Paclitaxel, Carboplatin, and Gemcitabine in the Treatment of Patients with Advanced Transitional Cell Carcinoma of the Urothelium

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1 2298 Paclitaxel, Carboplatin, and Gemcitabine in the Treatment of Patients with Advanced Transitional Cell Carcinoma of the Urothelium A Phase II Trial of the Minnie Pearl Cancer Research Network John D. Hainsworth, M.D. 1 Anthony A. Meluch, M.D. 1 Sharlene Litchy, R.N., M.S.N., C.R.A. 1 Frederick M. Schnell, M.D. 2 James D. Bearden,M.D. 3 Kathleen Yost, M.D. 4 F. Anthony Greco, M.D. 1 1 Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, Tennessee. 2 Central Georgia Hematology and Oncology Associates, Macon, Georgia. 3 Upstate Carolina Community Clinical Oncology Program, Spartanburg, South Carolina. 4 Grand Rapids Community Clinical Oncology Program, Grand Rapids, Michigan. Supported in part by grants from Eli Lilly, Inc.; Bristol-Myers Squibb; and The Minnie Pearl Foundation. Minnie Pearl Cancer Research Network participating sites included the following: Tennessee Oncology, PLLC (Nashville, TN), Central Georgia Hematology and Oncology (Macon, GA), Upstate Carolina Community Clinical Oncology Program (Spartanburg, SC), Grand Rapids Community Clinical Oncology Program (Grand Rapids, MI), Atlanta Cancer Care (Atlanta, GA), Northwest Georgia Oncology Centers (Marietta, GA), Consultants in Blood Disorders and Cancer (Louisville, KY), Earl A. Chiles Research Institute (Portland, OR), Terrebonne General Medical Center (Houma, LA), The Hematology and Oncology Clinic (Hattiesburg, MS), Thompson Oncology Group (Knoxville, TN), South Texas Hematology and Oncology (San Antonio, TX), Kingsport Hematology and Oncology Associates (Kingsport, TN), Medical Consultants (Milwaukee, WI), and Louisiana Oncology (Lafayette, LA). Address for reprints: John D. Hainsworth, M.D., The Sarah Cannon Research Institute, th Avenue North, Suite 110, Nashville, TN 37203; Fax: (615) ; jhainsworth@tnonc.com Received September 1, 2004; revision received January 4, 2005; accepted February 2, BACKGROUND. The objective of the current study was to evaluate the efficacy and toxicity of combination chemotherapy with paclitaxel, carboplatin, and gemcitabine in patients with advanced urothelial carcinoma. METHODS. Patients with metastatic or locally unresectable transitional cell carcinoma of the urothelium who had received either no or one previous systemic chemotherapy regimen were eligible. All patients received chemotherapy with intravenous paclitaxel at a dose of 200 mg/m 2 on Day 1, intravenous carboplatin at an area under the serum concentration-time curve of 5.0 on Day 1, and intravenous gemcitabine at a dose of 1000 mg/m 2 on Days 1 and 8. Treatment courses were repeated every 21 days. Patients were evaluated for response after they completed two treatment courses; patients who achieved an objective response and stable disease continued treatment for a total of six courses or until tumor progression. RESULTS. Sixty patients were treated between January 2000 and September Thirty-five patients (58%) had 1 visceral sites of metastases, and only 4 patients (7%) had received any previous systemic chemotherapy. Twenty-six patients (43%) had achieved objective responses to treatment (12% complete responses). The median actuarial survival was 11 months, and the actuarial 1-year and 2-year survival rates were 46% and 27%, respectively. Myelosuppression was the most frequent toxicity, and Grade 3 4 neutropenia (using the National Cancer Institute Common Toxicity Criteria [version 2.0]) occurred in 72% of patients (46% of courses). Ten patients were hospitalized for the treatment of neutropenia and fever, and 1 patient died of treatment-related causes. Nonhematologic toxicities were relatively uncommon. CONCLUSIONS. The combination of paclitaxel, carboplatin, and gemcitabine was an active and tolerable regimen for patients with advanced urothelial carcinoma. However, the regimen was more toxic and showed no obvious incremental increase in efficacy compared retrospectively with various two-drug regimens. Cancer 2005;103: American Cancer Society. KEYWORDS: response, toxicity, transitional cell carcinoma, treatment efficacy, urothelial carcinoma, gemcitabine, paclitaxel, carboplatin. Advanced transitional cell carcinoma of the urothelium is moderately sensitive to chemotherapy, and there are a number of agents that produce response rates in the 10 40% range. 1 However, the prognosis of patients with metastatic transitional cell carcinoma remains poor, with a median survival of only months. 2 5 The methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen has been considered a standard treatment for transitional cell carcinoma since its initial development, producing response rates of 40 72% with occasional long-term complete responses. 2 4 However, 2005 American Cancer Society DOI /cncr Published online 26 April 2005 in Wiley InterScience (

