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© 2000 American Society for Clinical Oncology Southwest Oncology Group Study of Paclitaxel and Carboplatin for Advanced Transitional-Cell Carcinoma: The Importance of Survival as a Clinical Trial End PointFrom the University of California San Francisco, San Francisco, CA; Southwest Oncology Group Statistical Center, Seattle, WA; University of Michigan Medical Center, Ann Arbor, MI; Columbia Presbyterian Medical Center, New York, NY; Montana Community Clinical Oncology Program, Billings, MT; Dayton Community Clinical Oncology Program, Dayton, OH; Louisiana State University/Shreveport, Shreveport, LA; and University of Colorado, Denver, CO. Address reprint requests to Operations Office, Southwest Oncology Group (SWOG-9457), 14980 Omicron Dr, San Antonio, TX 78245-3217.
PURPOSE: The combination of paclitaxel and carboplatin for the treatment of advanced transitional-cell carcinoma (TCC) of the urothelium has promising activity and acceptable toxicity. The purpose of this trial was to evaluate the efficacy of this regimen in a cooperative group setting. PATIENTS AND METHODS: Twenty-nine patients with advanced TCC were treated every 21 days with paclitaxel 200 mg/m2, administered as a 3-hour infusion, followed by carboplatin dosed to an area under the curve of 5. Prior systemic adjuvant or neoadjuvant platinum-based therapy was not permitted unless completed at least 1 year before enrollment. Patients were evaluated for response every three cycles, and follow-up was conducted to determine survival. RESULTS: Twenty-nine patients were enrolled and were assessable. Four (14%) had received prior adjuvant or neoadjuvant therapy. Node-only disease was present in 24%, and 76% of patients had extranodal disease. The median number of cycles received was five. Grade 4 toxicity consisted primarily of neutropenia (38% of patients). Neurologic toxicity was noted in 16 patients (grade 1 in four patients, grade 2 in five patients, grade 3 in six patients, and grade 4 in one patient). Six partial responses and no complete responses were noted, for a response proportion of 20.7% (95% confidence interval, 8% to 40%). Median progression-free survival time was 4 months, and overall survival time was 9 months. CONCLUSION: The combination of paclitaxel and carboplatin for the treatment of advanced TCC is reasonably well tolerated. However, a response proportion considerably lower than that previously reported was noted. In addition, the median survival time of 9 months was less than the survival time previously reported for patients treated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. Although our results may reflect enrollment of patients with poor prognostic features, they also call into question the utility of this regimen.
THE PROGNOSIS FOR patients with advanced transitional-cell carcinoma (TCC) is poor, even with aggressive systemic therapy.1-3 Cisplatin-based regimens such as the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) have become the standard of care for patients with advanced TCC and in single-institution studies have yielded response proportions of 50% to 72%.1 However, complete remissions are rare (generally occurring in no more than 20% of cases), and median survival time for these patients is only in the 8- to 14-month range, with the majority clustered around 12 months in the studies completed in the 1980s. An intergroup trial comparing MVAC with single-agent cisplatin therapy demonstrated the superiority of MVAC.4 However, the response proportion with MVAC (39%) was considerably lower than the response proportion in single-institution studies. A median survival time of 12.5 months was noted, comparable with the survival time in single-institution series. At 6 years, only 3.7% of the patients randomized to MVAC in the intergroup trial were alive and continuously free of disease.5 Furthermore, the toxicities associated with MVAC are not insignificant and include myelosuppression, mucositis, and renal, auditory, and neurologic toxicity. Investigations of treatment for patients with advanced TCC have therefore focused on reduction of toxicity and development of efficacious novel agents or combinations of agents. Some of the efforts to reduce the toxicity of MVAC have involved substitution of carboplatin for cisplatin. This approach has largely eliminated the risk of renal, auditory, and neurologic toxicities. In addition, the use of carboplatin has made treatment more widely available, because treatment is not limited by impaired renal function. This is particularly important in this group of patients, who frequently develop obstructive uropathy or have comorbid processes that make it difficult to undergo the vigorous intravenous (IV) hydration that the use of cisplatin requires. Several phase II studies of carboplatin-based regimens initially