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© 2000 American Society for Clinical Oncology Phase I-II Study of Paclitaxel, Cisplatin, and Gemcitabine in Advanced Transitional-Cell Carcinoma of the UrotheliumFrom the Hospital General Universitari Vall d’Hebron; Hospital del Mar, Barcelona; Instituto Valenciano de Oncología, Valencia; Hospital 12 de Octubre; Hospital Clínico San Carlos; Departamento de Estadística, Universidad Autónoma de Madrid, Madrid; Hospital General de Vic, Vic; Hospital Lozano-Blesa, Zaragoza; Hospital Marqués de Valdecilla, Santander; Hospital Germans Trias i Pujol, Badalona; Consorci Parc Taulí, Sabadell; and Hospital Mutua de Terrassa, Terrassa, Spain. Address reprint requests to Joaquim Bellmunt, MD, Medical Oncology Service, Hospital General Universitari Vall d’Hebron. P. Vall d’Hebron 119–129, 08035 Barcelona, Spain; email: bellmunt{at}hg vhebron.es.
PURPOSE: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium.
PATIENTS AND METHODS: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status RESULTS: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m2 and gemcitabine 1,000 mg/m2 was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up. CONCLUSION: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.
CISPLATIN-BASED combination chemotherapy regimens like methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) or cisplatin, methotrexate, and vinblastine (CMV) are considered the standard therapy for patients with advanced carcinoma of the urothelium.1,2 The overall response rate (complete plus partial) to these cisplatin-based combination regimens range from 50% to 70%, with complete responses (CRs) seen in 15% to 25% of the cases.2-5 Nonetheless, almost all responding patients ultimately relapse within the first year, with a median survival of approximately 12 to 14 months.6 M-VAC produces a modest, although significant, benefit on survival when compared, in randomized trials, with cisplatin as a single agent,7 with cyclophosphamide, doxorubicin, and cisplatin (CAP or CISCA),8 or with a carboplatin-based regimen.9 Long-term follow-up of M-VAC–treated patients shows a 12.5 months median survival and a disease-free survival of more than 6 years in 3.7% of patients.10 The results with M-VAC have not improved with dose-intensification of the regimen.11-13 In summary, the dismal long-term outcome with currently available regimens has led to the search of new treatment approaches. Among the recently available new chemotherapy agents, paclitaxel and gemcitabine have shown to have a promising activity profile in bladder carcinoma. Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ), a drug that stabilizes microtubules and promotes their assembly resulting in a M-phase cell-cycle arrest,14 is active against bladder cancer both in preclinical studies as well as in the clinic.15-17 In patients with advanced urothelial carcinoma who had not received prior radiotherapy or systemic chemotherapy, paclitaxel given at a dose of 250 mg/m2 by 24-hours continuous infusion every 3 weeks resulted in a response rate of 42%, including 27% CRs.17 Gemcitabine (Gemzar; Eli-Lilly and Company, Indianapolis, IN) is a pyrimidine antimetabolite that has single-agent activity against urothelial cancer in previously treated patients, with an overall response rate of 27% to 28%.18,19 Two trials evaluating gemcitabine in previously untreated patients have shown response rates from 24.3% to 28%.20,21 Considering the antitumor activity of these new drugs, several efforts have been aimed at integrating them into combination regimens, in particular with cisplatin. Several reports have described the antitumor activity of taxanes in combination with cisplatin in bladder cancer. Paclitaxel given in combination with cisplatin has been evaluated in at least three studies22-24 that have included a total of 82 patients, with an overall response rate ranging from 63% to 72%. In one study (including 25 patients) of the other widely used taxane docetaxel in combination with cisplatin, a response rate of 60% was reported.25 Median survival was 13 months in one of the cisplatin/paclitaxel studies24 and 13.6 months in the cisplatin/docetaxel study.25 The combination of gemcitabine and cisplatin has been evaluated in bladder cancer in three studies using different schedules of administration. In these studies, gemcitabine was administered on days 1, 8, and 15, every 4 weeks and cisplatin once every 4 weeks either on day 1 or 2 or on days 1, 8, and 15.26-28 In total, 115 patients have been treated with this combination, with an overall response rate ranging from 41% to 71% and with a CR rate ranging from 25% to 35%. The median survival time was consistently reported to be 13 months in two of the studies.26,28 Because of the high response rates found in these phase II trials using the above-mentioned combinations, randomized phase III trials comparing M-VAC with cisplatin/gemcitabine or with carboplatin/paclitaxel are ongoing. Taking into consideration the significant activity of paclitaxel and gemcitabine, either alone or in combination with cisplatin, their different mechanism of action, and their non-overlapping toxicities, we decided to study the feasibility of combining paclitaxel, gemcitabine, and cisplatin in patients with advanced urothelial transitional-cell carcinoma (TCC). Our goals were to establish the optimal dose of the combination, to study its toxicity profile, and to determine the level of activity.
