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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2162-2163 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.3630
Moving Forward in Advanced Bladder CancerAbramson Cancer Center, University of Pennsylvania, Philadelphia, PA In 2006, an estimated 61,420 Americans were diagnosed with bladder cancer and 13,060 died as a result of this malignancy.1 For patients with metastatic disease, chemotherapy development has reached a therapeutic plateau. Historically, the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) emerged as a standard based on randomized data demonstrating superior survival compared with single-agent cisplatin, albeit with more toxicity.2 More recently, gemcitabine plus cisplatin (GC) and high–dose intensity M-VAC (standard doses of M-VAC cycled every 2 weeks with granulocyte colony-stimulating factor support) have been prospectively compared with M-VAC, resulting in median survivals comparable with those seen with M-VAC, and with improved toxicity profiles.3,4 Presently, any of these regimens is acceptable first-line treatment for patients with metastatic bladder cancer with preserved renal function. However, the median survival for metastatic bladder cancer patients treated with cisplatin-based chemotherapy has not changed dramatically during the last two decades, and remains in the 12- to 15-month range. It is with this background that the National Cancer Institute–sponsored study reported by Hussain et al5 in this issue of the Journal of Clinical Oncology should be examined. On the basis of work demonstrating that a high proportion of primary and metastatic bladder carcinomas overexpress HER-2/neu,6 trastuzumab was combined with the three-drug regimen of paclitaxel, carboplatin, and gemcitabine (TPCG) for the first-line treatment of patients with HER-2/neu–positive metastatic urothelial cancer. During a 4.5-year enrollment period, the investigators screened 109 patients with metastatic urothelial cancer for HER-2/neu overexpression by immunohistochemistry of the primary or metastatic tumor, gene amplification, and serum HER-2/neu extracellular domain assay. They identified 57 patients who met the criteria for HER-2/neu positivity and treated 44 of these with the TPCG regimen. Hussain7 previously reported a phase II trial of the paclitaxel, carboplatin, and gemcitabine (PCG) triplet as first-line therapy for patients with advanced urothelial cancer, demonstrating a response rate of 68% and a median survival of 14.7 months. In the present trial of the triplet plus trastuzumab, the unconfirmed response rate reported was 70%, and the median survival was 14.1 months. At first glance, it appears that the addition of trastuzumab to the triplet did not significantly alter the response rate or the median survival. However, such comparison should be made with caution, given the potential for selection bias in clinical trials. In the initial PCG trial, 12% of patients had locally advanced nonmetastatic disease, whereas all patients in the TPCG trial had metastatic disease. In the TPCG trial, HER-2/neu–positive patients demonstrated an increased number of metastases compared with HER-2/neu–negative patients (two v one; P = .014), a greater probability of having two or more metastatic sites (51% v 31%; P = .051), and a trend toward more liver and bone metastases. Perhaps, then, the group treated in the TPCG trial represents a cohort of patients with an especially poor prognosis. Previously, Bajorin et al8 reported that Karnofsky performance status less than 80% and the presence of visceral sites of metastases (liver, lung, or bone) had independent poor prognostic significance for patients with advanced urothelial cancer treated with cisplatin-based chemotherapy. Patients with zero, one, and two risk factors had median survivals of 33, 13.4, and 9.3 months, respectively (P = .0001). An important message of the Bajorin study is that advanced bladder cancer trials should report the proportion of patients with zero, one, and two risk factors to allow more meaningful interpretation of the results. Does the choice of the platinum analog matter in bladder cancer? From the toxicity point of view, carboplatin certainly offers some advantages, especially in a group of patients in which a significant proportion may present with impaired renal function. Small randomized phase II trials comparing regimens that differ mainly in the choice of the platinum compound favor the cisplatin arms.9,10 Phase II trials of carboplatin plus either gemcitabine or paclitaxel doublets generally result in median survivals consistently less than those seen with the M-VAC and GC regimens. Although the evidence is indirect, cisplatin is probably the better agent. The effectiveness of the carboplatin-containing PCG triplet may be accounted