Japanese Journal of Clinical Oncology Advance Access originally published online on February 10, 2009
Japanese Journal of Clinical Oncology 2009 39(4):244-250; doi:10.1093/jjco/hyp003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author (2009). Published by Oxford University Press. All rights reserved
Combination of Gemcitabine and Paclitaxel as Second-line Chemotherapy for Advanced Urothelial Carcinoma
1 Division of Urology, Chiba Cancer Center, Chiba
2 Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan
For reprints and all correspondence: Takeshi Ueda, Division of Urology, Chiba Cancer Center, 666-2, Nitona-cho, Chuo-ku, Chiba 260-8717, Japan. E-mail: urolccc{at}yahoo.co.jp
Received November 23, 2008; accepted January 4, 2009
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
Objective: The aim of this study was to evaluate the efficacy and toxicities of the gemcitabine and paclitaxel combination regimen as second-line chemotherapy for patients with advanced or metastatic urothelial carcinoma (UC) who have previously been treated with platinum-based chemotherapy for the metastatic disease.
Methods: Thirty-three patients with advanced or metastatic UC who had received platinum-based chemotherapy were treated with an outpatient gemcitabine and paclitaxel combination regimen. A dose of 180 mg/m2 paclitaxel was administered by intravenous (IV) infusion on Day 1, and 1000 mg/m2 gemcitabine was administered by IV on Days 1, 8 and 15.The course was repeated every 28 days. Patients were evaluated after every 2 cycles of therapy using computed tomography.
Results: Of the 33 patients enrolled in this study, 30 could be evaluated to determine treatment efficacy; 10 had an objective response [overall response rate: 33.3%, 95% confidence interval (CI), 19.2–51.2%]. The median overall survival was 11.3 months (95% CI, 7.2–13.6 months). The chemotherapy sensitivity differed with disease site. The response rates of lung and bone metastases were 27% and 14%, and the progressive disease (PD) rates of lung and bone metastases were 13% and 14%, respectively. On the other hand, the response rate of liver metastasis was 14%, and its PD rate was 57%. None of the patients (n = 3) with adrenal metastasis responded to this regimen. Toxicities were mild, and no life-threatening complications occurred.
Conclusions: Gemcitabine and paclitaxel combination therapy is a tolerable and active regimen for patients with advanced UC after failure of platinum-based chemotherapy.
Key Words: gemcitabine • paclitaxel • second-line chemotherapy • advanced urothelial carcinoma
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
Urothelial carcinoma (UC) of the bladder is the fifth most common cancer in adults. It has an annual incidence rate of 67 160 and has caused 13 750 deaths in the United States in 2007 (1). Although many patients have localized disease at diagnosis and are cured with definitive local therapies, nearly two-thirds of those with muscle invasion subsequently show regional or systemic disease recurrence. The prognosis for patients with advanced or metastatic UC of the urinary tract remains poor, with the 5-year survival estimated to be <5% (2).
Platinum-based combination chemotherapy regimens are considered standard therapy for patients with advanced UC. The combination of methotrexate, vinblastine, doxorubisine and cisplatin (MVAC) and the combination of gemcitabine and cisplatin are considered standard treatments for advanced UC (3–5). Although platinum-based combination regimens have an overall response rate ranging from 50% to 70%, disease recurrence has been reported in nearly all patients within the first year. The median survival time is approximately 12–14 months (3–6).
Effective second-line non-platinum therapies are desired for treating advanced UC after platinum-based combination therapies fail. Although the currently available therapeutic options are minimal, it was shown that gemcitabine and paclitaxel combination regimen was effective in the treatment of patients with advanced UC with lower toxicities (7–9). There are several reports on the use of gemcitabine plus paclitaxel combination therapies as second-line treatment (7–13). However, these regimens differ among institutions, and the number of patients who have been treated with these regimens as a second-line therapy is relatively small. Different institutions have reported different responses, and hence, no reasonable schedule of treatment for second-line gemcitabine plus paclitaxel chemotherapy has been established. For pre-treated second-line patients, the most important criteria for a second-line therapy are that it can be safely administered and that it can be administered for a long duration with lower toxicities. According to these criteria, we have decided the precise dosage and protocols.
