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© 2002 American Society for Clinical Oncology Phase II Trial of Weekly Paclitaxel in Patients With Previously Treated Advanced Urothelial CancerByFrom the University of Pennsylvania Cancer Center, Philadelphia, PA; Northern Virginia Oncology Group, Fairfax, VA; Barbara Ann Karmanos Cancer Institute, Detroit, MI; Sidney Kimmel Cancer Center, San Diego, CA; and St Joseph Regional Cancer Center, Bryan, TX. Address reprint requests to David J. Vaughn, MD, University of Pennsylvania Cancer Center, 3400 Spruce St, 16 Penn Tower, Philadelphia, PA 19104; email: djv{at}mail.med.upenn.edu
PURPOSE: We evaluated the efficacy and toxicity of weekly paclitaxel in patients with previously treated advanced urothelial cancer. PATIENTS AND METHODS: Patients with urothelial cancer who had received one prior systemic chemotherapy regimen for advanced disease and had evidence of disease progression were eligible for enrollment. Patients received paclitaxel 80 mg/m2 by 1-hour intravenous infusion weekly. A cycle of therapy consisted of four weekly treatments. RESULTS: The study enrolled 31 patients. Mean age was 66 years, and 45% of patients had three or more involved metastatic sites. Only 26% of patients had responded to prior chemotherapy. The median number of cycles delivered was three (range, one to eight) at a mean weekly paclitaxel dose of 79 mg/m2. Three patients achieved a partial response (10%; 95% confidence interval, 0% to 20%). Median time to progression was 2.2 months, and median overall survival time was 7.2 months. Therapy was well tolerated with minimal hematologic toxicity. Grade 3 nonhematologic toxicities were also uncommon. CONCLUSION: Although the overall response rate to weekly paclitaxel in patients with previously treated advanced urothelial cancer was modest, the chemotherapy-refractory nature of the study population should be considered.
UROTHELIAL CANCER IS a chemotherapy-sensitive tumor. Platinum-based combination chemotherapy regimens have become standard first-line treatment for patients with advanced disease. Phase II trials of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) demonstrated overall response rates of 40% to 72%, with 13% to 28% of patients achieving a complete response.1-4 Phase III trials confirmed the efficacy of MVAC in patients with advanced urothelial cancer, leading to use of this regimen as a standard of care.5,6 Recently, a randomized trial of MVAC versus gemcitabine and cisplatin demonstrated that the doublet resulted in similar survival as MVAC but an improved toxicity profile.7 However, the median overall survival for patients treated with cisplatin-based combination chemotherapy remains approximately 12 to 14 months, and few patients will become long-term disease-free survivors.6-8 Because most patients with advanced bladder cancer will eventually fail first-line chemotherapy, effective salvage regimens are needed. Paclitaxel is an active agent in urothelial cancer. In an Eastern Cooperative Oncology Group phase II trial of previously untreated patients with advanced urothelial cancer, a response rate of 42% was demonstrated.9 The experience with paclitaxel as salvage therapy in advanced urothelial cancer is limited. One study administered paclitaxel at 175 to 250 mg/m2 by 24-hour infusion and reported one partial response among three patients who had progressed after prior chemotherapy for metastatic disease.10 A second study administered paclitaxel 200 mg/m2 by 3-hour infusion to 14 patients with previously treated advanced urothelial cancer, with one patient demonstrating a partial response.11 In a study of paclitaxel combined with cisplatin and methotrexate, 10 (40%) of 25 patients with refractory urothelial cancer achieved partial response.12 Recently, weekly administration schedules of paclitaxel in patients with breast cancer, ovarian cancer, lung cancer, and other solid tumors have been reported.13-19 At doses of 80 to 100 mg/m2 per week, therapy with weekly paclitaxel is well tolerated and usually without cumulative myelosuppression. However, peripheral neuropathy can be an important nonhematologic toxicity. Because paclitaxel is an active agent in urothelial cancer, and given the tolerability of weekly paclitaxel therapy in patients with various solid tumors, we conducted a phase II study to evaluate the efficacy and toxicity of weekly paclitaxel therapy in patients with previously treated advanced urothelial cancer.