Patient Eligibility Patients with histologically documented metastatic or locally advanced surgically incurable (T4b, N0-1) TCC of the urothelium (renal pelvis, ureter, bladder, or urethra) were eligible for the study. Patients were not allowed to have received pelvic radiotherapy or chemotherapy for metastatic disease, although prior adjuvant or neoadjuvant chemotherapy completed at least 12 months before enrollment was permitted. All patients had bidimensionally measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of  2.
Patients had adequate bone marrow reserve, with an absolute neutrophil count (ANC) more than 1,500/µL and platelet count more than 100,000/µL, and adequate hepatic and renal function (serum bilirubin level < 1.5 mg/dL, alkaline phosphatase and AST < 2.5 times the upper limit of normal levels, serum creatinine level < 1.5 mg/dL, or creatinine clearance
Pretreatment and Follow-Up Studies
Treatment Plan
Definition of Maximum-Tolerated Dose (MTD) and Dose Modification Toxicities were graded according to the National Cancer Institute common toxicity criteria (December 1994). Initially, dose-limiting toxicity (DLT) was defined as  grade 3 nonhematologic toxicity other than alopecia, nausea, vomiting, and/or nonbloody diarrhea, electrolyte disturbance reversible through intravenous route, or reversible nephrotic syndrome. Three patients were to be enrolled at each dose level. If at any dose level, one of three patients experienced a DLT after the first cycle, three additional patients were to be enrolled at that dose level. If no additional DLTs were observed, then dose escalation proceeded. The phase II portion of the study was to be performed at the recommended dose (the dose level immediately below the MTD) or at dose level 4 if the MTD was not reached. At the completion of dose level 4 of the phase I study and because of the appearance of early grade 2 asthenia that unexpectedly limited continuation of therapy, the protocol was amended and early appearance (after the first cycle) of grade 2 asthenia was also considered to be a DLT. Treatment cycles were given every 21 days provided the ANC was greater than 1,500 cells/µL and the platelet count was greater than 100,000 cells/µL. To keep on schedule granulocyte colony-stimulating factor (G-CSF) was given at a dose of 5 µg/kg/d for 7 days from day 9 of the next cycle if delay caused by an ANC less than 1.500 cells/µL occurred in the preceding cycle. During the phase II component of the study and after patient no. 39 was registered, the protocol was amended for safety reasons after a patient with febrile neutropenia died, and G-CSF was prophylactically administered for 7 days from day 9 (24 hours after chemotherapy administration on day 8) in the following cycle when afebrile grade 4 neutropenia was detected either on day 8 or 15. Dose reductions and omissions of cisplatin, gemcitabine, and paclitaxel were defined for hematologic and nonhematologic toxicity. On day 1 of therapy, a 50% dose reduction of cisplatin was applied to patients who developed impairment of renal function with creatinine clearance between 40 and 55 mL/min. If the clearance dropped below 40 mL/min, the patient was to be removed from the study. Grade 3 or 4 mucositis, neutropenic fever, or grade 4 thrombocytopenia required dose reduction of 25% for both paclitaxel and gemcitabine on subsequent cycles. Patients who developed grade 3 or 4 neurotoxicity or hepatotoxicity were to be removed from study. On day 8, the doses of gemcitabine and paclitaxel were reduced by 50% if the ANC was between 500 and 1,000/µL or if platelet count was between 50,000 and 75,000/µL on the day of treatment. A 25% dose reduction was applied if platelet count was between 75,000 and 100,000/µL. Treatment was omitted if the ANC was less than 500/µL or if the platelet count was less than 50.000/µL.
Definition of Response Progressive disease was defined as an increase of at least 25% in size of measurable lesions or the appearance of any new lesion. Progressive disease in bone was defined as the appearance of any new lesions in bone scan and/or worsening of a preexisting lytic lesion in plain radiographs. All major responses were confirmed by review of relevant radiographs by an independent radiologist not affiliated with the study.
