Weekly chemotherapy with docetaxel, gemcitabine and cisplatin in advanced transitional cell urothelial cancer: a phase II trial

D. Pectasides+, J. Glotsos, N. Bountouroglou, A. Kouloubinis, N. Mitakidis, N. Karvounis, N. Ziras and A. Athanassiou

First Department of Medical Oncology, Metaxa’s Memorial Cancer Hospital, Piraeus, Greece

Received 21 May 2001; revised 25 July 2001; accepted 17 August 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose

To evaluate the efficacy and toxicity of a combination of weekly docetaxel, gemcitabine and cisplatin in advanced transitional cell carcinoma (TCC) of the bladder.

Patients and methods

Thirty-five chemotherapy-naïve (adjuvant and neoadjuvant chemotherapy was allowed) patients with advanced TCC received intravenous docetaxel 35 mg/m2, gemcitabine 800 mg/m2 and cisplatin 35 mg/m2, on days 1 and 8 every 3 weeks. Prophylactic granulocyte-colony stimulating factor was given from days 3 to 6 and days 10 to 15; anti-emetics were used routinely.

Results

Most (27) patients (77.1%) had a performance status of 0 to 1 and eight (22.9%) had received prior adjuvant or neoadjuvant cisplatin-based chemotherapy. In the intention-to-treat analysis, the objective response rate was 65.6% [23/35 patients, 95% confidence interval (CI) 47.8% to 80.9%]. Ten patients (28.5%) achieved a complete response (95% CI 14.6% to 46.3%) and 13 (37.1%) a partial response (95% CI 21.5% to 55.0%). Median survival time was 15.5 months, median duration of response was 10.2 months and median time to progression was 8.9 months. Ten patients (28.5%) developed grade 3/4 neutropenia, including five (14.3%) who experienced febrile neutropenia, which was successfully treated. Grade 3/4 anaemia and thrombocytopenia occurred in 20% and 25.7% of patients, respectively; four patients required platelet transfusions. There were no treatment-related deaths.

Conclusions

Weekly docetaxel, gemcitabine plus cisplatin is a highly effective treatment for chemotherapy-naïve advanced TCC, and causes only moderate toxicity. This regimen should be considered as a suitable option that deserves further prospective evaluation through randomised phase III trials.

Key words: cisplatin, docetaxel, gemcitabine, transitional cell carcinoma, urothelial cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Carcinoma of the bladder is the fourth most common cancer in men and the ninth in women [1]. Of patients with muscle invasive transitional cell carcinoma (TCC) of the bladder, ~50% develop pelvic recurrence or distant metastases [2].

Cisplatin is one of the most effective single-agent treatments for metastatic urothelial TCC, with response rates of 12–40% [36], and forms the cornerstone of combination chemotherapy. Cisplatin-based combination chemotherapy has become standard care for patients with advanced urothelial TCC [7]. Combinations of methotrexate (MTX)/vinblastine (VLB)/doxorubicin/cisplatin (M-VAC) and cisplatin/MTX/VLB (CMV) are considered the most active regimens for metastatic TCC, with reported response rates of 46–72% [810]. One study recently reported a 5-year survival rate of 40% with M-VAC [11]. M-VAC has been shown to be superior to single-agent cisplatin, in terms of response rate and survival [3], and also to cisplatin, cyclophosphamide and adriamycin (CISCA) in terms of response rate [12]. Cisplatin-based chemotherapy has also been shown to be superior to carboplatin-based chemotherapy in advanced bladder carcinoma [13].

However, M-VAC is associated with significant toxicity, including grade 3/4 myelosuppression, mucositis, nephrotoxicity, nausea and vomiting, as well as drug-related mortality [3, 9]. Moreover, despite the use of haematopoietic growth factors to reduce myelotoxicity and allow dose intensification of M-VAC, response rates with this regimen have not improved. Therapeutic approaches with new agents are therefore required to improve response rate and survival while reducing toxicity [14].

During the last decade, several new chemotherapeutic agents have shown activity against advanced TCC, including docetaxel [15, 16] and gemcitabine [1720]. Docetaxel and gemcitabine exert differing mechanisms of cytotoxic activity to cisplatin. Docetaxel binds to the ß-subunit of tubulin, inhibiting the formation of stable microtubule bundles, which leads to cell death [21]. It also acts through phosphorylation of Bcl-2, which promotes apoptosis [22]. Gemcitabine is an antimetabolite that inhibits DNA synthesis and ribonucleotide reductase [23].