suggested that response proportions similar to those seen with MVAC could be obtained,6-9 although few randomized studies have been undertaken. In a randomized (and likely underpowered) phase II comparison of the combination of methotrexate, vinblastine, epirubicin, and cisplatin and the same regimen with carboplatin used in place of cisplatin, the cisplatin-based combination resulted in a higher response proportion (71% v 41%, P = .04) but there was no significant difference in progression-free or overall survival.10 A second trial comparing MVAC and the combination of methotrexate, vinblastine, and carboplatin (but not doxorubicin) found that both response proportion (52% v 39%) and disease-related survival time (16 v 9 months) were superior with MVAC.11 Conclusions cannot yet be drawn regarding the relative efficacy of carboplatin compared with cisplatin. Until recently, cisplatin was considered the most active single agent in the treatment of advanced TCC. However, several new agents, including paclitaxel, docetaxel, ifosfamide, and gemcitabine, have demonstproportiond significant antitumor activity as single agents.12-15 The Eastern Cooperative Oncology Group reported the results of a trial in which patients with advanced TCC of the urothelium who had not received prior systemic therapy were treated with paclitaxel 250 mg/m2 by 24-hour continuous infusion, along with granulocyte colony-stimulating factor. Of the 26 patients enrolled, five had a complete response and six had a partial response, for an overall response proportion of 42%.13 Numerous phase I studies have been undertaken in which paclitaxel is given in combination with carboplatin. In a study involving patients with non–small-cell cancer, the recommended phase II dose level of paclitaxel was projected to be 200 mg/m2 (given over 3 hours), with carboplatin following, dosed to a target area under the curve (AUC) of 7.16 Dose-limiting toxicity was primarily hematologic. In a second study, involving a similar group of patients, the carboplatin AUC was fixed at 6 and the recommended paclitaxel dose was 225 mg/m2.17 Given these data, the Southwest Oncology Group (SWOG) sought to evaluate, in a cooperative group setting, the efficacy of a 3-hour infusion of paclitaxel (at a dose of 200 mg/m2) followed by a carboplatin infusion (targeted to yield an AUC of 5) for treatment of advanced TCC. This study was activated in July 1996, around which time two preliminary reports regarding the combination of paclitaxel and carboplatin for the treatment of TCC appeared in abstract form. Schnack and colleagues18 treated 15 patients with advanced TCC with carboplatin dosed at an AUC of 5 and paclitaxel 135 mg/m2 and reported a response proportion of 66%.18 Vaughn et al19 treated 16 patients with advanced TCC on a phase I trial of the same combination and noted an overall response proportion of 56%. Since then, other trials of the combination have been reported. Promising response proportions of 50%20 and 51.5%21 have been noted with this regimen. A third group reported response proportions of 65%22 and 72%23 in two sepaproportion articles.
Patients Patients eligible for our trial had histologically proven stage T2 to T4, N0 to N3, M1 urothelial (bladder, renal pelvis, ureter, urethra) TCC not curable by surgery or radiation therapy. Patients with unresectable stage T2 to T4, N+, M0 disease were also eligible, provided there was measurable disease present. Patients with documented brain metastases were not eligible, nor were patients with adenocarcinoma, small-cell carcinoma, sarcomas, squamous cell carcinoma, or mixed adeno-squamous-transitional histology. Patients could have poorly differentiated TCC or predominant TCC with rare foci of squamous differentiation or rare foci of adenocarcinoma. Bidimensionally measurable disease documented within 28 days before registration was required. Soft tissue disease that had been irradiated in the 2 months before registration was not considered measurable disease. Patients who had had prior systemic cisplatin- or carboplatin-based chemotherapy (adjuvant or neoadjuvant) were not eligible, unless the therapy had been completed at least 1 year before enrollment and clear progressive disease had been documented more than 12 months after the most recent platinum-containing regimen. Prior chemotherapy with any taxane was an exclusion criterion. A SWOG performance status of 0 to 2 was required. Other inclusion criteria were as follows: absolute neutrophil count (ANC)  1,500/µL, platelet count 120,000/µL, alkaline phosphatase and AST levels  two times the institutional upper limits of normal, serum total bilirubin level 1.8 mg/dL, and calculated or measured creatinine clearance 30 mL/min. Written informed consent was obtained from all patients, and institutional review board approval was obtained at each participating institution.
