Weekly Paclitaxel and Gemcitabine in Advanced Transitional-Cell Carcinoma of the Urothelium: A Phase II Hoosier Oncology Group Study
http://www.100md.com
《临床肿瘤学》
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
Oncology Hematology Associates of Southwest Indiana, Evansville, IN
ABSTRACT
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.
INTRODUCTION
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 AND METHODS
Dosage and Administration
Paclitaxel 110 mg/m2 was administered intravenously over 1 hour on days 1, 8, and 15 of each 28-day cycle. Gemcitabine 1,000 mg/m2 was administered intravenously for 30 minutes on days 1, 8, and 15 of each 28-day cycle (after paclitaxel). All patients received dexamethasone 20 mg orally or intravenously, diphenhydramine 50 mg intravenously, and cimetidine 300 mg or ranitidine 50 mg intravenously, 30 to 60 minutes before paclitaxel. Therapy was continued for at least two courses unless there was disease progression or dose-limiting toxicity. The paclitaxel and gemcitabine doses were reduced to 90 and 800 mg/m2, respectively, for the last 12 patients after significant pulmonary toxicity was observed. All patients received the full dose of both drugs on the first day of treatment. Subsequent dose modifications were based on hematologic and nonhematologic toxicity. On days 8 and 15 of each cycle, full-dose paclitaxel and gemcitabine were administered if the patient had an ANC of more than 1.5 x 109/L and a platelet count of more than 75 x 109/L. For patients with an ANC of 1.0 to 1.49 x 109/L or a platelet count of 50 to 74.9 x 109/L, paclitaxel and gemcitabine were reduced by 25%. For patients with an ANC of 0.5 to 0.99 x 109/L or a platelet count of 25 to 49.9 x 109/L, a 50% dose reduction of paclitaxel and gemcitabine was instituted, and for patients with an ANC of less than 0.5 x 109/L or a platelet count of less than 25 x 109/L, the paclitaxel and gemcitabine doses were omitted. On the first day of each course, full doses of both drugs were administered if the ANC was more than 1.5 x 109/L and the platelet count was more than 75 x 109/L. If counts were below these levels, treatment was delayed for 1 week and then administered at full doses if the counts had increased to an ANC of more than 1.5 x 109/L and a platelet count of more than 75 x 109/L. The administration of a new cycle could have been delayed up to 2 weeks to allow sufficient time for recovery. Any patient with neutropenic fever, grade 4 granulocytopenia (ANC < 0.5 x 109/L) for over 5 days, or grade 4 thrombocytopenia received a 25% dose reduction of both agents with all subsequent cycles of treatment. Patients who developed reversible grade 3 to 4 nonhematologic toxicity had treatment held for 1 week or until the toxicity improved to less than grade 2, and then these patients received 50% of the dose of the offending agent(s). If there was no toxicity ≥ 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 ≤ 75 x 109/L after a 2-week delay or grade 2 or worse nonhematologic toxicity that persisted beyond 2 weeks was removed from the study. Dose escalation was not permitted.
Evaluation of Response
Disease re-evaluation was performed every two cycles. Patients who responded to therapy or had stable disease remained on study until progression or a maximum of six cycles of therapy was administered. CR was defined as the complete disappearance of all objective evidence of disease for at least 1 month, and partial response (PR) was defined as a decrease of 50% or more in the sum of products of diameters of measurable lesions for at least 1 month. Stable disease was defined as a decrease of less than 50% or increase of less than 25% in the sum of the products of diameters of measurable lesions with no new lesions during study, and progressive disease was defined as an increase of greater than 25% in the sum of the products of diameters of measurable lesions or appearance of new lesions during the study period. Patients were observed for survival and disease progression every 2 months for the first year, every 4 months for the second year, every 6 months for the third and fourth years, and yearly thereafter until death.
