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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1185-1191 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.089 Weekly Paclitaxel and Gemcitabine in Advanced Transitional-Cell Carcinoma of the Urothelium: A Phase II Hoosier Oncology Group StudyFrom the Division of Hematology/Oncology and Biostatistics, Indiana University School of Medicine; the Hoosier Oncology Group and Walter Cancer Institute, Indianapolis; Michiana Hematology and Oncology, South Bend; and Oncology Hematology Associates of Southwest Indiana, Evansville, IN Address reprint requests to Christopher J. Sweeney, MBBS, Indiana University, 535 Barnhill Dr, Rm 473, Indianapolis, IN 46202; e-mail: chsweene{at}iupui.edu
PURPOSE: To evaluate the efficacy and toxicity of weekly paclitaxel and gemcitabine in patients with advanced transitional-cell carcinoma (TCC) of the urothelial tract. PATIENTS AND METHODS: Patients with advanced unresectable TCC were enrolled onto this multicenter, community-based, phase II trial. Initially, patients were treated with paclitaxel 110 mg/m2 and gemcitabine 1,000 mg/m2 by intravenous infusion on days 1, 8, and 15 every 28 days. Patients who had an objective response or stable disease continued treatment for a maximum of six courses. Paclitaxel was decreased to 90 mg/m2 and gemcitabine was decreased to 800 mg/m2 for the last 12 patients because of a concerning incidence of pulmonary toxicity in the first 24 patients. RESULTS: Thirty-six patients were enrolled between September 1998 and March 2003. Twenty-four patients received the higher doses of paclitaxel and gemcitabine, and 12 patients received the lower doses. Twenty-five (69.4%) of 36 patients had major responses to treatment, including 15 patients (41.7%) with complete responses. With a median follow-up time of 38.7 months, the median survival time was 15.8 months. Grade 3 and 4 toxicities included granulocytopenia (36.1%), thrombocytopenia (8.3%), and neuropathy (16.7%). Five patients (13.9%) had grades 3 to 5 pulmonary toxicity, and one patient had grade 2 pulmonary toxicity. CONCLUSION: Weekly paclitaxel and gemcitabine is an active regimen in the treatment of patients with advanced TCC. However, because of the high incidence of pulmonary toxicity associated with this schedule of paclitaxel and gemcitabine, we recommend against the use of this regimen in this patient population.
Bladder cancer is the fourth most common cancer in men and the ninth most common cancer in women. In the United States, there are approximately 57,000 new cases of bladder cancer per year, with over 12,000 patients succumbing to this disease.1 The most frequent histologic type is transitional-cell carcinoma (TCC). Although most patients have localized disease at diagnosis and are cured with definitive local therapies, the prognosis of patients with metastatic TCC of the urothelial tract is poor. With the advent of platinum-based combination chemotherapy, a median survival of approximately 12 months,2 with approximately 3.7% long-term survivors,3 was observed with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Compared with cisplatin alone, the median survival of patients who received MVAC was 8.2 months, with 1.6% long-term survivors.3 In another randomized study, MVAC was also shown to be superior to a combination of cisplatin, cyclophosphamide, and doxorubicin, with higher response rates and longer survivals.4 However, treatment with MVAC is associated with substantial toxicity, including myelosuppression, mucositis, nephrotoxicity, and neuropathy. Therapy-related mortality rates range from 2% to 4%.2,5 A phase III study compared MVAC to cisplatin plus gemcitabine, and there was a similar degree of efficacy.6 The toxicity profiles of the regimens were different, with gemcitabine-cisplatin producing more grades 3 and 4 anemia than MVAC (27% v 18%, respectively) and more grades 3 and 4 thrombocytopenia (57% v 21%, respectively). However, more MVAC-treated patients, compared with patients treated with gemcitabine-cisplatin, experienced grades 3 and 4 granulocytopenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), and mucositis (22% v 1%, respectively), and MVAC-treated patients also had more hospital admissions. The incidence of clinically significant nausea and vomiting was similar. Thus, cisplatin toxicities are still problematic, and cisplatin is not feasible for patients who are frail, have renal insufficiency, and/or have other significant comorbidities. Therefore, the development of more active and less toxic treatment for advanced TCC is necessary. Gemcitabine, an analog of cytarabine, is a pyrimidine antimetabolite. Single-agent gemcitabine has demonstrated an overall response rate of approximately 25%, including some complete responses (CR), with minimal toxicity in patients with advanced bladder cancer.7 Paclitaxel is a mitotic spindle poison that promotes microtubular aggregation and interferes with essential cellular functions such as mitosis cell transport and cell motility. Single-agent paclitaxel was shown to have an overall response rate of 42% and a CR rate of 27% in previously untreated bladder cancer, making it one of the most active single agents in this disease.8 The majority of clinical experience with paclitaxel has been obtained using a once every 3 weeks dosing schedule, but weekly paclitaxel has also been explored. Previous investigators conducted a phase I dose-escalation trial evaluating weekly paclitaxel with gemcitabine in patients with refractory solid tumors.9 The recommended phase II dose was paclitaxel 110 mg/m2 and gemcitabine 1,000 mg/m2. Given the fact that both paclitaxel and gemcitabine have single-agent activity in advanced TCC of the bladder, this phase II study was performed to evaluate the efficacy and toxicity of this combination in this patient population.