Statistical Methods
Patient Characteristics Patient characteristics are listed in Table 2. From March 1997 to December 1998, a total of 61 patients from 11 participating institutions were included in the trial. The median age was 66 years (range, 36 to 79 years). The median ECOG performance status was 1 (range, 0 to 2). Five patients had previously received neoadjuvant/adjuvant chemotherapy. Fifteen patients were entered in the phase I component of the study (three at dose level 1, three at dose level 2, three at dose level 3, and six at dose level 4). Once dose level 3 was chosen for the phase II study, 46 additional patients were entered at this dose level (a total of 49 patients registered at dose level 3). Of these 46 additional patients, three patients were assessable for toxicity but not for response; in one patient, the pathology review failed to confirm the presence of TCC after having received day 1 of therapy of the first cycle. The second patient was excluded because of an early death secondary to a massive bowel infarction that was diagnosed 10 days after day 1 of the first cycle of therapy. A third patient at dose level 3 received treatment on day 1 only, refused further therapy, and was lost to follow-up. Overall, 58 patients on study were eligible and assessable for response and toxicity.
Toxicity Nonhematologic toxicities per dose level are listed in Table 3. During the phase I component of the study, early-onset grade 2 asthenia occurring after the first cycle was seen in two out of six patients at dose level 4. It was felt that this unexpected toxicity would have precluded prolonged treatment with the combination, and therefore, the DLT criteria were modified to include early (after the first cycle) grade 2 asthenia. At the phase II level (dose level 3), grade 2 asthenia occurred in 18 patients (37%), with early onset (after the first cycle) in five patients. Grade 3 asthenia was seen in four patients. Grade 1 or 2 paraesthesias were reported in 11 (22%) of 49 patients. In all but one patient, the neuropathy resolved upon discontinuation of therapy.
Neutropenia was the most common hematologic toxicity (Table 4). Overall, there were 12 episodes of febrile neutropenia in a total of 11 patients. These episodes occurred at the higher dose levels; two episodes occurred in six patients (33.3%) treated at dose level 4, and 10 episodes occurred in 49 patients (20%) at dose level 3. One patient at dose level 3 developed grade 4 neutropenia on day 15 of the fifth cycle, complicated by fever and gram-negative bacteriemia that evolved to a fatal septic shock despite aggressive medical management. When reviewing retrospective hematologic data about this patient, it was apparent that the only remarkable finding of his preceding hematologic data was the presence of afebrile grade 4 granulocytopenia on day 15 during the second cycle. After this observation, and as a safety measure, we decided after registering patient no. 39 to prophylactically administer G-CSF for 7 days from day 9 of the following cycles when afebrile grade 4 neutropenia was detected on day 8 or on day 15 during the hematologic monitoring of the first four cycles. At the phase II dose level, G-CSF was administered to 18 (39%) of 46 assessable patients during 42 cycles (20.4%). Before protocol modification, seven (28%) of 25 patients received G-CSF for 21 cycles (19.8%), and after the protocol amendment, it was given to 11 (52.4%) of 21 patients for 21 cycles (21%).
Overall, a total of 269 courses of the combination were administered. A median of five cycles was administered, and 32 (65%) of 49 patients at dose level 3 received more than four cycles. At the phase II dose level, 28 of 46 assessable patients did not receive the planned six cycles of therapy. Nine patients were removed from study for toxicity reasons (grade 4 hematologic toxicity in two patients [including a toxic death], grade 3/4 nonhematologic toxicity in four patients, and persistent grade 2 renal toxicity in three patients). Progression of disease was the reason for stopping therapy in four patients. One patient refused to continue on chemotherapy despite having obtained a PR. Fourteen additional patients discontinued therapy while on response (four in CR and seven in PR) or in stable disease (three patients) and received an alternative therapy at the discretion of the treating physician because the local investigator, after discussing the case with the principal investigator, judged that no further benefit for the patients would have been obtained with additional cycles of therapy. Administration of the full dose at the recommended phase II dose was possible in 15 (32.6%) of 46 assessable patients during all cycles. At the phase II dose level, dose reduction on day 1 was required in 14 (30.4%) of 46 patients during 14 of the 206 cycles administered (7% of cycles). Day-1 dose reduction according to cycles of therapy was required in 10 (22%) out of 46 cycles at cycle 2, in three (7.8%) out of 38 cycles at cycle 3, and in one (3.1%) out of 32 cycles at cycle 4. No day-1 dose reductions were required on cycles 5 and 6. The reasons that led to these day-1 dose reduction were a decline in creatinine clearance in five patients, grade 3/4 hematologic toxicity in eight patients, and grade 3/4 mucositis in one patient. On day 8, a dose reduction or omission was required in 24 patients (52%) during 55 cycles (27%); seven of these patients also had dose reductions on day 1. A 50% dose reduction of paclitaxel and gemcitabine was required in 45 cycles (22%), and a 100% dose omission was required in 10 cycles (5%), all because of neutropenia and or thrombocytopenia.
