Bladder cancer is the fifth most common cancer diagnosed in theUnited States. Prognosis for this disease is dependent on both tumorstage and grade. Radical cystectomy has been the standard treatmentfor muscle-invasive local disease; however, combined-modality approacheswith the use of chemotherapy are gaining momentum withdata suggesting survival improvement. Patients with metastatic diseasehave poor long-term survival rates despite systemic multiagent chemotherapy.A variety of agents, including newer cytotoxic drugs and biologicallytargeted agents, are under investigation to determine the mosteffective regimen. The special needs of specific patient populations,such as the elderly, those with a suboptimal performance status, andpatients with medical comorbidities have gained more attention.Progress in the treatment of this disease is dependent on supportingongoing and future clinical trials.
Bladder cancer is the fifth most common cancer diagnosed in the United States. Prognosis for this disease is dependent on both tumor stage and grade. Radical cystectomy has been the standard treatment for muscle-invasive local disease; however, combined-modality approaches with the use of chemotherapy are gaining momentum with data suggesting survival improvement. Patients with metastatic disease have poor long-term survival rates despite systemic multiagent chemotherapy. A variety of agents, including newer cytotoxic drugs and biologically targeted agents, are under investigation to determine the most effective regimen. The special needs of specific patient populations, such as the elderly, those with a suboptimal performance status, and patients with medical comorbidities have gained more attention. Progress in the treatment of this disease is dependent on supporting ongoing and future clinical trials.
Bladder cancer is the fifth most common malignancy, with an estimated 63,210 newly diagnosed cases and 13,180 deaths in the United States in 2005. Approximately 75% of patients present with superficial disease and are managed primarily by urologists with cystoscopy and transurethral resection (TUR) with or without intravesicular therapy, depending on grade, presence of carcinoma in situ, and depth of invasion. The remaining patients- approximately 25%-have muscleinvasive disease on a biopsy specimen and have a worse prognosis. Outcomes in these patients are dependent upon tumor stage and grade, and high recurrence rates are seen even with disease confined to the bladder wall managed with cystectomy or primary radiotherapy. Patients who subsequently develop metastatic disease or present with it can expect a median survival of about 14 months with combination systemic chemotherapy. Current areas of clinical research for urothelial carcinomas are focused on improving the outcomes of patients with muscle-invasive disease with the use of local and systemic therapy, as mounting evidence suggests a role for chemotherapy in the perioperative setting. Work continues toward the de velopment of multimodality, bladdersparing approaches that incorporate surgery, radiotherapy, and chemotherapy with the intent of avoiding radical cystectomy. For patients with metastatic disease, the focus has been on new cytotoxic agents and combinations that have better therapeutic and toxicity profiles in addition to investigating the role of targeted therapies. Management of Locally Invasive DiseaseSurgery
The current standard approach for treatment of muscle-invasive bladder cancer involves radical cystectomy and bilateral pelvic lymphadenectomy. Long-term survival in this setting has been evaluated in multiple surgical series (Table 1).[2-4] The 5-year survival rate is 68% for patients with pathologically organ-confined bladder cancer (pT2), compared with about 25% to 30% for those with extravesicular extension. Analysis of subsets of patients with muscle-invasive disease has determined that both extravesicular disease and node-positive disease are predictive of decreased survival. The poor outcomes seen with surgical resection alone have provided the rationale for investigating a multimodality approach to the management of invasive bladder cancer patients. Learning from the positive outcomes with the utilization of adjuvant or neoadjuvant chemotherapy for a variety of other solid tumors, such trials evaluating perioperative chemotherapy for invasive bladder cancer have been conducted.
