© 2005 Foundation for Promotion of Cancer Research
Combination Chemotherapy of Docetaxel, Ifosfamide and Cisplatin (DIP) in Patients with Metastatic Urothelial Cancer: a Preliminary Report
Department of Urology, Faculty of Medicine, Tokyo University, Tokyo, Japan
For reprints and all correspondence: Satoru Takahashi, Department of Urology, Faculty of Medicine, Tokyo University, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: takahashi-uro{at}h.u-tokyo.ac.jp
Received September 13, 2004; accepted December 20, 2004
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: The aim of this study was to evaluate the efficacy and toxicity of a new combination chemotherapy of docetaxel, ifosfamide and cisplatin (DIP) in the treatment of metastatic urothelial cancer.
Methods: Fourteen patients (nine male and five female; aged 59–82 years) with metastatic urothelial carcinoma, including five patients who have a history of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) chemotherapies, received the combination of docetaxel 60 mg/m2 on day 1, and ifosfamide 1.0 g/m2 and cisplatin 20 mg/m2 on days 2–6 and repeated every 21 days, to a maximum of six cycles. Eligibility criteria included performance status (World Health Organization) 0–3; normal bone marrow and liver function; and no symptomatic peripheral neuropathy.
Results: Ten of the 14 patients (72%) demonstrated a partial response (PR), with durations of response ranging from 3 to 12 months [median 6.5 months; 95% confidence interval (CI), 4.1–8.7 months]. The response rate of the five patients with MVAC-refractory cancer was 80% with median duration of response 5.5 months, comparable with that of the cases without previous MVAC therapies. Grade 3–4 granulocytopenia occurred in 10 cases (71%), resulting in three episodes (21%) of febrile neutropenia. Grade 3 thrombocytopenia was observed in five cases (36%). No toxic death was observed. Grade 2 peripheral neuropathy was identified in one case.
Conclusions: This pilot study demonstrated that DIP is an effective regimen for the treatment of metastatic urothelial cancer, and warrants further investigation.
Key Words: docetaxel • ifosfamide • cisplatin • metastatic urothelial cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) has dominated the landscape of chemotherapy for advanced urothelial cancer for >15 years. However, it exhibits a significant toxicity profile and achieves only a slight impact on patient survival (1–3). Recent efforts to improve the outcome of patients with the advanced disease have focused on the identification of new drugs with single agent activity and on their incorporation into platinum-based combination regimens. Newer agents, including the taxanes paclitaxel and docetaxel, have shown promising single-agent efficacy in advanced urothelial cancer (4–6). Paclitaxel was originally a natural product derived from the bark of the North American yew tree, Taxus brevifola. Clinical studies using paclitaxel commenced in the mid-1980 s. French researchers produced an extract of the European yew, Taxus baccata, and modified it with a chemically synthesized side chain. Docetaxel emerged as a result of these efforts and entered clinical trials in 1990 (7). Docetaxel is capable of inducing bcl2 phosphorylation and apoptotic cell death at 100-fold lower concentrations than paclitaxel (8). Docetaxel also has the advantage over paclitaxel of a lower incidence of peripheral neuropathy (9). Recent investigations demonstrated that the combination of paclitaxel with cisplatin and ifosfamide produced encouraging efficacy results in patients with advanced urothelial cancer, with manageable toxicity (10). Therefore, we designed a new combination regimen with docetaxel, ifosfamide and cisplatin (DIP) and evaluated its efficacy and toxicity in the treatment of metastatic urothelial cancer.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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From October 2002, we treated 14 patients with metastatic urothelial cancer. Of the patients, five cases had been treated previously with the MVAC regimen. One patient had received an additional two cycles of MEC (methotrexate, epirubicin and cisplatin) (11) after two cycles of MVAC. Eligibility criteria included performance status [World Health Organization (WHO)] 0–3; normal bone marrow and liver function; and no symptomatic peripheral neuropathy. All patients were required to sign an institutional review board-approved informed consent form. The patients were nine men and five women, with a mean age of 69.2 years (range 59–82). Five patients had bladder cancer, five patients had pelvic cancer and four had ureteral cancer. The pathological diagnoses of the primary tumors were all grade II–III transitional cell carcinoma (TCC). One patient had undergone radical cystectomy and five patients had undergone nephroureterectomy. Metastatic sites consisted of lymph node (10 cases), lung (seven), liver (three), soft tissue (three) and bone (four). Performance status was 0–2 in 10 cases and 3 in four cases. Table 1 shows the characteristics of the patients enrolled.
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TREATMENT
The treatment schedule for the combination DIP was docetaxel 60 mg/m2 on day 1, and ifosfamide 1.0 g/m2 (with mesna) and cisplatin 20 mg/m2 on days 2–6. Dexamethasone 8 mg/body was administered on day 1 in order to prevent edema and pleural effusion possibly induced by docetaxel. Cycles were repeated every 21 days to a maximum of six cycles in responding patients or patients with stable disease (no change), but they were discontinued in the presence of disease progression. A detailed medical interview, clinical examination and laboratory studies were obtained before each drug administration. Dose adjustment was based on assessment of the hematological and non-hematological toxicities. The median number and range of cycles of DIP therapy were 2.6 and 1–6, respectively.