Both agents have shown single-agent activity in advanced or metastatic TCC. Single-agent docetaxel 100 mg/m2 has achieved response rates ranging from 31–50% in patients with chemotherapy-naïve metastatic TCC, and 13% in previously treated patients [15, 16, 24, 25]. Single-agent gemcitabine, at doses ranging from 875–1350 mg/m2, yielded response rates of 23% and 28% in previously untreated patients [18, 19] and 27% and 23% in patients who had received prior chemotherapy with cisplatin [17, 20].

Combinations of these two agents with cisplatin have been found to achieve higher response rates than either docetaxel or gemcitabine alone. In three studies, cisplatin 75 mg/m2 plus docetaxel 75 mg/m2 produced response rates of 57–62% in chemotherapy-naïve patients with metastatic TCC [2628]. Similarly, gemcitabine 1000 mg/m2 plus cisplatin 70–100 mg/m2 every 4 weeks achieved response rates ranging from 40–66% in untreated and previously treated patients with advanced TCC [2932].

In a study of gemcitabine 800 mg/m2 (given on days 1, 8 and 15) and docetaxel 80 mg/m2 (given on day 1) in TCC patients who were either chemotherapy-naïve or had failed one prior non-gemcitabine or non-taxane-containing regimen [33], the overall response rate in the 14 evaluable patients was 43%.

Given these findings and the different mechanisms of action of cisplatin, docetaxel and gemcitabine, we conducted a phase II study to evaluate the efficacy and toxicity of a combination of all three agents, administered on a weekly basis. The weekly administration and sequence of agents was chosen on the basis of previous experience with combination studies [25–32, 34, 35]. It was also based on our unpublished data from a dose-finding phase I trial of weekly administration of these agents in advanced TCC and our experience using weekly chemotherapy for non-small-cell lung cancer.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
This study enrolled patients with histologically proven, bidimensionally measurable, advanced TCC of the bladder, renal pelvis or ureter, who had received no prior chemotherapy for advanced disease. Eligible patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3, life expectancy of at least 12 weeks, adequate haematological [white blood cell count (WBC) >=4000 cells/µl, absolute neutrophil count (ANC) >=2000 cells/µl, platelet count >=100 000/µl, haemoglobin >=10 g/dl], renal (serum creatinine <1.5 mg/dl, creatinine clearance >=60 ml/min) and liver functions [bilirubin <1.5-fold the upper normal limit (UNL) and AST <2-fold the UNL, unless liver metastases were present, in which case <5-fold the UNL was allowed]. Patients who had previously received intravesical chemotherapy or immunotherapy were not excluded, and prior adjuvant or neoadjuvant treatment was permitted if it had been completed more than 6 months before study entry. Patients who had previously been treated with radiotherapy were entered into the study, provided that measurable disease existed outside the radiation field.

Exclusion criteria comprised patients who had only malignant effusion, bone metastases or lesions assessable only by endoscopy; patients with brain metastases, history of atrial or ventricular cardiac arrhythmias, congestive heart failure, documented myocardial infarction or pre-existing motor or sensory neurotoxicity grade >=1 according to the WHO scale. Patients with active infection or other serious underlying medical conditions that would impair administration of the protocol treatment were also ineligible.

The study protocol was approved by the local ethics committee, and informed consent was obtained from all patients before enrolment.

Treatment plan
Chemotherapy was administered on an outpatient basis. Patients received the following chemotherapy sequence on days 1 and 8 of a 21-day cycle: docetaxel 35 mg/m2 in 250 ml 5% glucose as a 30 min intravenous (i.v) infusion with oral steroid premedication (dexamethasone 8 mg orally every 12 h for four doses); gemcitabine 800 mg/m2 in 500 ml normal saline as a 30 min i.v infusion; and cisplatin 35 mg/m2 in 250 ml normal saline as a 1 h i.v. infusion, with brief pre- [500 ml 5% glucose + 500 ml normal saline + 2 Amp KCl (26.8 mEq KCl) as a 2 h i.v. infusion] and post- [500 ml 5% glucose + 500 ml normal saline + 2 Amp KCl (26.8 mEq KCl) + 8 ml MgSO4 (2 g MgSO4 or 16.32 mEq Mg2+) + 100 ml mannitol 20% as a 3 h i.v. infusion] hydration and mannitol (50 ml i.v. bolus before the administration of cisplatin) diuresis. Anti-emetic prophylaxis (ondansetron) was given before the administration of each cycle. Prophylactic recombinant human granulocyte-colony stimulating factor (G-CSF) 150 µg/m2 was given subcutaneously from day 3 to day 6 and day 10 to day 15.