The goal of neoadjuvant chemotherapy is to improve survival via the "eradication" of micrometastatic disease. There are several potential advantages to the neoadjuvant approach, including the facilitation of bladdersparing strategies. In addition, because patients have the bladder in place, oncologists are able to monitor for response during treatment, which has prognostic value. Patients may also be better able to tolerate chemotherapy before surgery when their performance status is higher, whereas they may not be good candidates for chemotherapy following a major surgical procedure. One of the disadvantages of this approach is that patients with chemoresistant disease may progress while receiving neoadjuvant treatment and, therefore, risk progressing to a nonoperable stage due to the delay in providing definitive local therapy. Several randomized clinical trials have been performed to evaluate the use of neoadjuvant platinum-based regimens (Table 2).[6-15] Most of these trials failed to demonstrate a survival advantage, but many of the studies have shortcomings. They included small numbers of patients and are underpowered to detect a difference in survival. Some trials evaluated single-agent chemotherapy, which is known to be less efficacious than combination regimens. Other trials allowed patients to receive either radiation or cystectomy for local therapy, and these two modalities have not been directly compared. Poor local control may impact overall outcomes and affect the results of these studies. Three of these trials, however, strongly suggest an advantage for neoadjuvant chemotherapy.
Adjuvant chemotherapy has also been evaluated in an attempt to improve outcome in patients with muscle- invasive bladder cancer. By treating patients postoperatively, definitive local treatment is provided up front without delay. Because the surgery is performed first, complete pathologic staging information can be obtained for making treatment decisions, allowing better patient selection. Some of the limitations of the adjuvant approach include delay in initiating systemic therapy directed toward micrometastatic disease, an inability to assess response to chemotherapy postcystectomy, and difficulties in the delivery of chemotherapy in the adjuvant setting due to surgical complications and decreased patient tolerance.
Not all patients are candidates for radical cystectomy, either because of significant comorbidities or due to unresectable disease. Other patients refuse surgery for fear of compromising quality of life. As an alternative, these patients may be treated with definitive radiotherapy, but radiation alone has poor curative potential, as data indicate that up to 70% of these patients may experience a local recurrence and 5-year survival rates are generally suboptimal. The addition of chemotherapy to radiation has been shown to improve local control but not overall survival. Typically, a trimodality approach is used in which a maximum transurethral resection (TUR) is performed followed by bladder irradiation concurrent with radiosensitizing chemotherapy. In addition, either neoad- juvant or adjuvant chemotherapy is sometimes given. Periodic cystoscopies are performed to monitor for disease, and if recurrence is noted, patients undergo salvage radical cystectomy. To date, there has not been a randomized trial to address the issue of bladder preservation adequately.
Metastatic DiseaseSystemic Chemotherapy
Metastatic bladder cancer is a fatal disease, for which numerous chemotherapeutic regimens have been studied (Tables 3-5).[26-55] In randomized trials, MVAC resulted in superior survival rates as compared to either single-agent cisplatin or CISCA. Thus, MVAC was established as the gold standard against which other regimens are compared (Table 3). The experience with chemotherapy in general and MVAC in particular has been instructive as to the chemosensitivity of urothelial carcinoma, the importance of multiagent chemotherapy, the toxicities and treatment- related deaths associated with cisplatin-based therapy, the effects of clinical prognostic factors on outcome, and the inability of dose escalation with growth factor support in enhancing survival. (Attempts to improve the efficacy of MVAC by dose escalation with growth factor support failed to result in survival improvement.) In addition, although complete response rates are relatively high, cures are rare in advanced bladder cancer.
Clinically Relevant Prognostic Factors
As with locally advanced disease, significant prognostic factors have also been identified for patients with metastatic disease who have been predominantly treated with cisplatinbased regimens. Bajorin et al performed a retrospective trial of 203 patients treated with MVAC. The independent prognostic factors most predictive of poor survival included presence of lung, bone, or liver metastases and Karnofsky score < 80%. In patients with neither risk factor, 5-year survival was 33%, but in patients with both visceral metastases and poor performance status, 5-year survival was 0%. The investigators therefore recommended that phase III trials stratify patients according to the number of risk factors, to avoid imbalance in treatment arms. Similar results were seen in patients treated with the combination of paclitaxel, gemcitabine, and cisplatin.