Tumor Response and Survival At the phase II dose level, objective responses were observed in 35 of 46 assessable patients, for an overall response rate of 76%, (95% confidence interval, 60% to 98%), including 12 patients who obtained a CR (26%; 95% confidence interval, 17.5% to 40.5%). Seven patients had stable disease and four had progressive disease after two courses. For the whole group, the median follow-up time is 12 months, and the median survival time has not been reached at the time of this analysis (Fig 1).
To outline response rates by disease-site, patients from both the phase I and the phase II studies were pooled together in the following subgroups (Table 5): patients with locally advanced surgically incurable bladder tumors (T4b, N0-1), patients with N2-3 disease/pelvic mass, and patients with distant metastasis. Out of ten patients with locally advanced disease, eight achieved a response. Of this group, four responding patients (T4bN0, two patients and T4bN1M0, two patients) underwent surgical resection of the disease after chemotherapy, with two pathologically verified CRs and two pathologically verified PRs (including one patient with residual carcinoma-in-situ only).
Twenty-seven assessable patients had N2-3 disease/pelvic mass, 23 of whom achieved a major response (13 PR and 10 CR). Distant metastatic disease was seen in 21 patients, with 14 achieving a major response (12 PR and two CR). Response by predominant disease location included liver (five of six), lung (three of seven), bone (four of six), peritoneal (one of one), and adrenal (one of one). The two patients with visceral disease who had a CR had lung metastases in one case and peritoneal metastasis in the other.
Several considerations led us to explore the combination of paclitaxel, gemcitabine, and cisplatin in patients with advanced urothelial TCC. Paclitaxel and gemcitabine are highly active both as single agents and in combination with cisplatin in urothelial tumors17-24,26-28. In addition, these agents have different mechanisms of action that could result in lack of cross-resistance and increased therapeutic benefit. Preclinical studies have shown synergy of the combination of cisplatin and gemcitabine31,32 and cisplatin with paclitaxel.33 Similarly, a very high level of collateral sensitivity between gemcitabine and paclitaxel has been observed,34 and the combination of gemcitabine and paclitaxel is synergistic in vitro at clinically achievable doses.35 A major potential challenge in the design of this new combination was to find a feasible dose and schedule, including an optimal sequence of drug administration. Regarding the optimal dose and schedule, our main concern a priori was to minimize the potential myelotoxicity of this combination without jeopardizing its potential antitumor activity. To decrease the myelotoxicity of the combination, two steps were taken. First, gemcitabine was given on days 1 and 8, omitting the administration on day 15. Second, and of critical importance, a weekly paclitaxel administration schedule was chosen based on the lack of neutropenia and high activity observed with this schedule in patients with advanced breast cancer36 even after bone marrow transplantation.37 At the time of our study design, there were no data available to our knowledge on possible clinical drug interactions between gemcitabine and paclitaxel. However, an early study performed by Rothenberg et al38 suggested that same-day administration of paclitaxel followed by gemcitabine was safe and active and prompted us to use a similar sequence. This sequence of administration has now been further validated, in addition to our current study, by two recent studies. In one study, in patients with ovarian carcinoma, the sequence of gemcitabine followed by paclitaxel resulted in greater toxicity than paclitaxel followed by gemcitabine.39 Additionally, in a recent phase I/II study in patients with non–small-cell lung cancer, paclitaxel and gemcitabine did not affect each other’s pharmacokinetics, but paclitaxel administration before gemcitabine increased difluorodeoxycytidine triphosphate levels, the active metabolite of gemcitabine, suggesting that this sequence might enhance the antitumor activity of the combination.40 On the day of cisplatin administration, a sequence of paclitaxel followed by cisplatin was chosen based on the phase I study reported by Rowinsky et al,41 which showed that cisplatin administration before paclitaxel resulted in lower antitumor activity and a more profound neutropenia than the alternate sequence. In the phase I component of our study, we found that the DLT was grade 3 and early-onset grade 2 asthenia, and we chose, for the phase II study, a paclitaxel dose of 80 mg/m2 and gemcitabine dose of 1,000 mg/m2, both given on days 1 and 8 every 21 days, combined with a fixed dose of cisplatin 70 mg/m2 on day 1. During the phase II study, treatment was administered in the outpatient setting and demonstrated a good toxicity profile, with the predominant toxicities being grade 2 asthenia and myelosuppression. Asthenia was usually short-lived starting on the second or third day after the first day of treatment and lasting 8 to 10 days. In addition, no patient required withdrawal from the study because of asthenia. As a possible measure to improve the observed asthenia, we will initiate an extension study adding tapering doses of dexamethasone during the first 10 days of treatment. Additionally, grade 3 neurotoxicity in one patient and grade 4 ototoxicity in another patient with a preexisting hearing impairment were seen. All other nonhematologic toxicities were mild to moderate, fully reversible, and occasionally included grade 1/2 nephrotoxicity, diarrhea, mucositis, and nausea and vomiting. Neutropenia was commonly observed. Overall, there was a 55% incidence of grade 3/4 neutropenia and a 20% incidence of neutropenic fever that resulted in a neutropenic sepsis and death in one patient. As a result, G-CSF was added to the protocol whenever grade 4 neutropenia occurred on days 8 or 15 of the first two cycles.
