Introduction: This phase II trial evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, in combination with first-line chemotherapy in advanced urothelial cancer. Methods: Chemotherapy-naïve patients with advanced or metastatic urothelial carcinoma were randomized 1:1:1 to receive six cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8, and cisplatin 70 mg/m2 on day 1 of every cycle) concomitantly with gefitinib 250 mg/day (arm A); or with sequential gefitinib (arm B); or alone (arm C). The primary endpoint was the time to progression (TTP). Results: A total of 105 patients received study treatment. Median TTP for arms A, B, and C were 6.1, 6.3, and 7.8 months, respectively. There were no significant differences between treatment arms for any outcomes measured. The most common adverse events were nausea and vomiting. Conclusion: Gefitinib in combination with chemotherapy did not improve efficacy in advanced urothelial cancer.

Keywords:
Cisplatin, Gefitinib, Gemcitabine, Transitional cell carcinoma, Urothelial carcinoma
1.
Ferlay J, Randi G, Bosetti C, Levi F, Negri E, Boyle P, La Vecchia C: Declining mortality from bladder cancer in Europe. BJU Int 2008;101:11-19.
2.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.
3.
Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666-675.
4.
Ross JS, Schenkein DP, Pietrusko R, Rolfe M, Linette GP, Stec J, Stagliano NE, Ginsburg GS, Symmans WF, Pusztai L, Hortobagyi GN: Targeted therapies for cancer 2004. Am J Clin Pathol 2004;122:598-609.
5.
Petrelli NJ, Winer EP, Brahmer J, Dubey S, Smith S, Thomas C, Vahdat LT, Obel J, Vogelzang N, Markman M, Sweetenham JW, Pfister D, Kris MG, Schuchter LM, Sawaya R, Raghavan D, Ganz PA, Kramer B: Clinical cancer advances 2009: major research advances in cancer treatment, prevention, and screening - a report from the American society of clinical oncology. J Clin Oncol 2009;27:6052-6069.
6.
Petrelli A, Giordano S: From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage. Curr Med Chem 2008;15:422-432.
7.
Dreyer C, Raymond E, Faivre S: [Targeted therapies and their indications in solid neoplasias]. Rev Med Interne 2009;30:416-424.
8.
Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, Ribal MJ, Sherif A, Witjes JA: Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol 2011;59:1009-1018.
9.
Gallucci M, Merola R, Leonardo C, Ruggeri EM, Cianciulli AM: Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases. BJU Int 2005;96:440; author reply 440-441.
10.
Wright C, Mellon K, Johnston P, Lane DP, Harris AL, Horne CH, Neal DE: Expression of mutant p53, c-erbB-2 and the epidermal growth factor receptor in transitional cell carcinoma of the human urinary bladder. Br J Cancer 1991;63:967-970.
11.
Wang X, Zhang S, MacLennan GT, Eble JN, Lopez-Beltran A, Yang XJ, Pan CX, Zhou H, Montironi R, Cheng L: Epidermal growth factor receptor protein expression and gene amplification in small cell carcinoma of the urinary bladder. Clin Cancer Res 2007;13:953-957.
12.
Lipponen P, Eskelinen M: Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. Br J Cancer 1994;69:1120-1125.
13.
Khaled HM, Bahnassy AA, Raafat AA, Zekri AR, Madboul MS, Mokhtar NM: Clinical significance of altered nm23-H1, EGFR, RB and p53 expression in bilharzial bladder cancer. BMC Cancer 2009;9:32.
14.
Guo CC, Fine SW, Epstein JI: Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. Am J Surg Pathol 2006;30:883-891.
15.
Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 2001;7:1957-1962.
16.
Mellon K, Wright C, Kelly P, Horne CH, Neal DE: Long-term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 1995;153:919-925.
17.
Kramer C, Klasmeyer K, Bojar H, Schulz WA, Ackermann R, Grimm MO: Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome. Cancer 2007;109:2016-2024.
18.
Chow NH, Liu HS, Lee EI, Chang CJ, Chan SH, Cheng HL, Tzai TS, Lin JS: Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer. Anticancer Res 1997;17:1293-1296.
19.
Nutt JE, Foster PA, Mellon JK, Lunec J: hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours. Br J Cancer 2007;96:762-768.
20.
Petrylak DP, Tangen CM, Van Veldhuizen PJ Jr, Goodwin JW, Twardowski PW, Atkins JN, Kakhil SR, Lange MK, Mansukhani M, Crawford ED: Results of the Southwest oncology group phase II evaluation (study S0031) of ZD1839 for advanced transitional cell carcinoma of the urothelium. BJU Int 2010;105:317-321.
21.