Molecular Predictive/Prognostic Markers for Localized and Metastatic Disease
In various stages of bladder cancer, molecular markers are being evaluated as potential novel prognostic factors in order to better classify patients' risk of progression to invasive disease or systemic recurrence, and some are being evaluated as therapeutic targets (Table 6).[63-67] Other reviews have dealt with this subject in more detail.[63,68] Briefly, multiple genes have been evaluated,[64-67] but the most extensive data pertain to mutations of the tumor suppressor p53, which are associated with genomic instability and formation of carcinoma. Accumulation of p53 within tumor nuclei, when detected by immunohistochemical staining, has been associated with an increased risk of recurrence from bladder cancer in some studies but not others.[64,70] In a multivariate analysis stratified for tumor grade, pathologic stage, and nodal status, alteration in p53 was found to be an independent prognostic factor associated with increased recurrence and reduced survival. Other studies of p53 accumulation in both locally advanced and node-positive disease, however, have not demonstrated a correlation with disease-free survival.[64,70] Based on these observations, an ongoing National Cancer Institute (NCI)-sponsored trial is randomizing patients with invasive bladder cancer and mutations in p53 to adjuvant chemotherapy vs observation following radical cystectomy. The epidermal growth factor (EGF) receptor and HER2/neu are tyrosine kinases involved in cell proliferation, cell survival, angiogenesis, and metastasis.[ 63,71] The EGF receptor is overexpressed in high-grade invasive transitional cell carcinomas and is associated with more aggressive clinical behavior. Another member of the EGF receptor family, HER2/neu, has also been studied in urothelial tumors. In patients with metastatic bladder cancer, Jimenez et al demonstrated HER2/neu overexpression in 22 (37%) of 60 primary tumors, 20 (63%) of 32 regional lymph node metastases, and 6 (86%) of 7 distant metastases. Absence of overexpression of HER2/neu in the primary tumor failed to predict absence of HER2/neu overexpression in distant metastases. The increased expression in distant sites suggests that overexpression is an acquired feature during the metastatic process. Agents targeting the EGF receptor and HER2/neu have been developed, making these targets potentially of therapeutic value as well as prognostic significance. Preclinical studies in a murine model have suggested that the anti-EGF receptor antibody cetuximab (Erbitux) has activity in bladder cancer.[ 73] Based on prior results showing enhancement of antitumor activity of chemotherapy with the addition of trastuzumab (Herceptin) in patients with metastatic breast cancer overexpressing HER2/neu, studies are under way in advanced bladder cancer to evaluate both single-agent trastuzumab and the addition of trastuzumab to chemotherapy. The Cancer and Leukemia Group B (CALGB) is currently evaluating single-agent trastuzumab, and we have recently completed accrual to an NCI-sponsored trial designed to prospectively evaluate the frequency of HER2/neu overexpression and the feasibility of the combination of trastuzumab with paclitaxel, carboplatin, and gemcitabine. New Cytotoxic Therapies in Development
Other targeted therapies that are under investigation include the epothilone B analogs and the antifolate pemetrexed (Alimta). The epothilones comprise a new class of nontaxane tubulin-polymerizing agents that result in mitotic arrest at the G2/M transition. In both in vitro and in vivo tumor models of numerous solid tumors, epothilone B analogs have been shown to have a high level of antitumor activity, even in paclitaxel-resistant tumors.[75,76] The epothilone B analog ixabepilone is currently being evaluated in an Eastern Cooperative Oncology Group (ECOG) phase II trial (E3800) of previously treated patients with advanced transitional cell urothelial cancer. The antifolate agent pemetrexed has multiple enzyme targets involved in both purine and pyrimidine biosynthesis. It has previously been studied in other tumor types, both as a single agent and in combination with other chemotherapy agents, and it is now being evaluated in advanced urothelial cancer. A phase II trial of pemetrexed was conducted in 31 chemotherapy-naive patients with advanced bladder cancer, 61% of whom had visceral metastases.[ 77] The response rate was 32%, and median survival was 9.4 months. Toxicity was greater in pemetrexedtreated patients with bladder cancer compared to other primary tumors, which was thought to be due to a higher prevalence of renal insufficiency in these patients, resulting in delayed clearance of pemetrexed and higher rates of neutropenia. The other primary toxicity was hematologic, and therefore, subsequent studies have included folate and vitamin B12 supplementation along with pemetrexed. Pemetrexed is currently being evaluated in combination with gemcitabine in patients with advanced bladder cancer in a phase II study (ECOG-E4802). Conclusions Despite progress in the management of urothelial cancer, there remain several challenges that are driving research efforts. Transforming high response rates into cures, improving multiagent chemotherapy and multimodality treatment, investigating new agents, and defining second- line salvage therapy are some of the current research objectives. Improvement in understanding the biology of urothelial cancers has be- gun to define molecular markers that are not only prognostic but are also clinically relevant targets for existing or yet to be developed drugs. Progress in systemic therapy is the key to better outcome for newly diagnosed highrisk patients. Finally, particular attention to the toxicity of treatment is needed, as many bladder cancer patients are elderly or have comorbidities. Overall progress is only possible if all involved in the care of this disease support clinical trials.