Statistical Methods
The primary objective of this study was to determine the efficacy of combining gemcitabine and paclitaxel. Specifically, a response rate of 15% was to be considered low, whereas a response rate of 35% or higher would be considered worthy of further evaluation. Patient enrollment followed a two-stage sequential design. If two or fewer responses were observed among the initial 16 qualified patients, further accrual was to be halted. If three or more responses were observed, 20 more patients were to be enrolled. With this design, if the true response rate was 35% or higher, then the chance of terminating the trial early was less than 5% and the overall chance of rejecting the treatment was only 9.7%. However, if the response rate was 15% or lower, then the probability of early rejection was greater than 56% and the overall probability of rejection was more than 93%. This design yielded a power of 90.3 and a type I error of 7.3%.
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.
RESULTS
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
All of the 36 patients enrolled were evaluated for response. Fifteen patients (41.7%; 95% CI, 25.5% to 59.2%) had a CR, and 10 patients (27.8%; 95% CI, 14.2% to 45.2%) had a PR, with an overall response rate of 69.4% (92.7% CI, 53.3% to 82.7%). An additional four patients had stable disease. Of those who responded, the median duration of response was 5.3 months (95% CI, 3.9 to 9.3 months), with a median time to response of 1.9 months (95% CI, 1.7 to 3.1 months) and a median time to progression of 7.6 months (95% CI, 5.7 to 11.6 months). The response rate was higher (P = .01) for the 15 patients with locoregional or lymph node disease (93.3%; 95% CI, 68.1% to 99.8%) than for patients with visceral metastases (52.4%; 95% CI, 29.8% to 74.3%). Of the five patients who had prior adjuvant therapy, three patients had CRs, and two had PRs.
Survival
With a median follow-up time of 38.7 months (95% CI, 18.8 to 41.7 months), the median survival time was 15.8 months (95% CI, 9.4 to 22.5 months). Figure 1 illustrates the overall survival. Median survival was 9.8 months (95% CI, 5.2 to 16.1 months) for patients with visceral metastasis and 20.0 months (95% CI, 12.8 to 37.1 months) for patients with nonvisceral disease.
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.
DISCUSSION
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.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
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.
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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
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
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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
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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
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
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
16. Temporo MA, Brand R: Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 82:1800-1801, 1998
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
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
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
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
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
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(Jinxing Li, Beth Juliar, )
the Hoosier Oncology Group and Walter Cancer Institute, Indianapolis
Michiana Hematology and Oncology, South Bend
Oncology Hematology Associates of Southwest Indiana, Evansville, IN
ABSTRACT
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.
INTRODUCTION
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 AND METHODS
Dosage and Administration
Paclitaxel 110 mg/m2 was administered intravenously over 1 hour on days 1, 8, and 15 of each 28-day cycle. Gemcitabine 1,000 mg/m2 was administered intravenously for 30 minutes on days 1, 8, and 15 of each 28-day cycle (after paclitaxel). All patients received dexamethasone 20 mg orally or intravenously, diphenhydramine 50 mg intravenously, and cimetidine 300 mg or ranitidine 50 mg intravenously, 30 to 60 minutes before paclitaxel. Therapy was continued for at least two courses unless there was disease progression or dose-limiting toxicity. The paclitaxel and gemcitabine doses were reduced to 90 and 800 mg/m2, respectively, for the last 12 patients after significant pulmonary toxicity was observed. All patients received the full dose of both drugs on the first day of treatment. Subsequent dose modifications were based on hematologic and nonhematologic toxicity. On days 8 and 15 of each cycle, full-dose paclitaxel and gemcitabine were administered if the patient had an ANC of more than 1.5 x 109/L and a platelet count of more than 75 x 109/L. For patients with an ANC of 1.0 to 1.49 x 109/L or a platelet count of 50 to 74.9 x 109/L, paclitaxel and gemcitabine were reduced by 25%. For patients with an ANC of 0.5 to 0.99 x 109/L or a platelet count of 25 to 49.9 x 109/L, a 50% dose reduction of paclitaxel and gemcitabine was instituted, and for patients with an ANC of less than 0.5 x 109/L or a platelet count of less than 25 x 109/L, the paclitaxel and gemcitabine doses were omitted. On the first day of each course, full doses of both drugs were administered if the ANC was more than 1.5 x 109/L and the platelet count was more than 75 x 109/L. If counts were below these levels, treatment was delayed for 1 week and then administered at full doses if the counts had increased to an ANC of more than 1.5 x 109/L and a platelet count of more than 75 x 109/L. The administration of a new cycle could have been delayed up to 2 weeks to allow sufficient time for recovery. Any patient with neutropenic fever, grade 4 granulocytopenia (ANC < 0.5 x 109/L) for over 5 days, or grade 4 thrombocytopenia received a 25% dose reduction of both agents with all subsequent cycles of treatment. Patients who developed reversible grade 3 to 4 nonhematologic toxicity had treatment held for 1 week or until the toxicity improved to less than grade 2, and then these patients received 50% of the dose of the offending agent(s). If there was no toxicity ≥ 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 ≤ 75 x 109/L after a 2-week delay or grade 2 or worse nonhematologic toxicity that persisted beyond 2 weeks was removed from the study. Dose escalation was not permitted.