The present study was undertaken to evaluate the efficacy and toxicities of the gemcitabine plus paclitaxel combination regimen when used as second-line chemotherapy for advanced or metastatic UC, following the failure of platinum-based chemotherapy to treat the metastatic disease.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
Patients
From July 2004 and March 2008, patients with histologically confirmed UC of urothelial tract were entered into this study at Chiba Cancer Center. All the patients had received platinum-based chemotherapy for advanced or metastatic disease; those who had received adjuvant/neo-adjuvant chemotherapies were not included in this study. This study was initiated after a rest period of at least 4 weeks following previous chemotherapy. Patients were required to have clinically measurable disease. Adequate bone marrow, liver and renal functions were defined as follows: hemoglobin level of >9.5 g/dl, absolute neutrophil count of >2000/mm3, platelet count of >100 000/mm3, transaminase levels less than 2.0 times normal, a serum total bilirubin of <1.5 mg/dl and a serum creatinine of <1.5 mg/dl. Patients with other malignancies or concurrent uncontrolled medical illness were deemed ineligible for the study. Informed consent was obtained from all patients. This study was approved by the Institutional Review Board (IRB) of Chiba Cancer Center.
Patient characteristics are listed in Table 1. As prior treatment, 30 patients had received MVAC, whereas 3 patients had received mathotrexate, epirubicin and cisplatin. The median prior treatment cycle was 3 (range, 2–8). All the patients developed progressive disease (PD) after undergoing platinum-based chemotherapy.
|
Chemotherapy Regimen
All patients received 180 mg/m2 paclitaxel that was administered by intravenous (IV) infusion for 3 h on Day 1 and 1000 mg/m2 gemcitabine that was administered by IV infusion for 30 min on Days 1, 8 and 15. Dexamethazone (20 mg) and maleate chlorpheniramine (5 mg) were administered before the Day-1 treatment. Antiemetics and other supportive therapies were administered at the discretion of the physician. The treatment course was repeated every 28 days. Hospitalization was not required.
If either a white blood cell count of <2000 or a granulocyte count of <1000 was observed, granulocyte colony-stimulating factor was administered. Before each day of chemotherapy, laboratory tests were conducted to check for hematological, hepatic and renal toxicities. A 20% dose reduction was implemented in patients who experienced Grade 3/4 adverse events.
Response and Toxicity Criteria
Computed tomography (CT) was performed to determine tumor size and new lesions at the baseline and after every 2 cycles or as indicated clinically. Chemotherapy was continued until disease progression. Response was evaluated on the basis of the tumor images obtained by using CT and other techniques; laboratory data; subjective/objective symptoms; and signs before, during and after administration of the study drugs and during the period from the completion of treatment to final analysis. Evaluation was performed in compliance with the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines for antitumor activities. Toxicity grade was defined according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0.
The primary objective of this study was to assess the overall survival of the patients. Secondary objectives were to evaluate tumor responses, duration of response and toxicity. Survival was calculated as the time between the start of the treatment to death or the last follow-up. The duration of response was calculated as the time between the start of the treatment to the date of the first evidence of disease progression. The Kaplan–Meier method was used to asses overall survival. The Student t-test was used for statistical evaluation.
Treatment
Twenty-nine patients (88%) received at least two courses of treatment and were evaluated for response. One patient could not receive two courses because of evidence of rapid tumor progression after one course. Treatment response was evaluated in this patient. Three patients had an allergic reaction after the Day-1 treatment of one course: two developed a Grade 3 skin rash and one developed laryngeal edema. The cases of the two patients who developed a skin rash were complicated by other adverse events (one patient developed Grade 4 thrombocytopenia and one patient developed Grade 3 neuropathy). Treatment had to be discontinued for these patients, and they were excluded from the response evaluation. Thus, the treatment response rate was calculated for 30 patients. Toxicities were evaluated in all 33 patients.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
Treatment Efficacy
The median number of treatment courses was 5 (range, 1–15 courses). Of the 30 patients for whom the treatment response rate was calculated, 10 [33.3%; 95% confidence interval (CI), 19.2–51.2%] showed major responses to the treatment. Only one patient (3.3%) achieved a complete response. In addition, 12 of the 30 patients (40%) had stable disease after two courses of the treatment. Eight (26.4%) patients showed disease progression with this regimen (Table 2). The median duration of the response was 5.5 months (range, 1–15). At the time of analysis, 22 patients had died, 6 patients showed disease progression and 2 patients were under treatment. The median of overall survival was 11.3 months (95% CI, 7.2–13.6 months), as described in Fig. 1.