Treatment Plan
1,500/µL and the platelet count was 100,000/µL on the day of treatment. A reduction to dose level -1 (paclitaxel 175 mg/m2 and carboplatin at an AUC of 4) was undertaken if there was an ANC nadir of less than 500/µL, WBC count nadir of less than 1,000/µL, or platelet count nadir of less than 25, 000/µL; or if there was a treatment delay of more than 2 weeks because of a low ANC or WBC count on day 1 of therapy. Routine use of colony-stimulating factors (preventive use) was prohibited. Other reasons for dose reduction were any grade 2 or higher neurologic toxicity and any grade 4 toxicity (excluding renal, neurologic, and hematologic toxicity). Creatinine clearance was calculated before each treatment; a minimum value of 30 mL/min was required for treatment. Subsequent reductions to dose level -2 (paclitaxel 150 mg/m2 and carboplatin at an AUC of 3) and dose level -3 (paclitaxel 135 mg/m2 and carboplatin at an AUC of 3) were undertaken using the same criteria. Patients who required dose modification when being treated at dose level -3 were removed from the study. Patients were monitored on days 1 and 8 of every 3-week cycle; complete blood counts were performed and serum creatinine, magnesium, potassium, and sodium levels were measured. On day 1 of each cycle, patients were evaluated for toxicity and creatinine clearance was calculated and used in determining carboplatin dosage. Patients underwent baseline computed tomography of the abdomen and pelvis, chest radiography, and any additional imaging believed to be clinically indicated. When an image revealed disease, that technique was repeated every three cycles (9 weeks) to assess response. Computed tomography of the abdomen and pelvis and chest radiography were repeated every six cycles if no evidence of disease was shown at study entry. If a patient achieved a complete response, two additional cycles were to be given. Patients who achieved a partial response continued treatment until disease progressed, toxicity precluded further treatment, or they withdrew from the study. Patients with stable disease after three cycles of therapy or who achieved a partial response that remained the same for three cycles continued treatment for three additional cycles. If there was still stable disease after a total of six cycles (18 weeks) of therapy, the patient was withdrawn from protocol treatment. Standard response criteria were used for assessment of response.
Statistical Design
Between July 15, 1996, and May 1, 1997, 29 patients were enrolled. All were fully assessable. Patient characteristics are listed in Table 1. Median age was 63 years, and 20 patients (69%) were men. Ninety-three percent of patients had a performance status of 0 or 1. Four (14%) had received adjuvant or neoadjuvant chemotherapy, in all cases more than 1 year before enrollment. Median alkaline phosphate level was 98 U/L (range, 51 to 263 U/L). Median creatinine clearance was 61 mL/min (range 36 to 125.6 mL/min). Seven patients (24%) had nodal disease only, whereas 22 (76%) had extranodal disease. Eight (28%) had both nodal and extranodal disease. Nine patients (31%) had liver metastases. Nine patients (31%) had bone involvement, and 10 (34%) had pulmonary involvement. Two patients (7%) had adrenal metastases. Nine patients (31%) had at least two distinct extranodal sites of metastasis (eg, liver and bone).