Patients Patient eligibility criteria included histologically confirmed TCC of the urothelial tract, which was either metastatic or unresectable. Patients were required to have clinically measurable disease and be at least 3 weeks from major surgery or radiotherapy and have recovered from all toxicity. Patients were allowed to have received either adjuvant or neoadjuvant chemotherapy provided that the patient experienced a disease-free interval of at least 6 months. No prior therapy for metastatic disease was permitted. All patients were required to have a Karnofsky performance score of 80 to 100, and organ function criteria included an absolute neutrophil count (ANC) of greater than 1.5 x 109/L, a platelet count of greater than 100 x 109/L, a hemoglobin level of greater than 9 gm/dL, a serum creatinine of less than 1.5 mg/dL, transaminase levels less than 2.0 x normal, and a serum total bilirubin of less than 1.5 mg/dL. Patients with evidence of squamous cell or adenocarcinoma histology with or without concomitant transitional-cell histology were excluded from study. Additional exclusion criteria were pregnancy, severe congestive heart failure, and prior malignancy within 5 years. All patients gave written informed consent before entering onto this clinical trial. This study was approved by the Institutional Review Board at Indiana University and the review boards of all other participating sites. The study was conducted by the Hoosier Oncology Group.
Dosage and Administration
Evaluation of Response
Statistical Methods The second objective of this study was to determine safety of the proposed drug combination in this patient population. Therefore, toxicity was continuously monitored, and an early stopping rule was established if there was an excess of treatment-related deaths or any grade 4 drug-related nonhematologic toxicities. The study was to be stopped if more than four of 10, six of 20, or nine of 30 patients experienced such toxicities. With this design, if the true toxicity rate was 20%, then the chance of early termination would be less than 12%. Conversely, if the toxicity rate was 40% or higher, then the probability of early termination would be 87%. All survival analyses were performed using the Kaplan-Meier method. Comparison of response between visceral and locoregional disease was performed using Fisher's exact test, and all confidence intervals were determined by exact methods.
Patient Characteristics Between September 1998 and March 2003, 36 patients entered onto this phase II trial. The clinical characteristics of all patients are listed in Table 1. Patient age ranged from 36 to 79 years (median age, 64.5 years). Twenty-three patients (63.9%) were male, and 13 (36.1%) were female. Five patients had prior adjuvant chemotherapy, which included carboplatin and paclitaxel for one patient, MVAC for two patients, cisplatin, methotrexate, and vinblastine for one patient, and doxorubicin with cyclophosphamide for one patient. Fifteen patients had prior cystectomy. Twenty-one patients (58.3%) had visceral (bone, liver, or lung) metastases, and the remaining 15 patients (41.7%) had locoregional disease and/or disease confined to the lymph nodes. Median Karnofsky performance score was 90% (range, 80% to 100%).
Treatment Administered Thirty-three patients (92%) received at least two courses of treatment. Of the three patients who received less than two cycles of chemotherapy, two had rapid tumor progression, and one had severe toxicity. These three patients were included in the denominator for calculation of response rates. Patients received a median of five cycles (range, one to six cycles), with 17 patients (47.2%) receiving six cycles of therapy. The first 24 patients treated on study received a paclitaxel dose of 110 mg/m2 and a gemcitabine dose of 1,000 mg/m2 on days 1, 8, and 15 every 28 days. However, because of significant pulmonary toxicities observed in three patients, the study was amended (approved by the institutional review boards), and the paclitaxel dose was reduced to 90 mg/m2, and the gemcitabine dose was reduced to 800 mg/m2 for the remaining 12 patients. The dose modification was empirical. It was first noted that this patient population was older than those patients in the relapsed testicular cancer population10 who received the same regimen but did not experience pulmonary toxicity. Therefore, it was hypothesized that this population had a slower clearance of both chemotherapeutic agents, as has been described previously.11,12 Consequently it was postulated that a lower dose would lessen drug exposure and prevent the pulmonary toxicity. Furthermore, the significant activity observed before the dose reduction encouraged further exploration of this schedule, and it was thought that the lower dose would maintain the activity with less toxicity. A total of twenty-six patients (72.2%) had at least one dose reduction during treatment, and fifteen patients (41.7%) had a delay in treatment because of toxicity.