2 Chemotherapy for Advanced Bladder Ca/Hainsworth et al the MVAC regimen is relatively toxic, and it is difficult to administer to elderly patients and to patients who have a poor performance status. During recent years, several newer chemotherapeutic agents, including paclitaxel, docetaxel, and gemcitabine, have demonstrated substantial singleagent activity in the treatment of advanced transitional cell carcinoma. 7 9 A number of Phase II trials combining these new drugs either with a platinum agent or with each other as doublets have shown substantial activity. 5,6,10 13 In a randomized Phase III trial, the combination of gemcitabine plus cisplatin was similar in efficacy to MVAC but had less toxicity. 5 We previously conducted a Phase II trial using the combination of paclitaxel plus gemcitabine in patients with advanced transitional cell carcinoma. 13 In that experience, a 54% response rate and a median survival of 14.4 months was achieved in a group of 54 patients. In this subsequent Phase II trial, we added carboplatin to the paclitaxel/gemcitabine regimen in an attempt to increase efficacy. In this article, we detail the results of treatment with paclitaxel, carboplatin, and gemcitabine in patients with advanced transitional cell carcinoma. MATERIALS AND METHODS This Phase II trial was initiated in January 2000, and was performed in the Minnie Pearl Cancer Research Network, which is a multicenter, community-based collaborative clinical trials group. Eligibility Patients who were eligible for this trial were required to have histologically confirmed transitional cell carcinoma of the urothelial tract (bladder, ureter, or renal pelvis) that was either metastatic or locally advanced and unresectable. Patients with locally advanced, unresectable bladder carcinoma who had any possibility of curative therapy with combined-modality treatment were excluded from this trial. All patients were required to have measurable disease. Patients were allowed to have received a maximum of one previous systemic chemotherapy regimen for the treatment of bladder carcinoma as long as none of the three drugs in the current regimen were included. Previous intravesical treatment was allowed if the most recent intravesical therapy completed was 1 month prior to study enrollment. Previous radiation therapy also was allowed if the course had been completed 4 weeks prior to study enrollment and if measurable lesions were located outside the previous radiation therapy portal. Patients who had received previous radiation therapy to 25% of bone marrow-containing areas were not eligible. Additional eligibility requirements included the following: an Eastern Cooperative Oncology Group performance status 0 or 1, a leukocyte count 3000/ L, a platelet count 100,000/ L, serum bilirubin 1.5 mg/dl, serum creatinine 2.5 mg/dl, and age 18 years. Patients with other active malignancies or with any other serious or active medical conditions were excluded. Pregnant or lactating females were ineligible. All patients were required to provide written informed consent prior to study enrollment. This study was approved by the Institutional Review Board at Centennial Medical Center and by the institutional review boards at all participating network sites. Pretreatment Evaluation Prior to enrolling in this trial, all patients were required to have a complete history, physical examination, complete blood counts, differential, chemistry profile, and urinalysis. In addition, patients underwent computed tomography scans of the chest, abdomen, and pelvis with appropriate tumor measurements. Treatment All patients received treatment with the following regimen: paclitaxel at a dose of 200 mg/m 2 as a 1-hour intravenous infusion on Day 1, intravenous carboplatin at an area