|
|
Although there was no significant difference between the number of disease sites and response rates, patients with fewer metastatic sites were more likely to respond to the second-line therapy. The percentages of patients with PD increased as the number of disease sites increased. Among our patients, 18% developed PD at one site, 22% developed PD at two sites, 40% developed PD at three sites and 50% developed PD at four sites.
Response according to the disease site is shown in Table 3. Among disease sites, visceral metastasis (lung, liver or bone) has been considered difficult to treat (14). In this regimen, the response rates of lung and bone metastases were 27% and 14%, respectively, and the PD rates of lung and bone metastases were 13% and 14%, respectively. On the other hand, the response and PD rates of liver metastasis were 14% and 57%, respectively. All three patients with adrenal metastasis did not respond to this regimen. The disease control rate (CR + PR + SD) was significantly low in the patients with liver/adrenal metastatic disease when compared with in the others (37.5% versus 86.4%, respectively, P = 0.0097). The median survival time of the liver/adrenal metastasis group was 7.2 months, and median survival of the patients without liver/adrenal metastatic disease was 12.0 months (P = 0.06).
|
Outcomes were also assessed on the basis of prior treatment sensitivity. When the patients were categorized into two groups based on the results of prior chemotherapy, namely responder (n = 21) and non-responder (n = 9) groups. The groups did not differ in response rates (33.3% and 33.3%, respectively) or median survival time (9.6 and 11.3 months, respectively, P = 0.75). Next, the patients were divided into two groups: those who had received 3 or less cycles of first-line chemotherapy (n = 16) and those who had received more than 3 cycles of first-line chemotherapy (n = 14). Although there was no significant difference in response rates (31% and 36%, respectively) or median survival time (7.2 and 12.6 months, respectively, P = 0.08) between the groups, patients who had experienced rapid relapse following the first-line therapy were less likely to benefit from our second-line therapy.
Toxicity
Treatment-related death was not observed with this regimen. Myelosuppression (predominantly neutropenia) was the most common Grade 3/4 toxicity caused by this treatment regimen (Table 4). Fifteen patients (45%) experienced Grade 3/4 neutropenia, but no patient required hospitalization for treating the neutropenia. The patients responded very well to treatment with granulocyte colony-stimulating factor. Grade 3/4 thrombocytopenia occurred in two patients, but they did not require thrombocyte transfusion.
|
Peripheral neuropathy was the most common non-hematologic toxicity with this treatment regimen. Two (6%) patients experienced Grade 3 neuropathy, and 17 (52%) patients experienced Grade 2 neuropathy. In most cases, neuralgia and/or myalagia of the legs began 3 days after paclitaxel administration; it was strong for approximately 3 days, and then, it became milder. Digestive-organ toxicities were much milder with this therapy than with platinum-based chemotherapy. In three patients, strong allergic reactions were observed: two patients developed a Grade 3 skin rash and one developed laryngeal edema. Further, seven patients (21%) developed a skin rash, which were considered an allergic reaction. Pulmonary toxicity was not observed in any patient.
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
This study demonstrates that gemcitabine plus paclitaxel combination therapy can induce a 33.3% response rate with a manageable toxicity profile when administered as an outpatient second-line treatment for metastatic UC. In addition, this therapy is associated with a disease control rate (CR + PR + SD) of 73.3% after 2 cycles of chemotherapy. The median overall survival time is 11.3 months, and the 1-year survival is 37.4%.