Dr. Hussain receives research support from and is a consultant for Bristol-Myers Squibb, and has received research support from Genentech.
1. American Cancer Society: Cancer Facts and Figures, 2005. Available at www.cancer.org/ downloads/STT/CAFF2005f4PWSecured.pdf. Accessed August 9, 2005.
2. Dalbagni G, Genega E, Hashibe M, et al: Cystectomy for bladder cancer: A contemporary series. J Urol 165:1111-1116, 2001.
3. Gschwend JE, Dahm P, Fair WR: Disease specific survival as endpoint of outcome for bladder cancer patients following radical cystectomy. Eur Urol 41:440-448, 2002.
4. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001.
5. Splinter TA, Scher HI, Denis L, et al: The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. European Organization for Research on Treatment of Cancer- Genitourinary Group. J Urol 147:606-608, 1992.
6. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: A randomised controlled trial. International collaboration of trialists. Lancet 354:533-540, 1999.
7. Neoadjuvant chemotherapy in invasive bladder cancer: A systematic review and metaanalysis. Lancet 361:1927-1934, 2003.
8. 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 14:2901-2907, 1996.
9. 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 349:859- 866, 2003.
10. Malmstrom PU, Rintala E, Wahlqvist R, et al: Five-year followup of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 155:1903-1906, 1996.
11. Martinez-Pineiro JA, Gonzalez Martin M, Arocena F, et al: Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: A prospective randomized phase III study. J Urol 153:964-973, 1995.
12. Sherif A, Holmberg L, Rintala E, et al: Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: A combined analysis of two Nordic studies. Eur Urol 45:297-303, 2004.
13. Sherif A, Rintala E, Mestad O, et al: Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer-Nordic cystectomy trial 2. Scand J Urol Nephrol 36:419- 425, 2002.
14. 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 16:3576-3583, 1998.
15. Wallace DM, Raghavan D, Kelly KA, et al: Neo-adjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 67:608-615, 1991.
16. Hall RR, for the International Collaboration of Trialists of the MRC Advanced Bladder Cancer Group: Updated results of a randomized trial of neoadjuvant cisplatin (C), methotrexate (M), and vinblastine (V) chemotherapy for muscle-invasive bladder cancer (abstract 710). Proc Am Soc Clin Oncol 21:178a, 2002.
17. 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- 467 (incl discussion), 1991.
18. Stockle M, Meyenburg W, Wellek S, et al: Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 148:302-307 (incl discussion), 1992.
19. Sylvester R, Sternberg C: The role of adjuvant combination chemotherapy after cystectomy in locally advanced bladder cancer: What we do not know and why. Ann Oncol 11:851- 856, 2000.
20. Montie JE, Bahnson RR, Cohen SM, et al: The NCCN Bladder Cancer Clinical Practice Guidelines in Oncology. JNCCN 3:4-34, 2005.
21. Pollack A, Zagars GZ: Radiotherapy for stage T3b transitional cell carcinoma of the bladder. Semin Urol Oncol 14:86-95, 1996.