Tumor Response
Survival
Adverse Events Table 2 lists the common toxicities observed during this study. As expected, the most common grade 3 and 4 toxicities were hematologic, with a 36.1% incidence of grade 3 to 4 granulocytopenia and 8.3% incidence of grade 3 to 4 thrombocytopenia. There were no cases of neutropenic fever. Grade 3 to 4 neuropathy occurred in 16.7% of the patients. In addition, six patients developed significant pulmonary toxicities, with four patients experiencing toxicity before the amendment with the dose reduction. There were two grade 5, two grade 4, one grade 3, and one grade 2 pulmonary toxicity. Three of these patients had a clinical presentation similar to adult respiratory distress syndrome (ARDS), as manifested by acute dyspnea, hypoxemia, and diffuse bilateral pulmonary infiltrates; and the ARDS experienced by two of these patients occurred without an identifiable cause. These two patients had full recovery after discontinuation of the treatment. No mechanical ventilation was required during the acute phase. The other patient had ARDS associated with sepsis without neutropenia and died. There was one more patient who developed nonspecific pulmonary infiltrates with mild dyspnea (grade 2 pulmonary toxicity) that resulted in cessation of therapy after five cycles. Two of these six events occurred after the dose reduction of paclitaxel and gemcitabine. One patient had grade 3 dyspnea and noncardiogenic pulmonary edema that responded to high-dose dexamethasone and fully recovered. Another patient developed progressive pulmonary fibrosis and died. Those pulmonary toxicities are listed in Table 3. It did not appear that the pulmonary toxicity was associated with prior chemotherapy because none of the five patients who received adjuvant chemotherapy developed such toxicity.
Despite significant progress with combination chemotherapy, advanced urothelial carcinoma remains a fatal disease for the vast majority of patients with metastatic disease. MVAC became the standard of care on the basis of randomized studies demonstrating a survival advantage compared with single-agent cisplatin and the combination of cyclophosphamide, doxorubicin, and cisplatin.2,4 However, the CR rate in multicenter trials has been low, and less than 5% of patients remain disease free after 5 years.2-5 In addition, the MVAC regimen has substantial toxicity and is not feasible in patients with compromised renal function as a result of the inclusion of cisplatin and methotrexate. Therefore, regimens with better efficacy and reduced toxicity are needed. In this phase II study, we report the efficacy and toxicity of a combination of weekly paclitaxel and gemcitabine in the treatment of advanced urothelial cancer. An overall response rate of 69.4% was observed, with a CR rate of 41.7%. The response rate in patients with regional disease or metastases in lymph nodes was higher than the response rate in patients with visceral metastasis (93.3% and 52.4%, respectively). With a median follow-up time of 38.7 months, the median survival time was 15.8 months. Consistent with previous reports, patients with visceral metastasis fared worse, with a median survival of 9.8 months, compared with a median survival of 20.0 months for patients with locoregional or lymph node only disease.13 The most frequent toxicity associated with this weekly paclitaxel and gemcitabine regimen was myelosuppression, which was easily managed and not associated with the clinically significant event of neutropenic fevers. Of greater concern was the fact that five patients developed grade 3 to 5 pulmonary toxicities. Serious and even fatal pulmonary toxicity from treatment with gemcitabine has been previously reported.14-17 Patients usually present with a clinical picture consistent with acute respiratory distress syndrome with hypoxemia, pulmonary infiltrates, and no evidence of left ventricular failure. The incidence of serious pulmonary toxicity associated with gemcitabine-based therapy has been reported through a retrospective review from two Eli Lilly databases (Indianapolis, IN).18 On the basis of an estimated 217,400 patients treated with commercial gemcitabine worldwide, the crude incidences of dyspnea and other severe pulmonary toxicity were 0.02% and 0.06%, respectively. The authors concluded that severe pulmonary toxicity associated with gemcitabine was uncommon. Both interstitial and parenchymal pulmonary toxicity have also been reported in association with paclitaxel.19,20 It is unclear whether the high incidence of pulmonary toxicity in this study was specifically associated with the weekly dosing regimen or the combination of paclitaxel and gemcitabine in this older patient population. It is of note that this toxicity was not observed with this same dosing regimen in a study of patients with refractory testicular cancer.10 However, in another Hoosier Oncology Group study of this dosing regimen of paclitaxel and gemcitabine in patients with non–small-cell lung cancer, pulmonary toxicity was observed in four of 42 patients, including one treatment-related death.21 The cause of the apparent increase in pulmonary toxicity is unknown, but interestingly, it was reported in a gemcitabine and paclitaxel pharmacokinetic study using a similar regimen that paclitaxel increased the accumulation of gemcitabine triphosphate, the active metabolite of gemcitabine.22 In this pharmacokinetic study, paclitaxel was administered over 3 hours. Early administration of corticosteroids may be of clinical benefit in patients treated with paclitaxel plus gemcitabine with new and unexplained pulmonary infiltrates. The benefit of corticosteroids for gemcitabine-associated pulmonary toxicity has been previously reported.23 Paclitaxel and gemcitabine have been combined in other schedules and also evaluated in phase II trials for the treatment of advanced bladder cancer (Table 4). 24-28 None of these other regimens had paclitaxel and gemcitabine administered together on days 1, 8, and 15 every 28 days. These two agents have also been used in combination with platinums as triplets in advanced urothelial cancer. It is difficult to compare across separate studies, but there seemed to be a higher incidence of pulmonary toxicity in our study, as well as higher CR and overall response rates.