All 29 patients were assessable for response. Six partial responses were noted, and there were no complete responses. The partial and overall response proportions were thus 20.7% (95% confidence interval [CI], 8% to 40%). Characteristics of responding patients are summarized in Table 2. In the subset of four patients who had received prior adjuvant or neoadjuvant chemotherapy, a similar response proportion was found: one patient (25%) achieved a partial response, one patient was withdrawn from therapy with stable disease, one patient developed progressive disease, and one patient died at 13 weeks, before response assessment. Response duration in this subset ranged from 2 to 36+ months. Median progression-free survival time for all patients was 4 months. Median overall survival time for all patients was 9 months (95% CI, 6 to 12 months) (Fig 1). Median overall survival did not change if the four patients who received adjuvant or neoadjuvant chemotherapy were excluded. Although the study design called for a second stage of accrual based on the observed number of responses in the first stage, the study was permanently closed after accrual of the first 29 patients (representing an overaccrual of four patients) because the overall survival rate was not favorable enough to warrant exposing additional patients to this regimen rather than other known regimens.
A total of 116 cycles of chemotherapy were administered. The median number of cycles received per patient was five (range, one to nine). Of the 29 patients, 22 (76%) received at least three planned cycles of therapy before reimaging. Fourteen patients (48%) received more than three cycles of therapy. Three patients received two cycles, and four patients received only one cycle. Overall, 17 patients were ultimately withdrawn from therapy because of progressive disease, nine patients because of adverse events, two patients because of completion of therapy, and one by patient choice (inconvenient schedule).
Toxicity
Until recently, MVAC was the standard of care for patients with advanced TCC of the urothelium. However, the long-term follow-up in the intergroup trial that compared MVAC with single-agent cisplatin therapy supports the contention that MVAC has failed to produce the good results that were expected after promising early results.1 In that intergroup trial, the response proportion to MVAC was only 39%, and median survival was 12.5 months.4 Durable progression-free survival was rare, with only 3.7% of patients alive and remaining free of disease at 6 years.5 Although median survival time with this regimen was 4 months longer than that achieved with cisplatin therapy, MVAC was associated with greater toxicity. The need for more efficacious, less toxic therapy has prompted the evaluation of a variety of novel regimens, including the combination of carboplatin and paclitaxel. Vaughn et al20 reported the results of a phase I/II trial of carboplatin and paclitaxel in patients with advanced TCC. During the phase I portion of this trial, the carboplatin dose was fixed at an AUC of 6, and the paclitaxel dose was increased from 150 to 225 mg/m2. A total of 20 patients were treated at the phase II dose levels (paclitaxel 225 mg/m2 and carboplatin at an AUC of 6), and objective responses were achieved in 10 patients (50%). Although overall survival was not reported for the patients treated at the phase II dose levels, the Kaplan-Meier estimate for median overall survival time for the entire group was 8.5 months. Redman et al21 subsequently reported the results of a phase II trial of carboplatin dosed at an AUC of 5 and paclitaxel 200 mg/m2 in 36 patients with advanced TCC. There were 18 responses, for an overall response proportion of 51.5%. There were seven complete responses (19%). The median survival time was 9.5 months. Zielinski et al22 treated 20 patients with advanced TCC with this regimen (paclitaxel 175 mg/m2 and carboplatin at an AUC of 5). Overall, 65% of patients achieved a response. With a mean follow-up of 11.4 months, 80% of patients remained alive. The same group subsequently reported on a second series of 32 patients.23 It is unclear whether this series included the group of patients previously studied. In that second series, a response proportion of 72% was achieved. Results from the present study are discordant with those from these earlier trials, with only 21% of our study patients experiencing a response (Table 4). Initial analysis suggested a response proportion of less than 15%,24 so accrual was temporarily halted after analysis of data from the first stage. After accrual had ceased for more than 1 year, reassessment suggested a response proportion of 21%, which barely exceeded the minimum response proportion of interest. Furthermore, mature survival data, which was by then available, suggested that survival with this regimen was inferior to that reported with MVAC and was in fact no better than survival reported with single-agent cisplatin therapy.4 Although the trial was not designed with survival as a primary end point, nevertheless, from an ethical perspective, it was difficult to justify going forward with the trial, given that the regimen in question had geneproportiond a response proportion of 21% and a median survival time of just 9 months (albeit with a 95% CI of 6 to 12 months).