22. Rodel C, Grabenbauer GG, Kuhn R, et al: Combined-modality treatment and selective organ preservation in invasive bladder cancer: Long-term results. J Clin Oncol 20:3061-3071, 2002.
23. Shipley WU, Kaufman DS, Zehr E, et al: Selective bladder preservation by combined modality protocol treatment: Long-term outcomes of 190 patients with invasive bladder cancer. Urology 60:62-68 (incl discussion), 2002.
24. Sternberg CN, Pansadoro V, Calabro F, et al: Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 97:1644-1652, 2003.
25. Scher HI, Kantoff PW: Chemotherapy for muscle-infiltrating bladder cancer. Hematol Oncol Clin North Am 6:169-178, 1992.
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 10:1066-1073, 1992.
27. 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 8:1050-1055, 1990.
28. Sternberg CN, de Mulder PH, Schornagel JH, et al: Randomized phase III trial of highdose- intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colonystimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 19:2638-2646, 2001.
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 18:3068-3077, 2000.
30. Dreicer R, Manola J, Roth BJ, et al: Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer 100:1639-1645, 2004.
31. Siefker-Radtke AO, Millikan RE, Tu SM, et al: Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol 20:1361-1367, 2002.
32. 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 22:220-228, 2004.
33. 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.
34. Moore MJ, Winquist EW, 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.
35. Hussain SA, Stocken DD, Riley P, et al: A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer. Br J Cancer 91:844-849, 2004.
36. LladÃ³ A, Bellmunt J, Kaiser G, et al: A dose finding study of carboplatin with fixed doses of gemcitabine in “unfit” patients with advanced bladder cancer (abstract 1354). Proc Am Soc Clin Oncol 19:344a, 2000.
37. Carles J, Nogue M, Domenech M, et al: Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology 59:24- 27, 2000.
38. Nogue-Aliguer M, Carles J, Arrivi A, et al: Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract: An alternative therapy. Cancer 97:2180-2186, 2003.
39. Shannon C, Crombie C, Brooks A, et al: Carboplatin and gemcitabine in metastatic transitional cell carcinoma of the urothelium: Effective treatment of patients with poor prognostic features. Ann Oncol 12:947-952, 2001.
40. Vaughn DJ, Manola J, Dreicer R, et al: Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): A trial of the Eastern Cooperative Oncology Group. Cancer 95:1022-1027, 2002.
41. Meluch AA, Greco FA, Burris HA 3rd, et al: Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 19:3018-3024, 2001.
42. 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.
43. Sternberg CN, Calabro F, Pizzocaro G, et al: Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 92:2993- 2998, 2001.
44. Parameswaran R, Fisch MJ, Ansari RH, et al: A Hoosier Oncolgy Group phase II study of weekly paclitaxel and gemcitabine in advanced transitional cell (TCC) carcinoma of the bladder(abstract 798). Proc Am Soc Clin Oncol 20:200a, 2001.
45. Kaufman DS, Carducci MA, Kuzel TM, et al: A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer. Urol Oncol 22:393-397, 2004.
46. 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. J Clin Oncol 18:1058-1061, 2000.
47. Burch PA, Richardson RL, Cha SS, et al: Phase II study of paclitaxel and cisplatin for advanced urothelial cancer. J Urol 164:1538-1542, 2000.
48. 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.
49. Garcia del Muro X, Marcuello E, Guma J, et al: Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer. Br J Cancer 86:326-330, 2002.
50. Dimopoulos MA, Bakoyannis C, Georgoulias V, et al: Docetaxel and cisplatin combination chemotherapy in advanced carcinoma of the urothelium: A multicenter phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 10:1385-1388, 1999.
51. 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. Spanish Oncology Geni tourinary Group. J Clin Oncol 18:3247-3255, 2000.
52. Hussain M, Vaishampayan U, Du W, et al: Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 19:2527-2533, 2001.
53. Pagliaro LC, Millikan RE, Tu SM, et al: Cisplatin, gemcitabine, and ifosfamide as weekly therapy: A feasibility and phase II study of salvage treatment for advanced transitional-cell carcinoma. J Clin Oncol 20:2965-2970, 2002.