Previously tested gemcitabine plus paclitaxel combination therapies are summarized in Table 5 (7–13). The trials of second-line chemotherapy for advanced pre-treated UC are summarized in Table 6 (15–36). A number of these trials included patients who had received adjuvant/neo-adjuvants as their prior treatment. Although all our patients had received first-line chemotherapy for their metastatic disease, our results were more favorable than those of other trials, especially in terms of overall survival. A comparison of the results of second-line monotherapies and combination therapies reveals that a high response rate does not always result in survival benefits. Our regimen's survival benefits might be because it was mild.
|
|
Our gemcitabine plus paclitaxel combination regimen can be safely used to treat patients with impaired renal function. Patients with advanced UC often have impaired renal function because of advanced age, prior platinum-containing chemotherapy, prior nephrectomy or disease-related hydronephrosis. The gemcitabine dose in our regimen was relatively low because all our patients had received prior cisplatin-based chemotherapy (median, 3 cycles; range, 2–8 cycles). This was to avoid the severe pulmonary toxicities that have been reported in a previous study of gemcitabine plus paclitaxel combination therapy (10). The 28-day schedule provided the patients with a 1-week rest period between cycles.
The following features support the clinical applicability of this regimen: outpatient administration and a tolerable toxicity profile in previously treated patients. No life-threatening complication was seen with this treatment. The most frequent Grade 3/4 toxicity associated with this regimen was myelosuppression; Grade 3/ 4 neutropenia occurred in 15 (45%) patients. However, the neutropenia was easily managed and not associated with the clinically significant event of neutropenic fevers. Grade 2/3 neuropathy occurred in 19 (58%) patients. This neuropathy was not life-threatening and was considered a dose-limiting factor; however, it occasionally resisted treatment with medication. Additional effective preventive methods are required. Pulmonary toxicities such as interstitial pneumonitis have been reported with gemcitabine plus paclitaxel-containing regimens (10,13). However, none of the 33 patients in the current study experienced pulmonary toxicities. Although it is not clear if pulmonary toxicities occur in a dose-dependent manner, these complications are more likely to occur with high-dose regimens (37). Our regimen has appropriate doses, a schedule with favorable efficacy and no fatal toxicities. However, a major limitation of this regimen is the high frequency of allergic reactions. Of the 33 patients, 7 (21%) developed a skin rash. This reaction was believed to be due to the absolute ethanol in paclitaxel. Ethanol was not only the allergen but it might have induced allergic reactions to other allergens since it up-regulates the total serum IgE levels (38).
As listed in Tables 5 and 6, previous trials that assessed the efficacy of chemotherapy as a second-line treatment for UC have demonstrated variable success. The variability in the response rates of these studies is likely due to the variability in drug activity and also confounding factors among the different patient populations. In view of this, previous reports have emphasized the prognostic factor of patients. Response to second-line therapy appears to be predicted by chemosensitivity to first-line therapy (39), performance status (8), presence of visceral metastasis (7), prior therapy (adjuvant versus metastatic) (7) or a combination of performance status and the presence of visceral metastasis (7).
We analyzed each prognostic factor. We emphasize the importance of the sites of metastasis as predictors of the response to second-line chemotherapy. With regard to visceral metastasis, there are differences in response according to the disease site. Bone metastasis is considered to achieve low response rates with platinum-based therapy. In our study, the response rates of bone metastasis to the gemcitabine plus paclitaxel therapy were not very high but the progression rates were also not high (14% and 14%, respectively). Lung metastasis had favorable response rates in our study. We analyzed how each type of visceral metastasis could be controlled by our regimen. The control rates of liver and adrenal metastasis were very low: 30%. Lung and bone metastases had more favorable control rates (87% and 86%, respectively). Although Bajorin et al. (14) make no mention of adrenal metastasis in their prognostic risk categories, adrenal metastasis is not rare in advanced UC. Among patients who had died of advanced bladder cancer, 13% showed adrenal metastasis at autopsy (40). The possibility of adrenal metastasis may be higher in pre-treated second-line chemotherapy patients. It is important that adrenal metastasis be considered a poor prognostic factor.
|
CONCLUSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
Gemcitabine plus paclitaxel combination therapy is a tolerable and active regimen for treating advanced UC previously treated with platinum-based chemotherapy regimens. It should be recommended as a candidate for second-line chemotherapy for advanced UC. Liver and adrenal metastases are believed to be indicators of a poor response to this regimen.
|
Conflict of interest statement |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
None declared.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONConflict of interest statementReferences |
|---|
1 Gralow J, Ozols RF, Bajorin DF, Cheson BD, Sandler HM, Winer EP, et al. Clinical cancer advances 2007: major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol (2008) 26:313–25.
