol 5:182-184, 1994.
14. 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. Eur J Cancer 34:1208-1212, 1998.
15. Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15:3394-3398, 1997.
16. Moore MJ, Tannock IF, Ernst DS, et al: Gemcitabine: A promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 15:3441-3445, 1997.
17. Von der Masse H, Anderson L, Crino L, et al: A phase II study of gemcitabine and cisplatin in patients with transitional cell carcinoma (TCC) of the urothelium (abstract). Proc Am Soc Clin Oncol 16:324a, 1997.
18. Moore MJ, Winquist E, Murray N, et al: Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 17:2876-2881, 1999.
19. Kaufman D, Raghavan D, Carducci M, et al: Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 18:1921-1927, 2000.
20. Von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin vs methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 17:3068-3077, 2000.
21. Neill HB, Rangel C, Miller A, et al: The activity of antimicrotubular agents in human bladder cancer cell lines (abstract). Proc Am Assoc Cancer Res 34:202, 1993.
22. 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 (E1892). J Clin Oncol 12: 2264-2270, 1994.
23. Dreicer R, Manola J, Roth BJ, et al: Phase II study of cisplatin and paclitaxel in advanced carcinoma of the urothelium: An Eastern cooperative Oncology Group Study (abstract). J Clin Oncol 18(5):1058-61, 2000.
24. Burch PA, Richardson RL, Cha SS, et al: Phase II trial of paclitaxel and cisplatin in advanced urothelial cancer (UC) (abstract). Proc Am Soc Clin Oncol 18:329a, 1999.
25. Bajorin DE, McCaffrey JA, Dodd PM, et al: Ifosfamide, paclitaxel, and cisplatin for patients with advanced transitional cell carcinoma of the urothelial tract: Final report of a phase II trial. Cancer 88(7):1671-1678, 2000.
26. Dodd PM, McCaffrey JA, Hilton S, et al: Phase I evaluation of sequential doxorubicin + gemcitabine then ifosfamide + paclitaxel + cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract. J Clin Oncol 18:840-846, 2000.
27. Waxman J, Barton C: Carboplatin-based chemotherapy for bladder cancer. Cancer Treat Rev 19(suppl C):21-25, 1993.
28. Calvert AH, Newell DR, Grumbell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989.
29. 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 156:1606-1608, 1996.
30. 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: 255-260, 1998.
31. 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: 1844-1848, 1998.
32. Pycha A, Grbovic M, Posch B, et al: Paclitaxel and carboplatin in patients with metastatic transitional cell carcinoma of the urinary tract. Urology 53:510-515, 1999.
33. 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 18:2537-2544, 2000.
34. Vaughn DJ, Dreicer R, Manola J, et al: E2896 Paclitaxel (P)/Carboplatin (C) in advanced urothelial carcinoma and renal insufficiency: A phase II trial of the Eastern Cooperative Oncology Group (ECOG) (abstract). Proc Am Soc Clin Oncol 19:343a, 2000.
35. Meluch AA, Greco FA, Burris III HA, et al: Paclitaxel and gemcitabine chemotherapy for advanced transitional cell carcinoma (TCC) of the urothelial tract: A phase II trial of the Minnie Pearl Cancer Research Network (abstract). Proc Am Soc Clin Oncol 19:340a, 2000.
36. Kaufman DS, Stadler WM, Carducci MA, et al: Gemcitabine (G) and paclitaxel (P) every two weeks (GP2W): A multicenter phase I trial in locally advanced or metastatic urothelial cancer (UC) (abstract). Proc Am Soc Clin Oncol 19:341a, 2000.
37. deWit R, Kruit WHJ, Stotler G, et al: Docetaxel (Taxotere): An active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-pretreated patients. Br J Cancer 78:1342-1345, 1998.
38. Bellmunt J, Guillem V, Paz-Ares L, et al: Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. J Clin Oncol 18:3247-3255, 2000.
39. Vaishampayan UN, Smith DC, Dickow B, et al: Carboplatin, paclitaxel and gemcitabine in advanced urothelial carcinoma: Updated results (abstract). Proc Am Soc Clin Oncol 19:341a, 2000.