54. Bajorin DF, 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 evaluating two dosing schedules. Cancer 88:1671-1678, 2000.
55. Edelman MJ, Meyers FJ, Miller TR, et al: Phase I/II study of paclitaxel, carboplatin, and methotrexate in advanced transitional cell carcinoma: A well-tolerated regimen with activity independent of p53 mutation. Urology 55:521- 525, 2000.
56. Raghavan D, Shipley WU, Garnick MB, et al: Biology and management of bladder cancer. N Engl J Med 322:1129-1138, 1990.
57. Charlson M, Szatrowski TP, Peterson J, et al: Validation of a combined comorbidity index. J Clin Epidemiol 47:1245-1251, 1994.
58. Overcash J: Symptom management in the geriatric patient. Cancer Control 5:46-47, 1998.
59. Rao AV, Seo PH, Cohen HJ: Geriatric assessment and comorbidity. Semin Oncol 31:149-159, 2004.
60. Carteni G, Dogliotti L, Crucitta E, et al: Phase II randomised trial of gemcitabine plus cisplatin and gemcitabine plus carboplatin in patients with advanced or metastatic transitional cell carcinoma of the urothelium (abstract 1543). Proc Am Soc Clin Oncol 22:384, 2003.
61. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitionalcell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17:3173- 3181, 1999.
62. Bellmunt J, Albanell J, Paz-Ares L, et al: Pretreatment prognostic factors for survival in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, cisplatin, and gemcitabine. Cancer 95:751-757, 2002.
63. Bellmunt J, Hussain M, Dinney CP: Novel approaches with targeted therapies in bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family. Crit Rev Oncol Hematol 46(suppl):S85-S104, 2003.
64. Jahnson S, Karlsson MG: Predictive value of p53 and pRb immunostaining in locally advanced bladder cancer treated with cystectomy. J Urol 160:1291-1296, 1998.
65. Sarkis AS, Dalbagni G, Cordon-Cardo C, et al: Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: A marker for disease progression. J Natl Cancer Inst 85:53-59, 1993.
66. Cordon-Cardo C, Wartinger D, Petrylak D, et al: Altered expression of the retinoblastoma gene product: Prognostic indicator in bladder cancer. J Natl Cancer Inst 84:1251- 1256, 1992.
67. Logothetis CJ, Xu HJ, Ro JY, et al: Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 84:1256- 1261, 1992.
68. Al-Sukhun S, Hussain M: Current understanding of the biology of advanced bladder cancer. Cancer 97:2064-2075, 2003.
69. Esrig D, Elmajian D, Groshen S, et al: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331:1259-1264, 1994.
70. Fleshner N, Kapusta L, Ezer D, et al: p53 nuclear accumulation is not associated with decreased disease-free survival in patients with node positive transitional cell carcinoma of the bladder. J Urol 164:1177-1182, 2000.
71. Chow NH, Chan SH, Tzai TS, et al: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 7:1957- 1962, 2001.
72. Jimenez RE, Hussain M, Bianco FJ Jr, et al: Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: Prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res 7:2440- 2447, 2001.
73. Inoue K, Slaton JW, Perrotte P, et al: Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res 6:4874-4884, 2000.
74. Hussain M, Petrylak D, Dunn R, et al: Trastuzumab, paclitaxel, carboplatin, and gemcitabine in the treatment of advanced HER-2 positive urothelial cancer: Results of a multicenter phase II NCI trial (abstract 4507). J Clin Oncol 23(16S):379s, 2005.
75. Lee FY, Borzilleri R, Fairchild CR, et al: BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7:1429-1437, 2001.
76. Mani S, McDaid H, Hamilton A, et al: Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289- 1298, 2004.
77. Paz-Ares L, Bezares S, Tabernero JM, et al: Review of a promising new agent-pemetrexed disodium. Cancer 97:2056-2063, 2003.