under the serum concentration-time curve of 5.0 on Day 1, and intravenous gemcitabine at a dose of 1000 mg/m 2 on Days 1 and 8. The regimen was repeated every 21 days. The carboplatin dose was calculated using the method reported by Calvert et al. 14 On Day 1 of each course, paclitaxel was administered first, followed by gemcitabine, and then by carboplatin. Patients received standard paclitaxel premedication and antiemetic prophylaxis. Dose Modifications All patients received full doses of all 3 agents on Day 1 of the first course of treatment. Subsequent doses were based on hematologic and nonhematologic toxicity observed. Dose modifications for myelosuppression were determined by the blood counts measured on the day of scheduled treatment. Nadir blood counts were not used as a basis for dose reduction. On Day 1 of each course, full doses of all drugs were administered if the leukocyte count was 3000/ L and the platelet count was 100,000/ L. If the leukocyte count was / L or the platelet count was 75, ,000/ L, then 75% doses of all drugs were administered. If the leukocyte count was 2000/ L or the platelet count was 75,000/ L, then treatment was delayed for 1 week, and subsequent treatment was administered using 75% doses of all 3

3 2300 CANCER June 1, 2005 / Volume 103 / Number 11 drugs when blood counts had improved to a leukocyte count 3000/ L and a platelet count had improved to 100,000/ L. For the Day-8 dose of gemcitabine, a full dose was administered if the leukocyte count was 2000/ L and the platelet count was 75,000/ L. The Day-8 dose of gemcitabine was omitted if the leukocyte count was 2000/ L or the platelet count was 75,000/ L. If the initiation of a treatment course was delayed by 2 weeks due to persistent myelosuppression, then the patient was removed from this clinical trial. All patients who required hospitalization for the treatment of neutropenia and fever received 75% doses of all drugs during all subsequent courses. Patients with other episodes of reversible Grade 3 or 4 nonhematologic toxicity (with the exception of nausea, emesis, or alopecia) had doses of the offending drug or drugs withheld until the toxicity resolved to Grade 1; then, treatment was continued with 75% doses of the offending drugs. Patients who developed irreversible Grade 3 or 4 nonhematologic toxicity or who had toxicity that failed to resolve after a 2-week delay of treatment were removed from the study. Assessment of Treatment Efficacy Patients were evaluated for response to treatment after the completion of 2 courses (6 weeks). Reevaluation included a repeat of all previously abnormal radiologic studies with repeat of objective tumor measurements. Patients who achieved an objective response (complete or partial) or stable disease after the completion of two courses of therapy continued treatment with this regimen. Reevaluations were performed after the completion of each additional two courses of therapy. Treatment was continued for a total of six courses. Patients who completed 6 courses and remained in remission were followed without further specific treatment and were reevaluated for ongoing response at 3-month intervals. Response Definitions Responses were defined using World Health Organization Response criteria. A complete response required the total disappearance of all clinically and radiographically detected tumor for at least 4 weeks. Patients had partial response if treatment produced a reduction 50% in the size of measurable lesions, as measured by the product of the greatest perpendicular dimensions, with no evidence of new disease, for at least 4 weeks. Patients had stable disease if measurable lesions were reduced by 50% or increased by 25%, as determined by measurement of the products of greatest perpendicular dimensions, with no new lesions appearing. Patients who had the appearance of any new lesions or who had an increase 25% in the size of any existing lesions had progressive disease. Statistical Analysis This nonrandomized, multicenter, Phase II study was designed to evaluate the feasibility, toxicity, and efficacy of this three-drug chemotherapy regimen in patients with advanced urothelial carcinoma. Previous experience with either gemcitabine plus platinum regimens or with paclitaxel plus platinum regimens had produced response rates of 41 56%, with median survivals in the range of months. Therefore, the achievement of a response rate 60% or a median survival 14 months with this regimen would be indicative of sufficient activity to proceed with further development. To evaluate the response rate adequately, accrual of 50 patients was targeted for this clinical trial. Progression-free survival was defined as the interval between the date of first treatment and the date of documented tumor progression. Overall survival was measured from the date of first treatment until the date of death. Actuarial survival curves were constructed using the method of Kaplan and Meier. 