In summary, the regimen of weekly paclitaxel and gemcitabine administered together on days 1, 8, and 15 every 28 days has significant activity. However, the apparent benefit of substituting cisplatin and avoiding its associated nausea, vomiting, and nephrotoxicity is offset by the significant pulmonary toxicity observed with this dosing schedule in this patient population. Because of the high incidence of pulmonary toxicity associated with this regimen, we recommend against the use of this regimen in this patient population.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Lawrence H. Einhorn, Bristol-Myers Squibb. Honoraria: Christopher J. Sweeney, Eli Lilly. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Supported by grant No. B9E-MC-X185 from Eli Lilly and Co, Indianapolis, IN. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003 2. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 10:1066-1073, 1992[Abstract]
3. 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 4. 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] 5. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelial: Efficacy and patterns of response and relapse. Cancer 64:2448-2458, 1989[CrossRef][Medline]
6. von der Maase VDH, 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
7. Stadler W, Kuzel T, Roth BJ, et al: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15:3394-3398, 1997
8. 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. J Clin Oncol 12:2264-2270, 1994 9. Einhorn LH, Raghaven D, Kindler H, et al: A phase I trial of gemcitabine plus paclitaxel combination therapy in patients with refractory solid tumors. Proc Am Soc Clin Oncol 17:207a, 1998 (abstr 796)
10. Hinton SW, Catalano P, Einhorn LH, et al: Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E 9897): A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 20:1859-1863, 2002 11. Smorenburg CH, ten Tije AJ, Verweij J, et al: Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer. Eur J Cancer 39:196-202, 2003 12. Lichtman SM, Villani G: Chemotherapy in the elderly: Pharmacologic considerations. Cancer Control 7:548-556, 2000[Medline]
13. 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 14. Pavlakis N, Bell DR, Millward MJ, et al: Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 80:286-291, 1997[CrossRef][Medline] 15. Marruchella A, Fiiorenzano G, Merrizzi A, et al: Diffuse alveolar damage in a patient treated with gemcitabine. Eur Respir J 11:504-506, 1998[Abstract] 16. Temporo MA, Brand R: Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 82:1800-1801, 1998[Medline] 17. Heilborn AS, Kath R, Schneider CP, et al: Severe non-hematological toxicity after treatment with gemcitabine. J Cancer Res Clin Oncol 125:637-640, 1999[CrossRef][Medline] 18. Roychowdhury DF, Cassidy CA, Peterson P, et al: A report on serious pulmonary toxicity associated with gemcitabine-based therapy. Invest New Drugs 20:311-315, 2002[CrossRef][Medline]
19. Ramanathan RK, Reddy VV, Holbert JM, et al: Pulmonary infiltrates following administration of paclitaxel. Chest 110:289-292, 1996
20. Ayoub JP, North L, Greer J, et al: Pulmonary changes in patients with lymphoma who receive paclitaxel. J Clin Oncol 15:2476, 1997 21. Bhatia S, Hanna N, Ansari R, et al: A phase II study of weekly gemcitabine and paclitaxel in patients with previously untreated stage IIIb and IV non small cell lung cancer. Lung Cancer 38:73-77, 2002[CrossRef][Medline] 22. Shord SS, Faucette SR, Gillenwater HH, et al: Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 51:328-336, 2003[Medline]
23. Vander Els NJ, Miller V: Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 114:1779-1781, 1998 24. 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[CrossRef][Medline]
25. Meluch AA, Greco AG, Burris HA, 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 26. Kaufman D, Stadler W, Carducci M, et al: Gemcitabine and paclitaxel every two weeks: A multicenter phase II trial in locally advanced or metastatic urothelial cancer. Proc Am Soc Clin Oncol 19:341a, 2000 (abstr 1341)
27. 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
28. 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 Submitted May 17, 2004; accepted November 8, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
grade 2 after the dose reduction, the doses for the next cycle were increased to 75% of the original doses. Any patient with ANC 
1.5 x 109/L and/or platelets 