2 Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, 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 (1997) 15:2564–9.
3 Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer (1989) 64:2448–58.[CrossRef][Web of Science][Medline]
4 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.[Web of Science][Medline]
5 von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol (2000) 18:3068–77.
6 von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol (2005) 23:4602–8.
7 Sternberg CN, Calabro F, Pizzocaro G, Marini L, Schnetzer S, Sella A. Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer (2001) 92:2993–8.[CrossRef][Web of Science][Medline]
8 Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, et al. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol (2001) 19:3018–24.
9 Kaufman DS, Carducci MA, Kuzel TM, Todd MB, Oh WK, Smith MR, et al. A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer. Urol Oncol (2004) 22:393–7.[Web of Science][Medline]
10 Li J, Juliar B, Yiannoutsos C, Ansari R, Fox E, Fisch MJ, et al. Weekly paclitaxel and gemcitabine in advanced transitional-cell carcinoma of the urothelium: a phase II Hoosier Oncology Group study. J Clin Oncol (2005) 23:1185–91.
11 Fechner G, Siener R, Reimann M, Kobalz L, Albers P. Randomised phase II trial of gemcitabine and paclitaxel second-line chemotherapy in patients with transitional cell carcinoma (AUO Trial AB 20/99). Int J Clin Pract (2006) 60:27–31.[Web of Science][Medline]
12 Takahashi T, Higashi S, Nishiyama H, Segawa T, Nakamura E, Kinoshita H, et al. Biweekly paclitaxel and gemcitabine for patients with advanced urothelial cancer ineligible for cisplatin-based regimen. Jpn J Clin Oncol (2006) 36:104–8.
13 Matsumoto K, Irie A, Satoh T, Okazaki M, Iwamura M, Baba S. Gemcitabine and paclitaxel chemotherapy as a second-line treatment for advanced or metastatic urothelial carcinoma. Int J Urol (2007) 14:1000–4. discussion 4.[CrossRef][Web of Science][Medline]
14 Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol (1999) 17:3173–81.
15 Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol (1997) 15:589–93.
16 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.
17 Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. Eur J Cancer (1998) 34:1208–12.[CrossRef][Web of Science][Medline]
18 Akaza H, Naito S, Usami M, Miki T, Miyanaga N, Taniai H. Efficacy and safety of gemcitabine monotherapy in patients with transitional cell carcinoma after Cisplatin-containing therapy: a Japanese experience. Jpn J Clin Oncol (2007) 37:201–6.
19 Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol (2002) 20:937–40.
20 Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol (2006) 24:3451–7.
21 Culine S, Theodore C, De Santis M, Bui B, Demkow T, Lorenz J, et al. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Br J Cancer (2006) 94:1395–401.[CrossRef][Web of Science][Medline]
22 Dreicer R, Li S, Manola J, Haas NB, Roth BJ, Wilding G. Phase 2 trial of epothilone B analog BMS-247550 (ixabepilone) in advanced carcinoma of the urothelium (E3800): a trial of the Eastern Cooperative Oncology Group. Cancer (2007) 110:759–63.[CrossRef][Web of Science][Medline]
23 Gomez-Abuin G, Winquist E, Stadler WM, Pond G, Degendorfer P, Wright J, et al. A phase II study of PS-341 (Bortezomib) in advanced or metastatic urothelial cancer. A trial of the Princess Margaret Hospital and University of Chicago phase II consortia. Invest New Drugs (2007) 25:181–5.[CrossRef][Web of Science][Medline]
24 Tu SM, Hossan E, Amato R, Kilbourn R, Logothetis CJ. Paclitaxel, cisplatin and methotrexate combination chemotherapy is active in the treatment of refractory urothelial malignancies. J Urol (1995) 154:1719–22.[CrossRef][Web of Science][Medline]
25 Sweeney CJ, Williams SD, Finch DE, Bihrle R, Foster RS, Collins M, et al. A Phase II study of paclitaxel and ifosfamide for patients with advanced refractory carcinoma of the urothelium. Cancer (1999) 86:514–8.[CrossRef][Web of Science][Medline]
26 De Mulder PH, Theodore C, Sella A, Koriakine O, Sternberg CN, Collette L, et al. Phase II EORTC trial with 5-fluorouracil, cisplatin and interferon-alpha as second-line treatment of advanced transitional cell cancer of the urothelial tract. Ann Oncol (2000) 11:1391–4.