Eligibility Criteria Patients 18 years of age or older with histologically confirmed bidimensionally measurable carcinoma (any histology) of the urothelium (bladder, renal pelvis, and ureter) were eligible for study. Patients had evidence of progressing regional or metastatic disease. Patients must have received one prior treatment for advanced disease, specified as a single regimen of chemotherapy. Patients may also have received prior adjuvant chemotherapy. Patients may have received prior taxane therapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and have adequate hematologic, renal, and hepatic function. All patients had a life expectancy of 3 months or longer. Patients with prior radiation to more than 30% of bone marrow and those with preexisting peripheral neuropathy of grade 2 or higher were excluded. Patients with serious cardiac disease that was not adequately controlled were excluded. All patients provided written informed consent per institutional review board guidelines
Study Design
Response and Toxicity Assessment Tumor measurements, using the same methods as for the baseline evaluation, were repeated every three cycles (12 weeks). All responses were confirmed on a second evaluation after an additional 4 weeks. Response criteria were as follows: complete response was the disappearance of all clinical and radiographic evidence of disease determined on two observations not less than 4 weeks apart and partial response was a decrease of 50% or more in the sum of products of measurable lesions confirmed on two observations not less than 4 weeks apart, along with no simultaneous increase of 25% or greater in any lesion or the appearance of any new lesion.
Statistical Methods
Patient Characteristics The study enrolled 31 patients, 26 men and five women (Table 1). The median age was 66 years, and most patients (87%) had an Eastern Cooperative Oncology Group performance status score of 0 or 1. Most patients (87%) had transitional cell histology. Most patients (94%) had bladder as the primary site. Approximately half of the patients enrolled had three or more involved metastatic sites. Visceral involvement, classified as bone, liver, or lung metastases, was present in 24 patients (77%). All patients had received one prior chemotherapy regimen for advanced urothelial cancer, with MVAC being the most common regimen given. Eight patients (26%) had a documented response to prior chemotherapy. Five patients (16%) had received prior adjuvant chemotherapy, and 13 patients (42%) had received prior radiation therapy.
Therapy Delivery and Toxicity Thirty patients received therapy (one patient who rapidly deteriorated did not get treated). The median number of cycles delivered was three (range, one to eight). The mean delivered weekly dose was 79 mg/m2. Overall, therapy was well tolerated (Table 2). Neutropenia and thrombocytopenia were mild and occurred infrequently. Anemia occurred with greater frequency, although only four patients experienced grade 3 toxicity. Neuropathy and asthenia were the predominant nonhematologic toxicities; however, toxicity was limited to grade 1 to 2 in most patients.
Tumor Response and Survival By intent-to-treat analysis, three of the 31 patients enrolled achieved a partial response, for an overall response rate of 10% (95% confidence interval, 0% to 20%). Responses occurred after a median of three cycles of therapy, and response durations were 1.8, 3, and 4 months. All three of the patients who achieved a partial response with weekly paclitaxel had either a complete or partial response to their previous chemotherapy. All had transitional cell histology. Two responders had received both adjuvant therapy and an advanced disease regimen. Two responders had previously responded to a paclitaxel-based regimen. The median time to disease progression for all patients was 2.2 months, and median overall survival time was 7.2 months.
Platinum-based regimens such as MVAC or gemcitabine/cisplatin are often effective initial treatment for patients with advanced urothelial cancer. Because most patients will develop disease progression, there is a need for effective and tolerable salvage therapy. At this time, the options for patients with previously treated urothelial cancer are limited. Although the overall response rate to weekly paclitaxel in patients with previously treated urothelial cancer was modest at 10%, it is important to consider the chemotherapy-refractory nature of the patients enrolled on this study. Only 26% of patients had achieved an objective response to their previous chemotherapy for advanced urothelial cancer. This is lower than generally expected for first-line therapy with MVAC or other platinum-based regimens. In addition, 77% of the patients enrolled had visceral sites of metastases. Studies have noted that the pretreatment prognostic factors most predictive of poor outcome in patients with advanced urothelial cancer are the presence of visceral metastases and poor performance status.8,21,22 A recently developed prognostic model suggests that the presence of visceral metastases (lung, liver, or bone) and poor performance status are independent risk factors for survival.21 If we apply these criteria to our pretreated population, seven patients had zero risk factors, 20 patients had one risk factor, and four patients had two risk factors. Of the three patients who achieved partial responses to weekly paclitaxel therapy, two had zero risk factors and one had one risk factor. In addition to these prognostic risk factors, response to prior therapy may also be informative with respect to predicting response to salvage therapy. All three of the responders had previously responded to prior chemotherapy. All of the patients who had disease progression on prior therapy also had disease progression with weekly paclitaxel. Given the small number of patients enrolled on this study, our data are insufficient to construct a prognostic risk model for salvage therapy similar to that proposed for first-line therapy. However, it seems possible that factors such as disease progression on prior therapy, presence of visceral metastases, and poor performance status may be predictive of poor response to salvage therapy. If confirmed, this information may help in the selection of patients who may benefit most from salvage therapy. In conclusion, weekly paclitaxel therapy is associated with a low response rate in previously treated patients with advanced urothelial cancer. However, this is a difficult population of patients for whom additional options are needed. Development of a validated prognostic model, including clinical criteria such as prior chemotherapy response, presence of visceral metastatic disease, and performance status, would be useful in clinical practice to determine which patients are most likely to benefit from salvage cytotoxic chemotherapy and which are best served with supportive care alone. In addition, investigation into the molecular mechanisms of drug resistance in urothelial cancer may allow future development of more effective treatments for this group of patients.