EFFICACY AND TOXICITY EVALUATION
All patients who completed at least one therapy cycle were analyzed every month for chemotherapeutic efficacy and toxicity. After discontinuation of treatment, patients were evaluated every month to assess the survival and disease-free status. The evaluation of the tumor response was based on the standard WHO criteria for measurable disease (12). Toxicity was evaluated at each chemotherapy visit according to National Cancer Institute-Common Toxicity Criteria; Version 2 (NCI-CTC). For the evaluations of the tumor response and survival, the following definitions were used: time to progression, i.e. the time from the day of the initiation of treatment to the date of evidence of progression; duration of partial response (PR), i.e. the time from first evidence of PR to the time of disease progression; duration of complete response (CR), i.e. the time from first evidence of CR to the time of disease progression; and survival, i.e. the time from the day of the initiation of treatment to death. Kaplan–Meier analysis was used for analysis of the survival and time to progression, and the 95% confidence interval (CI) was also calculated.
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RESULTS |
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RESPONSE
Ten of the 14 patients (72%) showed PR. No cases achieved a CR, and one showed no change (Table 1). Time to progression in 10 patients who demonstrated an objective response ranged from 3 to 12 months (median 6.5; 95% CI, 4.1–8.7). One patient has maintained PR at the time of analysis (8 months). Figure 1 shows chest and abdominal computed tomography (CT) of a representative case (patient 2) before and after four cycles of DIP therapy. Metastatic lesions in the left lung, mediastinal lymph nodes and liver markedly decreased in size, and PR was obtained. A total of six cycles was carried out, and PR was continued for 8 months. The patient survived for 15 months. In the five patients previously treated with MVAC, four cases (80%) obtained PR and one showed PD. The response rate in the MVAC-refractory cancer cases was 80%, with median duration of response 5.5 months (range 3–8; 95% CI 1.7–9.3), comparable with that of the cases without previous MVAC therapies. Figure 2 indicates an abdominal CT of a case with MVAC/MEC-refractory ureteral cancer (patient 7) before and after DIP therapy. After each two courses of MVAC and MEC, progression of lung and lymph node metastases was identified. After three cycles of DIP, PR was obtained. Para-aortic lymph node metastases decreased in size. PR was maintained for 7 months. The patient survived for 11 months. Table 2 shows the efficacy of DIP therapy according to the sites of tumor. Five cases had measurable primary lesions, and their objective response rate was 80% (PR). The response rate in lung metastases was 100% (PR). The response rate in lymph node, liver and soft tissue metastases was 80, 67 and 67%, respectively, while bone metastases did not respond significantly. Performance status of all four patients with bone metastasis was grade 3. At the time of analysis, eight patients (57%) had died of the disease and no treatment-related deaths were identified. Median follow-up for surviving patients was 13.0 months (range 8–21). Overall median survival was 10.0 months (range 3–21; 95% CI 7.5–13.1). Median survival in the five patients with MVAC-refractory cancer was also 10.0 months (range 3–11; 95% CI 4.4–12.4). Of the 10 patients who had obtained an objective response, four cases (40%) survived >12 months (Table 1).
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TOXICITY
NCI-CTC grade 3–4 granulocytopenia occurred in 10 cases (71%), resulting in three episodes (21%) of febrile neutropenia (Table 3). Grade 3 thrombocytopenia was observed in five cases (36%), but not grade 4 thrombocytopenia. No toxic death was observed. There were no cases of grade 3–4 biochemical toxicity of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), alkaliphosphatase (ALP) or bilirubin, and no transient elevation of AST, ALT or ALP. No patients had grade 3–4 elevation of the serum creatinine level. Although one case reported parethesia of the feet (grade 2), neither serious peripheral neuropathy nor edema were observed.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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TCC of the urothelium is a chemosensitive tumor, as demonstrated by its overall response rate of 35–70% to MVAC chemotherapy (1). The toxicity of this regimen, however, is significant, and the median survival of all treated patients does not greatly exceed 12 months (13,14). These results have prompted a search for new active agents which could be incorporated into more effective and less toxic regimens. A newer agent, docetaxel, has shown promising single-agent efficacy in advanced urothelial cancer, with a 31% objective response rate (5,6,15). However, its response rate in patients with prior platinum-based chemotherapy was only 13.3% (5).