for by the addition of a third cytotoxic agent. Certainly, other triplets such as gemcitabine/paclitaxel/cisplatin11 and ifosfamide/paclitaxel/cisplatin12 demonstrate survival results that compare favorably with doublet regimens. The European Organisation for Research and Treatment of Cancer (EORTC) has completed accrual to a phase III trial in which patients with previously untreated metastatic bladder cancer are randomly assigned to either GC or to the triplet GC plus paclitaxel. The results of this important trial are forthcoming. Besides HER-2/neu, what are other rational molecular targets in bladder cancer? Studies have demonstrated that more than half of bladder carcinomas overexpress the epidermal growth factor receptor (EGFR). EGFR overexpression correlates with tumor stage, progression, and survival.13 The EGFR tyrosine kinase inhibitor gefitinib was not effective as a single agent in patients with previously treated advanced bladder cancer.14 This is not surprising, given what has been learned about the importance of specific EGFR mutations in predicting sensitivity to tyrosine kinase inhibitors. Another trial, Cancer and Leukemia Group B (CALGB) 90102, combined gefitinib with GC, resulting in response rate and survival in the range seen with M-VAC or GC without a targeted agent.15 Trials combining cetuximab with chemotherapy in advanced bladder cancer are in progress. Given that both EGFR and HER-2/neu may be overexpressed in bladder cancer, dual kinase inhibitors are also being studied. Finally, trials incorporating strategies to inhibit angiogenesis in bladder cancer with anti–vascular endothelial growth factor (VEGF) agents and small molecule inhibitors of VEGF are also under way. In fact, a phase III trial of GC plus bevacizumab versus GC plus placebo for the first-line treatment of metastatic urothelial cancer has been proposed by CALGB. So where does this leave us in choosing optimal first-line treatment of advanced bladder cancer? Unlike the situation in breast cancer, where the role of targeted agents such as trastuzumab has been well defined in both the metastatic and adjuvant settings, we are still in the early stage of development of these agents in bladder cancer. Our increased understanding of the molecular basis of bladder cancer provides a compelling case for further investigation of targeted agents in this disease. The present study by Hussain et al opens the door to a new era of promising therapeutic trials for patients with advanced bladder cancer. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
1. Jemal A, Siegel R, Ward E, et al: Cancer Statistics, 2006. CA Cancer J Clin 56:106-130, 2006 2. 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[Abstract] 3. Von der Masse 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, multiinstitutional, multicenter, phase III study. J Clin Oncol 18:3068-3077, 2000 4. Sternberg CN, de Mulder PHM, Schornagel JH, et al: Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for the Research and Treatment of Cancer Protocol No. 30924. J Clin Oncol 19:2638-2646, 2001 5. Hussain MHA, MacVicar GR, Petrylak DP, et al: Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu–positive urothelial carcinoma: Results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 25:2218-2224, 2007 6. 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 7. Hussain M, Vaishampayan U, Du W, et al: Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial carcinoma. J Clin Oncol 19:2527-2533, 2001 8. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17:3173-3183, 1999 9. Bellmunt J, Ribas A, Eres N, et al: Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 80:1966-1972, 1997[CrossRef][Medline] 10. Petriolo R, Frediani B, Manganelli A, et al: Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients: A randomized phase II study. Cancer 77:344-351, 1996[CrossRef][Medline] 11. 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 Genitourinary Group. J Clin Oncol 18:3247-3255, 2000 12. 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[CrossRef][Medline] 13. Nguyen PL, Swanson PE, Jaszcz W, et al: Expression of epidermal growth factor receptor in invasive transitional cell carcinoma of the urinary bladder: A multivariate survival analysis. Am J Clin Pathol 101:166-176, 1994[Medline] 14. Petrylak D, Faulkner JR, Van Veldhuizen PJ, et al: Evaluation of ZD1839 for advanced transitional cell carcinoma (TCC) of the urothelium: A Southwest Oncology Group trial. Proc Am Soc Clin Oncol 22:403, 2003 (abstr 1619) 15. Philips G, Sanford B, Halabi S, et al: Phase II study of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial carcinoma (UC): Analysis of the second cohort of CALGB 90102. J Clin Oncol 24:236s, 2006 (suppl; abstr 4578) Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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