15 All patients who received at least one dose of treatment were included in the toxicity analysis. Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria (version 2.0). RESULTS Patient Characteristics Between January 2000 and September 2003, 60 patients were entered into this clinical trial by 16 participating sites in the Minnie Pearl Cancer Research network. Patient characteristics are summarized in Table 1. The majority of patients (78%) had metastatic disease, and 58% of patients had metastases that involved 1 visceral sites. Twenty-four patients (40%) had metastatic disease at the time of diagnosis, whereas 26 patients had developed recurrent disease after primary therapy. Four patients (7%) had received previous chemotherapy. Treatment Received Fifty-two patients (87%) received at least 2 courses of treatment and were evaluated for response. One of the eight patients who received less than two courses was withdrawn from treatment due to evidence of rapid tumor progression. The remaining seven patients were removed early from the study for the following reasons: treatment-related toxicity in four patients, intercurrent illness in one patient, physician decision

4 Chemotherapy for Advanced Bladder Ca/Hainsworth et al TABLE 1 Patient Characteristics (n 60 patients) Characteristic No. of patients (%) Age (yrs) Median 63 Range Gender Male 46 (77) Female 14 (23) ECOG performance status 0 18 (30) 1 42 (70) Disease stage Stage III 13 (22) Stage IV 47 (78) Previous treatment Primary therapy only 34 (56) Radical cystectomy 26 Cystectomy and radiation therapy 2 Cystectomy and chemotherapy 1 Cystectomy, radiation therapy, and chemotherapy 1 Radiation therapy only 1 Intravesical treatment 3 Chemotherapy 1 (2) Chemotherapy and radiation therapy 1 (2) No previous treatment 24 (40) Site of tumor Locoregional/lymph node only 24 (42) Distant metastases 35 (58) Site of treatment Sarah Cannon Research Institute 14 (23) Network sites 46 (77) TABLE 2 Treatment-Related Toxicity (n 60 patients/250 courses) Toxicity a No. of patients (%) No. of courses (%) Hematologic Neutropenia Grade 3 17 (28) 65 (26) Grade 4 26 (43) 49 (20) Thrombocytopenia Grade 3 1 (2) 1 (0.4) Grade 4 0 (0) 0 (0) Anemia Grade 3 13 (22) 22 (9) Grade 4 0 (0) 0 (0) Myelosuppression-related complications Neutropenia/fever 10 (17) Platelet transfusion 12 (20) Bleeding episodes 0 (0) RBC transfusions 26 (43) Nonhematologic (Grade 3/4) Infection (nonneutropenic) 15 (25) Fatigue/asthenia 9 (15) Peripheral neuropathy 9 (15) Nausea/emesis 6 (10) Constipation 4 (7) Arthralgia/myalgia 3 (5) Hypersensitivity reaction 3 (5) Diarrhea 3 (5) Dehydration 3 (5) Mucositis 1 (2) Insomnia 1 (2) RBC: red blood cells. a Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria (version 2.0). ECOG: Eastern Cooperative Oncology Group. in one patient, and patient request in one patient. All 60 patients were included in calculating the rates of response to treatment. The median number of treatment courses received was four (range, one to six courses). During the first 2 treatment courses, patients received a high percentage of the planned Day-1 doses of all 3 drugs (paclitaxel, 97%; carboplatin, 97%; and gemcitabine, 97%). A full Day-8 dose of gemcitabine was administered during 76% of courses; gemcitabine was omitted or administered at reduced doses in 15% and 9% of courses, respectively. The large majority of dose modifications in this clinical trial were on the basis of myelosuppression. Treatment Efficacy Twenty-six of 60 patients (43%; 95% confidence interval, 29 57%) had major responses to treatment. Seven patients (12%) achieved complete responses. In addition, 21 patients (35%) had stable disease after 2 courses of treatment. After a median follow-up of 31 months, 13 patients remained alive