27 Vaishampayan UN, Faulkner JR, Small EJ, Redman BG, Keiser WL, Petrylak DP, et al. Phase II trial of carboplatin and paclitaxel in cisplatin-pretreated advanced transitional cell carcinoma: a Southwest Oncology Group study. Cancer (2005) 104:1627–32.[CrossRef][Web of Science][Medline]
28 Shinohara N, Harabayashi T, Suzuki S, Nagao K, Seki H, Murakumo M, et al. Salvage chemotherapy with paclitaxel, ifosfamide, and nedaplatin in patients with urothelial cancer who had received prior cisplatin-based therapy. Cancer Chemother Pharmacol (2006) 58:402–7.[CrossRef][Web of Science][Medline]
29 Kouno T, Ando M, Yonemori K, Matsumoto K, Shimizu C, Katsumata N, et al. Weekly paclitaxel and carboplatin against advanced transitional cell cancer after failure of a platinum-based regimen. Eur Urol (2007) 52:1115–22.[CrossRef][Web of Science][Medline]
30 Pectasides D, Aravantinos G, Kalofonos H, Kiamouris C, Bafaloukos D, Xiros N, et al. Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group. Ann Oncol (2001) 12:1417–22.
31 Krege S, Rembrink V, Borgermann C, Otto T, Rubben H. Docetaxel and ifosfamide as second line treatment for patients with advanced or metastatic urothelial cancer after failure of platinum chemotherapy: a phase 2 study. J Urol (2001) 165:67–71.[CrossRef][Web of Science][Medline]
32 Pagliaro LC, Millikan RE, Tu SM, Williams D, Daliani D, Papandreou CN, et al. Cisplatin, gemcitabine, and ifosfamide as weekly therapy: a feasibility and phase II study of salvage treatment for advanced transitional-cell carcinoma. J Clin Oncol (2002) 20:2965–70.
33 Uhm JE, Lim HY, Kim WS, Choi HY, Lee HM, Park BB, et al. Paclitaxel with cisplatin as salvage treatment for patients with previously treated advanced transitional cell carcinoma of the urothelial tract. Neoplasia (2007) 9:18–22.[CrossRef][Web of Science][Medline]
34 Lin CC, Hsu CH, Huang CY, Keng HY, Tsai YC, Huang KH, et al. Gemcitabine and ifosfamide as a second-line treatment for cisplatin-refractory metastatic urothelial carcinoma: a phase II study. Anticancer Drugs (2007) 18:487–91.[CrossRef][Medline]
35 Soga N, Onishi T, Arima K, Sugimura Y. Paclitaxel Carboplatin chemotherapy as a second-line chemotherapy for advanced platinum resistant urothelial cancer in Japanese cases. Int J Urol (2007) 14:828–32.[CrossRef][Web of Science][Medline]
36 Dreicer R, Manola J, Schneider DJ, Schwerkoske JF, George CS, Roth BJ, et al. Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: a trial of the Eastern Cooperative Oncology Group. Cancer (2003) 97:2743–7.[CrossRef][Web of Science][Medline]
37 Dunsford ML, Mead GM, Bateman AC, Cook T, Tung K. Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma. Ann Oncol (1999) 10:943–7.
38 Gonzalez-Quintela A, Vidal C, Gude F. Alcohol, IgE and allergy. Addict Biol (2004) 9:195–204.[CrossRef][Web of Science][Medline]
39 Albers P, Siener R, Hartlein M, Fallahi M, Haeutle D, Perabo FG, et al. Gemcitabine monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma—prognostic factors for response and improvement of quality of life. Onkologie (2002) 25:47–52.[CrossRef][Web of Science][Medline]
40 Wallmeroth A, Wagner U, Moch H, Gasser TC, Sauter G, Mihatsch MJ. Patterns of metastasis in muscle-invasive bladder cancer (pT2-4): an autopsy study on 367 patients. Urol Int (1999) 62:69–75.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||