This combination was found to be highly active. The overall response rate of 77.5% is the highest reported in a multi-institutional study, a setting that usually results in lower response rates. Interestingly, a high response rate was also observed in the phase I trial, with responses seen at all dose levels, which suggests that exploration of lower doses of paclitaxel and gemcitabine may be warranted in the future. This encouraging response rate has to be analyzed, as with all other chemotherapy combinations in advanced TCC, taking into consideration that differences in patient selection criteria account for differences in reported outcomes. Investigators at Memorial Sloan-Kettering Cancer Center have retrospectively conducted a multivariate analysis in 203 patients examining prognostic factors for survival with chemotherapy. The presence of baseline Karnofsky performance status less than 80%, visceral metastasis (lung, liver, or bone), or both had a profound negative impact on survival.42 In this regard, our patient population had favorable characteristics for response and survival because fifty-six of the 61 registered patients had a good performance status (ECOG performance status In patients with locally advanced surgically incurable bladder tumors (T4b, N0-1), in addition to the high response rate, four out of the 10 patients underwent successful surgical resection of their disease at the completion of therapy. This suggests that this regimen could potentially have a significant impact on the outcome of patients with lower burden of disease. An interesting finding in our study was that one of the two locally advanced patients with a surgically verified CR had a 70% squamous differentiation in the initial tumor. It has been reported that regimens currently in use have limited efficacy against non–transitional-cell histologies, such as adenocarcinomas and squamous cell tumor.43 If responses in non–transitional-cell components would be confirmed, this new regimen could be particularly useful in the therapy of non-transitional histologies, a common occurrence in certain areas of the world.43 It is too early to draw conclusions about the impact of this regimen on survival because the median follow-up period is short (12 months), the median survival time has not yet been reached, and additional follow-up is needed. However, the median survival time of 24 months of the phase I component of the study seems promising in view of the consistently observed median survival time of 12 months reported in the M-VAC series.7,8 In addition to our study, other triple-agent combinations using these new agents are either underway or have recently been completed. The combination of ifosfamide, paclitaxel, and cisplatin (ITP) has a reported response rate of 79% and a median survival time of 18.3 months.44 An early report of the combination of paclitaxel, carboplatin, and escalating doses of methotrexate with G-CSF and leucovorin support45 shows a median survival time of 17.7 months, and a phase II trial using carboplatin, paclitaxel, and gemcitabine46 in patients with advanced urothelial malignancy has a response rate of 58% in a patient population with a preponderance of visceral metastases. As mentioned, comparisons between these different regimens are difficult because of differences in pretreatment prognostic factors resulting in different outcomes. An important research area in the years to come will be to define whether these new two- and three-agent combinations will offer an advantage in terms of response rate, survival, or quality of life over the currently available standard regimens, such as M-VAC or cisplatin, methotrexate, and vinblastine (CMV). Comparisons with historical series would be inappropriate not only for differences in pretreatment prognostic factors but also because of the possibility of a shift toward an improved median survival in modern trials caused by stage migration (as we presently have better imaging techniques). The results of the ongoing multinational phase III study of M-VAC versus gemcitabine/cisplatin and two additional trials comparing M-VAC with other combinations will hopefully start to address these issues. As a further step in this direction, we are planning within the Spanish Oncology Genitourinary Group (SOGUG), the Genitourinary Group of the EORTC, and other cooperative groups, a phase III study comparing our three-agent combination with the best regimen resulting from these ongoing trials. In summary, the combination of cisplatin, gemcitabine, and paclitaxel is a highly active regimen with a tolerable toxicity profile in patients with advanced urothelial tumors. Survival data is encouraging, although long-term follow-up evaluation is needed. Planned phase III studies will further define the role of this combination in the treatment of advanced bladder cancer.
Supported in part by Eli-Lilly, Madrid, Spain, and Bristol-Myers-Squibb, Madrid, Spain.
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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
= 0.05 and ß = 0.2). Overall survival was defined as the interval between start of chemotherapy to death or last follow-up visit. Median overall survival was estimated using the Kaplan-Meier analysis method.