A recent phase II study of the combination of docetaxel and cisplatin (DC) as first-line treatment in patients with advanced urothelial carcinoma showed a 52% response rate, with 12% of patients achieving a CR (16). Another study of the DC regimen reported a comparable response rate of 58% (CR 18% + PR 39%) with 10.4 months overall survival (17). A recent study demonstrated that the three-agent regimen of paclitaxel, cisplatin and ifosfamide combined with metastatectomy produced a 68% response rate (CR 23% + PR 45%) with 20 months overall survival (10). As for the three-agent regimen including docetaxel for the treatment of advanced urothelial cancer, a combination of docetaxel, epirubicin and cisplatin has been reported with a 67% response rate (CR 30% + PR 37%) and 14.5 months overall survival (18). These results encouraged us to design a new combination regimen of DIP by substituting docetaxel for paclitaxel in order to minimize a possible adverse event of peripheral neuropathy. The present study first demonstrated that this combination is effective, with a 72% response rate for the treatment of metastatic urothelial cancer. It is noteworthy that DIP therapy also showed encouraging efficacy in MVAC-refractory cancer, with an 80% response rate. However, median time to progression and overall survival are not long enough at present, which might be partly due to the baseline characteristics of the patients included in this study. The present study enrolled a significant number of patients with poor performance status, including four cases with grade 3. Actually, these patients could not undergo enough cycles of DIP, and showed no objective response with poor survival. Out-patient-based maintenance chemotherapy may prolong the duration of the response and enhance the clinical usefulness of DIP regimens. Further studies with longer follow-up periods and a search for active regimens of maintenance therapy to improve the duration of the response and overall survival are warranted.
The toxicity profile of DIP therapy may compare favorably with that reported for MVAC (1–3). Neither unexpected toxic effects nor treatment-related deaths were found. No grade 3 or more peripheral neuropathy and edema/pleural effusion were observed. Taken together, the present study demonstrates that the DIP combination is an effective regimen for the treatment of metastatic urothelial cancer, especially attractive for MVAC-refractory cancer, and warrants further investigation.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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1 Sternberg C, Yakoda A, Scher HI, Watson RC, Herr HW, Morse MJ, et al. M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 1988;139:461–9.[ISI][Medline]
2 Loehrer PJ, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma. J Clin Oncol 1992;10:1066–73.[Abstract]
3 Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990;8:1050–5.[Abstract]
4 Roth BJ, Dreicer R, Einhorn LH, Neuberg D, Johnson DH, Smith JL, 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 1994;12:2264–70.
5 McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 1997;15:1853–7.
6 Dimopoulos MA, Deliveliotis C, Moulopoulos LA, Papadimitriou C, Mitropoulos D, Anagnostopoulos A, et al. Treatment of patients with metastatic urothelial carcinoma and impaired renal function with single-agent docetaxel. Urology 1998;52:56–60.[CrossRef][ISI][Medline]
7 Vaishampayan U, Parchment RE, Jasti BR, Hussain M. Taxanes: an overview of the pharmacokinetics and pharmacodynamics. Urology 1999;54 (Suppl 6A):22–9.[CrossRef][ISI][Medline]
8 Haldar S, Basu A, Croce CM. Bcl2 is the guardian of micro-tubule integrity. Cancer Res 1997;57:229–33.
9 Vasey PA. Role of docetaxel in the treatment of newly diagnosed advanced ovarian cancer. J Clin Oncol 2003;21:136–44.
10 Bajorin DF, McCaffrey JA, Hilton S, Mazumdar M, Kelly WK, Scher HI, et al. Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: a phase II trial. J Clin Oncol 1998;16:2722–7.[Abstract]
11 Kuroda M, Kotake T, Akaza H, Hinotsu S, Kakizoe T. Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Japanese Urothelial Cancer Research Group. Jpn J Clin Oncol 1998;28:497–501.
12 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–214.[CrossRef][ISI][Medline]
13 Tannock I, Gospodarowicz M, Connolly J, Jewett M. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) chemotherapy for transitional cell carcinoma: the Princess Margaret Hospital experience. J Urol 1989;142:289–92.[ISI][Medline]
14 Dimopoulos MA, Finn L, Logothetis CJ. Pattern of failure and survival of patients with metastatic urothelial tumors relapsing after cisplatinum-based chemotherapy. J Urol 1994;151:598–600.[ISI][Medline]
15 de Wit R, Kruit W, Stoter G, de Boer M, Kerger J, Verweij J. Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in nonchemotherapy-pretreated patients. Br J Cancer 1998;78:1342–5.[ISI][Medline]
16 Dimopoulos MA, Bakoyiannis C, Georgoulias V, Papadimitriou C, Moulopoulos LA, Deliveliotis C, et al. Docetaxel and cisplatin combination chemotherapy in advanced carcinoma of the urothelium: a multicenter phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 1999;10:1385–8.
17 Garcia del Muro X, Marcuello E, Guma J, Paz-Ares L, Climent MA, Carles J, et al. Phase II multicentre study of docetaxel plus cisplatin in patients with advanced urothelial cancer. Br J Cancer 2002;86:326–30.[CrossRef][ISI][Medline]
18 Pectasides D, Visvikis A, Aspropotamitis A, Halikia A, Karvounis N, Dimitriadis M, et al. Chemotherapy with cisplatin, epirubicin and docetaxel in transitional cell urothelial cancer. Phase II trial. Eur J Cancer 2000;36:74–9.[ISI][Medline]
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