40. Dimopoulos MA, Moulopoulos LA: Role of adjuvant chemotherapy in the treatment of bladder cancer. J Clin Oncol 16:1601-1612, 1998.
41. McCaffrey JA, Bajorin DF, Adjuvant and neoadjuvant chemotherapy for invasive bladder cancer, in Vogelzang NJ, Scardino PT, Shipley WU, et al (eds): Comprehensive Textbook of Genitourinary Oncology, pp 473-482. Philadelphia, Lippincott Williams & Wilkins, 2000.
42. 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 145:459-464, 1991.
43. Stockle M, Wellek S, Meyenberg W, et al: Radical cystectomy with or without adjuvant polychemotherapy for non-organ confined transitional cell carcinoma of the urinary bladder: Prognostic impact of lymph node involvement. Urology 48:868-875, 1996.
44. Hall R: Neoadjuvant CMV chemotherapy and cystectomy or radiation in muscle-invasive bladder cancer: First analysis of MRC/EORTC intercontinental trial (abstract). Proc Am Soc Clin Oncol 15:612, 1997.
45. Stein JP, Grossfeld GD, Ginsberg DA, et al: Prognostic markers in bladder cancer: A contemporary review of the literature. J Urol 160:645-659, 1998.
46. Grossman HB, Dinney CPN: Markers of bladder cancer: State of the art. Urol Oncol 5:3-10, 2000.
47. Chang F, Syrjanen S, Syrjanen K: Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13:1009-1022, 1995.
48. Esrig D, Spruck CH, Nichols PW, et al: p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 143:1389-1397, 1993.
49. Vet JAM, Bringuier PP, Schaafsma E, et al: Comparison of p53 protein overexpression with p53 mutation in bladder cancer: Clinical and biological aspects. Lab Invest 73:837, 1995.
50. Esrig D, Elmajian D, Groshen S, et al: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331:1259, 1994.
51. Lipponen PK: Over-expression of the p53 nuclear oncoprotein in transitional cell carcinoma of the bladder and its prognostic value. Int J Cancer 53:365, 1993.
52. Jahnson S, Karlsson MG: Predictive value of p53 and pRb immunostaging in locally advanced bladder cancer treated with cystectomy. J Urol 160:1291-1296, 1998.
53. El-Deiry W, Tokino T, Velculescu VE, et al: WAF1, a potential mediator of p53 tumor suppression. Cell 75:817, 1993.
54. Michieli P, Chedid M, Lin D, et al: Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res 54:3391, 1994.
55. Stein JP, Ginsberg DA, Grossfeld GD, et al: Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90:1072, 1998.
56. Xu H, Cairns P, Hu SX, et al: Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression. Int J Cancer 53: 781-784, 1993.
57. Cote RJ, Dunn MD, Chatterjee SJ, et al: Elevated and absent pRB expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res 58:1090-1094, 1998.
58. Grossfeld GD, Ginsberg DA, Stein JP, et al: Thrombospondin-1 expression in bladder cancer: Association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 89:219-227, 1997.
59. Bochner BH, Esrig D, Groschen S, et al: Relationship of tumor angiogenesis and nuclear p53 accumulation in invasive bladder cancer. Clin Cancer Res 3:1615-1622, 1997.
60. Sarkis A, Bajorin DF, Reuter, VE, et al: Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant M-VAC. J Clin Oncol 13:1384, 1995.
61. Cote RJ, Esrig D, Groshen S, et al: p53 and treatment of bladder cancer. Nature 385:123, 1997.
62. Siu LL, Banerjee D, Khurana RJ, et al: The prognostic role of p53, metallothionein, p-glycoprotein, and MIB-1 in muscle-invasive urothelial transitional cell carcinoma. Clin Cancer Res 4:559-565, 1998.
63. Kakehi Y, Ozdemir E, Habuchi T, et al: Absence of p53 overexpression and favorable response to cisplatin-based neoadjuvant chemotherapy in urothelial carcinomas. Jpn J Cancer Res 89:214-220, 1998.
64. Wagner U, Moch H, Kononen J, et al: Evaluation of prognostic markers in urinary bladder cancer using tumor tissue arrays. J Urol 161(suppl):174, 1999.