Giaccone G, Gonzalez-Larriba JL, van Oosterom AT, Alfonso R, Smit EF, Martens M, Peters GJ, van der Vijgh WJ, Smith R, Averbuch S, Fandi A: Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors. Ann Oncol 2004;15:831-838.
22.
Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 1. J Clin Oncol 2004;22:777-784.
23.
Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG: Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000;6:4885-4892.
24.
World Medical Association: WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects, 2008. http://www.wma.net/en/30publications/10policies/b3/ (accessed May 7, 2013).
25.
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF: 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 2000;18:3068-3077.
26.
Sargent DJ, Goldberg RM: A flexible design for multiple armed screening trials. Stat Med 2001;20:1051-1060.
27.
Rosenberg JE, Carroll PR, Small EJ: Update on chemotherapy for advanced bladder cancer. J Urol 2005;174:14-20.
28.
Wallerand H, Bernhard JC, Culine S, Ballanger P, Robert G, Reiter RE, Ferriere JM, Ravaud A: Targeted therapies in non-muscle-invasive bladder cancer according to the signaling pathways. Urol Oncol 2011;29:4-11.
29.
Serrano C, Morales R, Suárez C, Núñez I, Valverde C, Rodón J, Humbert J, Padrós O, Carles J: Emerging therapies for urothelial cancer. Cancer Treat Rev 2012;38:311-317.
30.
Pezaro C, Liew MS, Davis ID: Urothelial cancers: using biology to improve outcomes. Expert Rev Anticancer Ther 2012;12:87-98.
31.
Dogliotti L, Carteni G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L: Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol 2007;52:134-141.
32.
Mallick JA, Ali SA, Siddiqui N, Fareed A: Impact of gemcitabine and cisplatin with radiotherapy in locally advanced or metastatic transitional cell carcinoma of urinary bladder. J Pak Med Assoc 2003;53:547-552.
33.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M: Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005;23:4602-4608.
34.
Philips GK, Halabi S, Sanford BL, Bajorin D, Small EJ: A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of cancer and leukemia group B (CALGB) 90102. Ann Oncol 2009;20:1074-1079.
35.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
36.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957.
37.
Yang JL, Qu XJ, Hayes VM, Brenner PC, Russell PJ, Goldstein D: Erlotinib (OSI-774)-induced inhibition of transitional cell carcinoma of bladder cell line growth is enhanced by interferon-alpha. BJU Int 2007;99:1539-1545.
38.
Villares GJ, Zigler M, Blehm K, Bogdan C, McConkey D, Colin D, Bar-Eli M: Targeting EGFR in bladder cancer. World J Urol 2007;25:573-579.
39.
Flaig TW, Su LJ, McCoach C, Li Y, Raben D, Varella-Garcia M, Bemis LT: Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to cisplatin in a dose- and sequence-dependent manner. BJU Int 2009;103:1729-1737.
40.
Chaux A, Cohen JS, Schultz L, Albadine R, Jadallah S, Murphy KM, Sharma R, Schoenberg MP, Netto GJ: High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues. Hum Pathol 2012;43:1590-1595.
41.
Blehm KN, Spiess PE, Bondaruk JE, Dujka ME, Villares GJ, Zhao YJ, Bogler O, Aldape KD, Grossman HB, Adam L, McConkey DJ, Czerniak BA, Dinney CP, Bar-Eli M: Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy. Clin Cancer Res 2006;12:4671-4677.
42.
Inoue R, Matsuyama H, Yano S, Yamamoto Y, Iizuka N, Naito K: Gefitinib-related gene signature in bladder cancer cells identified by a cDNA microarray. Anticancer Res 2006;26:4195-4202.
43.
Kassouf W, Dinney CP, Brown G, McConkey DJ, Diehl AJ, Bar-Eli M, Adam L: Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of gefitinib in bladder cancer cells. Cancer Res 2005;65:10524-10535.
44.
Memon AA, Sorensen BS, Meldgaard P, Fokdal L, Thykjaer T, Nexo E: The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Br J Cancer 2006;94:1703-1709.
45.
Hsu PY, Liu HS, Cheng HL, Tzai TS, Guo HR, Ho CL, Chow NH: Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. J Urol 2006;176:2262-2267.
46.
Choueiri TK, Vaishampayan UN, Yu EY, Quinn DI, Hahn NM, Hutson TE, Ross RW, Rosenberg JE, Jacobus SJ, Kantoff PW: A double-blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer. J Clin Oncol 2011;29(suppl 7):abstract LBA239.
47.
Gakis G, Efstathiou J, Lerner SP, Cookson MS, Keegan KA, Guru KA, Shipley WU, Heidenreich A, Schoenberg MP, Sagaloswky AI, Soloway MS, Stenzl A: ICUD-EAU international consultation on bladder cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2013;63:45-57.
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