Evaluation of Response
Disease re-evaluation was performed every two cycles. Patients who responded to therapy or had stable disease remained on study until progression or a maximum of six cycles of therapy was administered. CR was defined as the complete disappearance of all objective evidence of disease for at least 1 month, and partial response (PR) was defined as a decrease of 50% or more in the sum of products of diameters of measurable lesions for at least 1 month. Stable disease was defined as a decrease of less than 50% or increase of less than 25% in the sum of the products of diameters of measurable lesions with no new lesions during study, and progressive disease was defined as an increase of greater than 25% in the sum of the products of diameters of measurable lesions or appearance of new lesions during the study period. Patients were observed for survival and disease progression every 2 months for the first year, every 4 months for the second year, every 6 months for the third and fourth years, and yearly thereafter until death.
Statistical Methods
The primary objective of this study was to determine the efficacy of combining gemcitabine and paclitaxel. Specifically, a response rate of 15% was to be considered low, whereas a response rate of 35% or higher would be considered worthy of further evaluation. Patient enrollment followed a two-stage sequential design. If two or fewer responses were observed among the initial 16 qualified patients, further accrual was to be halted. If three or more responses were observed, 20 more patients were to be enrolled. With this design, if the true response rate was 35% or higher, then the chance of terminating the trial early was less than 5% and the overall chance of rejecting the treatment was only 9.7%. However, if the response rate was 15% or lower, then the probability of early rejection was greater than 56% and the overall probability of rejection was more than 93%. This design yielded a power of 90.3 and a type I error of 7.3%.
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.
RESULTS
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
All of the 36 patients enrolled were evaluated for response. Fifteen patients (41.7%; 95% CI, 25.5% to 59.2%) had a CR, and 10 patients (27.8%; 95% CI, 14.2% to 45.2%) had a PR, with an overall response rate of 69.4% (92.7% CI, 53.3% to 82.7%). An additional four patients had stable disease. Of those who responded, the median duration of response was 5.3 months (95% CI, 3.9 to 9.3 months), with a median time to response of 1.9 months (95% CI, 1.7 to 3.1 months) and a median time to progression of 7.6 months (95% CI, 5.7 to 11.6 months). The response rate was higher (P = .01) for the 15 patients with locoregional or lymph node disease (93.3%; 95% CI, 68.1% to 99.8%) than for patients with visceral metastases (52.4%; 95% CI, 29.8% to 74.3%). Of the five patients who had prior adjuvant therapy, three patients had CRs, and two had PRs.
Survival
With a median follow-up time of 38.7 months (95% CI, 18.8 to 41.7 months), the median survival time was 15.8 months (95% CI, 9.4 to 22.5 months). Figure 1 illustrates the overall survival. Median survival was 9.8 months (95% CI, 5.2 to 16.1 months) for patients with visceral metastasis and 20.0 months (95% CI, 12.8 to 37.1 months) for patients with nonvisceral disease.
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.
DISCUSSION
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.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
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.
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