Although the 95% CI for the response proportion in this trial did overlap slightly with the 95% CIs in the trials by Vaughn et al20 and Redman et al21 (Table 4), the point estimate of 21% was substantially smaller than that in other trials. In an attempt to determine why such a profound difference in response proportion existed, we compared these reports with regard to known adverse prognostic factors in patients with metastatic TCC (Table 5).
Previously published data3-5,25 suggest that pretreatment patient characteristics (particularly performance status and site of disease) have dramatic impacts on both response proportion and survival in patients with advanced TCC who are treated with MVAC. Such prognostic features have not been assessed with regimens other than MVAC. Nevertheless, it seems reasonable to evaluate carboplatin-paclitaxel regimens in the context of these prognostic features, with the caveat that results of analysis of prognostic factors in a small trial such as this should be regarded with caution. Summarized in Table 5 are the main differences between this trial and previously reported trials of carboplatin plus paclitaxel with regard to a variety of prognostic features. Performance status did not seem to be appreciably different. Prior adjuvant or neoadjuvant chemotherapy has not previously been considered as a potential prognostic marker, although clearly such therapy might have an impact on outcome, given the potential for inadvertently treating a group of patients with chemoresistant disease. The percentages of patients who had received prior adjuvant chemotherapy did not differ substantially. In the present study, four patients (14%) had received prior adjuvant or neoadjuvant chemotherapy, although the protocol required that such therapy have been completed at least 1 year before study enrollment. Although there clearly exist limitations to subset analyses, both the response proportion (25%) and the distribution of survival duration (3, 3, 8, and 36 months) among these four patients are consistent with those in the entire group or with those in the entire group when the patients who had received prior adjuvant and neoadjuvant chemotherapy were excluded. Thus, the inclusion of these four patients likely did not negatively affect response proportion or survival, although this cannot be absolutely proven. Nevertheless, even if it were assumed that the three patients who had received prior neoadjuvant therapy and who did not achieve an objective response had in fact responded to therapy, the overall response proportion would have reached only 31% (nine of 29 patients). The distribution of sites of disease in the present trial compared with the other trials was clearly skewed toward patients with worse prognostic features. In the present series, only 24% of patients had lymph node disease only. In four other trials, this number was more than doubled (55% in the study by Vaughn et al,20 which included two of 33 patients with locally advanced disease only; 60% in the study by Zielinski et al22; 64% in the study by Redman et al21; and 69% in the study by Pycha et al,23 which included two of 33 patients with local recurrence only). Liver metastases were present in one third of patients (31%) in the present study, a greater frequency than in the other studies. The frequency of liver and/or bone metastases, clearly an adverse prognostic feature, was considerably greater in this study (62% v 48%,20 25%,22,23 and 22%21 ). It seems likely that the differences in response proportion can be attributed to patient selection. In particular, it seems likely that the response proportion in our series was affected by the fact that a small proportion of patients had node-only disease and that a larger proportion of patients had liver, bone, or lung metastases. These data suggest that the combination of carboplatin and paclitaxel may have less utility in patients with visceral metastases. Such a hypothesis requires prospective validation. There was a marked disparity in overall response proportion to MVAC in the original studies of MVAC conducted by Memorial Sloan-Kettering Cancer Center (72%) and those involving the Intergroup series (39%), although median survival time was comparable (around 12 months).3,4,25 More recently, a median survival time of 17 months with