and 8 were free of disease progression. The median progression-free survival for the entire group was 7.4 months; for patients with objective responses, the median progression-free survival was 9.7 months. Two of 7 patients with a complete response remained progression free with remission durations of 19 months and 31 months, respectively. The median survival of all patients was 11 months, and the actuarial 1-year and 2-year survival rates were 46% and 27%, respectively. Toxicity Myelosuppression (predominantly neutropenia) was the most common Grade 3 or 4 toxicity produced by this treatment regimen (Table 2). Forty-three patients (72%) experienced Grade 3 4 neutropenia (46% of courses), and 10 patients required hospitalization for the treatment of neutropenia and fever. Grade 3 4 thrombocytopenia occurred in only 1 patient, and there were no bleeding episodes reported. Twenty-six patients (43%) required red blood cell transfusions,

5 2302 CANCER June 1, 2005 / Volume 103 / Number 11 and 73% of patients also received erythropoietin agents at some point during their therapy. One patient died of treatment-related sepsis. Severe nonhematologic toxicity was uncommon with this treatment regimen (Table 2). Fifteen patients (25%) experienced various infections during nonneutropenic periods; several of these were urinary tract infections, and their relation to treatment was unclear. Nine patients (15%) experienced severe treatment-related fatigue, and 9 patients (15%) developed peripheral neuropathy. Other nonhematologic toxicities occurred in 10% of patients. DISCUSSION Although several active combination chemotherapy regimens have been described for the treatment of advanced or metastatic urothelial carcinoma, to our knowledge the optimum regimen remains unclear. Several regimens have combined newer agents (i.e., paclitaxel, docetaxel, and gemcitabine) with a platinum agent and, in Phase II trials, the activity of these regimens appeared comparable to previously reported results using the MVAC regimen. 6 9,13 In addition, these regimens appeared to produce less toxicity compared with the MVAC regimen. In a Phase III trial, the gemcitabine/cisplatin combination was equivalent to MVAC with less toxicity. 5 In the Phase II trial reported here, we attempted to improve on our previous results with paclitaxel/ gemcitabine by adding carboplatin, a third active agent. Our previous experience in patients with advanced nonsmall cell lung carcinoma or carcinoma of unknown primary site had indicated that the threedrug combination of paclitaxel, carboplatin, and gemcitabine was active and was tolerated relatively well, with myelosuppression as the major toxicity. 16,17 After we had initiated this study, favorable results with a similar paclitaxel/carboplatin/gemcitabine regimen were reported by Hussain et al. in patients with advanced urothelial carcinoma. 18 Using a regimen that differed only because it contained a slightly lower dose of gemcitabine (800 mg/m 2 on Days 1 and 8), Hussain et al. reported a 68% overall response rate (32% complete responses) and a median survival of 14.7 months. Unfortunately, our results with the paclitaxel/carboplatin/gemcitabine regimen did not duplicate the results reported previously. In the current trial, the overall response rate was 43%, with only 12% complete responses. In addition, the median survival was 11 months, with actuarial 1-year and 2-year survival rates of 46% and 27%, respectively. The reasons for the apparent differences in efficacy are difficult to explain, because the patient characteristics appeared to be similar in the two trials. The rates of Grade 3 4 neutropenia and thrombocytopenia also were increased compared with the rates reported previously by Hussain et al., possibly due to the modestly higher gemcitabine dose used in our regimen. When compared retrospectively with our previous clinical trial, the addition of carboplatin to paclitaxel/gemcitabine did not appear to improve treatment results. In summary, the addition of carboplatin to the paclitaxel/gemcitabine regimen was found to increase toxicity without any evidence of improved efficacy. Because of the increased toxicity of this regimen compared with other two-drug regimens, further use of this three-drug regimen should be limited to clinical trials. 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