Supported by a grant from Bristol-Myers Squibb Oncology, Princeton, NJ.
1. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 133: 403-407, 1985[Medline] 2. Tannock I, Gospodarowicz M, Connolly J, et al: M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy for transitional cell carcinoma: The Princess Margaret Hospital experience. J Urol 142: 289-292, 1989[Medline] 3. Igawa M, Ohkuchi T, Ueki T, et al: Usefulness and limitations for methotrexate, vinblastine, doxorubicin, and cisplatin for the treatment of advanced urothelial cancer. J Urol 144: 662-665, 1990[Medline] 4. 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[CrossRef][Medline] 5. 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[Abstract] 6. Loehrer PJ, Einhorn LH, Elson P, 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]
7. 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, multinational, multicenter phase III trial. J Clin Oncol 18: 3068-3077, 2000
8. 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
9. 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 10. Dreicer R, Gustin DM, See WA, et al: Paclitaxel in advanced urothelial carcinoma: Its role in patients with renal insufficiency and salvage therapy. J Urol 156: 1606-1608, 1996[CrossRef][Medline] 11. Papamichael D, Gallagher CJ, Oliver RT, et al: Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. Br J Cancer 75: 606-607, 1997[Medline] 12. Tu SM, Hossan E, Amato R, et al: Paclitaxel, cisplatin, and methotrexate combination chemotherapy is active in the treatment of refractory urothelial malignancies. J Urol 154: 1719-1722, 1995[CrossRef][Medline] 13. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16: 3353-3361, 1998[Abstract] 14. Perez EA, Irwin DH, Patel R, et al: A large phase II trial of paclitaxel administered as a weekly one hour infusion in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 18: 126a, 1999 (abstr 480) 15. Breier S, Lebedinsky C, Ayiviri A, et al: Long-term weekly paclitaxel (P) in metastatic breast cancer (MBC): A phase II trial in pretreated patients (pts). Proc Am Soc Clin Oncol 17: 192a, 1998 (abstr 740) 16. Chang AY, Boros L, Asbury R, et al: Dose-escalation study of weekly 1-hour paclitaxel administration in patients with refractory cancer. Semin Oncol 24: S17-S71, 1997 (5 suppl 17)[Medline]
17. Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 15: 187-192, 1995 18. Klaassen U, Wilke H, Strumbers D, et al: Phase I study with a weekly one hour infusion of paclitaxel in patients with metastatic breast and ovarian cancer. Eur J Cancer 32A: 547-549, 1996[CrossRef][Medline] 19. Abu-Rustum NR, Aghajanian C, Barakat RR, et al: Salvage weekly paclitaxel in recurrent ovarian cancer. Semin Oncol 24: 62-67, 1997 (suppl 15) 20. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]
21. 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: 3173-3181, 1999 22. Geller NL, Sternberg CN, Penenberg D, et al: Prognostic factors for survival of patients with advanced urothelial tumors treated with methotrexate, vinblastine, and doxorubicin, and cisplatin chemotherapy. Cancer 67: 1525-1531, 1991[CrossRef][Medline] Submitted March 3, 2001; accepted October 5, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