dose-intense MVAC was reported,25 perhaps reflecting the effect of stage migration. Although these differences can be attributed to patient selection, the impact of conducting a trial within a cooperative group should also be considered. Our study of carboplatin-paclitaxel therapy was conducted by a large cooperative group (SWOG), whereas the other trials of the combination were conducted at single institutions,22,23 two institutions,21 or a university academic center with a community consortia, with 60% of patients coming from a single university center.20 In the SWOG trial, 29 patients were accrued from 23 centers, and no center enrolled more than three patients. Although this distribution of care providers reflects the real world and undoubtedly results in less of a selection bias, it could be argued that it also results in less aggressive dosing and less aggressive support of the patient. Nevertheless, although one third of patients in the present series ultimately discontinued treatment because of toxicity or by choice, the median number of cycles administered was five, compared with six21,23 and five20 in other series. Perhaps the most important observation that can be made is that despite the large decrement in response proportion, the overall survival in this study was virtually identical to that in at least two other series. Vaughn et al20 reported an overall response proportion of 50% and an overall survival time of 8.5 months. Redman et al21 noted a slightly higher response proportion (65%) but a similar median overall survival time (9.5 months). In the current study, although the response proportion was lower (21%), median survival time was 9.0 months. Although survival can be meaningfully compared only in a randomized study, this observation raises questions regarding the utility of response proportion as a surrogate end point for survival in the evaluation of novel regimens for the treatment of advanced TCC. Although comparison of survival across phase II trials is fraught with difficulty, these data suggest that an important end point to report when novel agents and combinations of agents are explored is overall survival. The median survival time of 9 months noted with carboplatin-paclitaxel therapy is not different from the median survival time of 8.2 months observed in the control arm of the Intergroup trial, which consisted of single-agent cisplatin.4 Although direct comparison is not possible outside a randomized study, the survival time achieved with the carboplatin-paclitaxel regimen is considerably shorter than the 12 months achieved with MVAC. Thus, although it seems likely that MVAC is more toxic than the combination of carboplatin and paclitaxel, and the carboplatin-paclitaxel regimen clearly is an important alternative for patients with compromised renal function, with regard to efficacy the regimen against which all other regimens should be compared is still MVAC. Ongoing trials comparing MVAC with other regimens may help clarify this issue. Updates from trials that have reported preliminary results with the combination of cisplatin plus paclitaxel26-28 may also shed light on the relative efficacy of carboplatin compared with cisplatin. In summary, in this cooperative group study of the combination of carboplatin and paclitaxel in patients with advanced urothelial carcinoma, the response proportion was substantially lower than the response proportions achieved in previous studies of the same regimen. However, overall survival was similar. Although not directly comparable, survival in this trial was similar to that achieved with single-agent cisplatin therapy and seems to be inferior to survival in an intergroup study of MVAC. Ongoing evaluations of novel agents and combinations of agents with increased activity against TCC are required.
Supported in part by Bristol-Myers Squibb and also in part by the following Public Health Service Cooperative Agreement grants, awarded by the National Cancer Institute: CA38926, CA32102, CA27057, CA52386, CA35090, CA42777, CA96429, CA68183, CA67663, CA58416, CA46282, CA63850, CA52654, CA58861, and CA35431. We thank Derek Raghavan, MD, for his helpful comments and review of the manuscript.
1. Levine EG, Raghavan D: MVAC for bladder cancer: Time to move forward again. J Clin Oncol 11:387-389, 1993 (editorial)
2.
Harker WG, Meyers FJ, Freiha FS, et al: Cisplatin, methotrexate, and vinblastine (CMV): An effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract—A Northern California Oncology Group study. J Clin Oncol 3:1463-1470, 1985 3. Sternberg SN, 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[Medline] 4. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: A cooperative group study. J Clin Oncol 10:1066-1073, 1992[Abstract]
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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 6. Waxman J, Abel P, James N, et al: New combination chemotherapy programme for bladder cancer. Br J Urol 63:68-71, 1989[Medline] 7. Small EJ, Fippin LJ, Ernest ML, et al: A carboplatin-based regimen for the treatment of patients with advanced transitional cell carcinoma of the urothelium. Cancer 78:1775-1780, 1996[Medline] 8. Klocker J, Pont J, Schumer J, et al: Carboplatin, methotrexate and vinblastin (Carbo-MV) for advanced urothelial cancer: A phase II trial. Am J Clin Oncol 14:328-330, 1991[Medline] 9. Bellmunt J, Ribas A, Albanell J, et al: M-CAVI, a neoadjuvant carboplatin-based regimen for the treatment of T2-4N0M0 carcinoma of the bladder. Am J Clin Oncol 19:344-348, 1996[Medline] 10. Petrioli R, Frediani B, Manganelli A, et al: Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. Cancer 77:344-351, 1996[Medline] 11. Bellmunt J, Ribas A, Eres N, et al: Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 80:1966-1972, 1997[Medline]
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Witte R, Elson P, Bono B, et al: Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 15:589-593, 1997
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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
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Stadler WM, Kuzel TM, Roth B, 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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Moore MJ, Tannock IF, Ernst DS, et al: Gemcitabine: A promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 15:3441-3445, 1997 16. Rowinsky EK, Sartorius SE, Bowling MK, et al: Paclitaxel on a 3-hour schedule and carboplatin in non-small cell lung cancer: Use of maximally toleproportiond and clinically relevant single agent doses in combination is feasible. Proc Am Soc Clin Oncol 14:354a, 1995 (abstr 1075) 17. Bellmunt J, Ribas A, Bermejo B, et al: M-VAC versus M-CAVI [methotrexate (M), carboplatin (CA), vinblastine (VI)] in advanced surgically incurable bladder cancer. Proc Am Soc Clin Oncol 15:265a, 1996 (abstr 696) 18. Schnack B, Grbovic M, Brodowicz T, et al: High effectivity of a combination of Taxol and carboplatin in the treatment of metastatic urothelial cancer. Proc Am Soc Clin Oncol 16:325a, 1997 (abstr 1159) 19. Vaughn DJ, Malkowicz SB, Zoltick B, et al: Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: A well-toleproportiond outpatient regimen. Proc Am Soc Clin Oncol 15:240a, 1996 (abstr 597)
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Vaughn DJ, Malkowicz SB, Zoltick B, et al: Paclitaxel plus carboplatin in advanced carcinoma of the urothelium: An active and tolerable outpatient regimen. J Clin Oncol 16:255-260, 1998 21. Redman BG, Smith DC, Flaherty L, et al: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol 16:1844-1848, 1998[Abstract] 22. Zielinski CC, Schnack B, Grbovic M, et al: Paclitaxel and carboplatin in patients with metastatic urothelial cancer: Results of a phase II trial. Br J Cancer 78:370-374, 1998[Medline] 23. Pycha A, Grbovic M, Posch B, et al: Paclitaxel and carboplatin in patients with metastatic transitional cell cancer of the urinary tract. Urology 53:510-515, 1999[Medline] 24. Small EJ, Lew D, Petrylak DP, et al: Carboplatin and paclitaxel for advanced transitional cell carcinoma of the urothelium. Proc Am Soc Clin Oncol 18:333a, 1999 (abstr 1280) 25. Geller NL, Sternberg CN, Penenberg D, et al: Prognostic factors for survival of patients with advanced urothelial tumors treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy. Cancer 67:1525-1531, 1991[Medline] 26. Burch PA, Richardson RL, Cha SS, et al: Combination paclitaxel and cisplatin is active in advanced urothelial carcinoma. Proc Am Soc Clin Oncol 16:329a, 1997 (abstr 1175) 27. Murphy BA, Johnson DR, Smith J, et al: Phase II trial of paclitaxel and cisplatin for metastatic or locally unresectable urothelial cancer. Proc Am Soc Clin Oncol 15:245a, 1996 (abstr 617) 28. Dreicer R, Roth B, Lipsitz S, et al: Cisplatin and paclitaxel in advanced carcinoma of the urothelium: A phase II trial of the Eastern Cooperative Oncology Group (ECOG). Proc Am Soc Clin Oncol 17:320a, 1998 (abstr 1233) Submitted September 20, 1999; accepted March 8, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