Doses of chemotherapy agents were modified according to WBC and platelet counts, as well as renal and hepatic function. Chemotherapy was given as above on day 1 if the ANC was >2000 cells/µl and the platelet count was >100 000/µl on the day of treatment. However, if the ANC nadir was <1000 cells/µl and/or platelet nadir was <75 000/µl, the doses were reduced to docetaxel 30 mg/m2, gemcitabine 700 mg/m2 and cisplatin 30 mg/m2 (level 1) if the ANC was <500 cells/µl and/or platelet count <50 000/µl the doses were further reduced to docetaxel 25 mg/m2, gemcitabine 600 mg/m2 and cisplatin 25 mg/m2 (level 2). Any patient who required treatment delay on day 1 because of toxicity had the dose reduced to level 1 for subsequent cycles.

On day 8, the full doses were given if the ANC was >1500 cells/µl, platelet count was >=100 000/µl and any non-haematological toxicity was grade 2 or lower. However, if the ANC was 1000–1500 cells/µl or the platelet count was 75 000–99 000/µl, the dosage was reduced to level 1, and if the ANC was <1000 cells/µl or the platelet count was <50 000/µl the treatment was withheld. Any patient who required treatment to be withheld on day 8 because of toxicity had the dosage reduced to level 2 for subsequent cycles.

The dose of cisplatin was also adjusted according to creatinine clearance. If creatinine clearance was <50 ml/min, treatment was delayed until recovery (but for no longer than 10 days, otherwise the patient was removed from the study). A dose reduction of 25% was made if the creatinine clearance was between 50 and 59 ml/min. If patients experienced any grade 3 or 4 non-haematological toxicity, chemotherapy was withheld until recovery to grade 1 or less.

Assessments
Before entering the study, all patients underwent a physical examination, complete blood count (CBC), blood chemistry, chest X-ray, bone scan and abdominal computed tomography (CT) scan. A thoracic CT scan and other specific tests were performed when indicated. Cystoscopic evaluation was performed only when necessary for local recurrence.

Response was assessed every two cycles of treatment according to WHO criteria [36]. Most of the imaging examinations were performed in different private centres. All these tests were reviewed by two consultant radiologists at our institution. Patients were treated with at least six cycles of chemotherapy unless there was evidence of disease progression or unacceptable toxicity occurred during treatment. After completing six cycles of treatment, patients were followed up. Patients who were stable for six cycles were considered to have completed protocol therapy and went off treatment. Patients who achieved either a complete or partial response after six cycles could continue treatment for a further two cycles at the discretion of the investigator. Complete blood count and serum creatinine levels were monitored weekly and toxicity was evaluated weekly. The WHO scale was used to grade toxicity.

Complete response was defined as the complete disappearance of all measurable disease for at least 4 weeks. Partial response was defined as a more than 50% reduction in all measurable disease for at least 4 weeks. Stable disease was defined as a 50% or less reduction of all measurable lesions. Progressive disease was defined as an increase in any lesion or the appearance of new lesions. All responses were confirmed 4 weeks later.

Statistics
The primary endpoints of this study were to evaluate the response and toxicity. Sample size was based on overall response rate. According to Simon’s two-stage minimax design, assuming that the expected overall response rate would not be <=50% or >=70%, a sample size of 20 patients would be required for the first step and 15 patients for the second step. If <=11 or >=16 responses were seen at step 1, then the study would be discontinued. If 12 to 15 responses were observed, then an additional 15 patients would be required.

Survival was calculated from the day of commencement of chemotherapy to the day of death using the Kaplan–Meier method [37]. Duration of response was calculated from the first day response was noted until the date of progression. Time to tumour progression was defined as the time elapsed from the start of treatment to renewed disease progression.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
From October 1997 to June 1999, 35 eligible patients were enrolled and treated. The analysis was performed in May 2000; all patients were assessable for toxicity and 32 for response. One patient withdrew consent after the first treatment cycle because of severe asthenia and fatigue, one had a stroke and one died soon after the first cycle because of rapid deterioration of his disease (in the liver). Baseline patient characteristics are shown in Table 1. Median age was 65 years, and three-quarters of patients were male. More than half of the patients had an Eastern Co-operative Oncology Group (ECOG) performance status of 1. Eight patients had previously received either adjuvant or neoadjuvant chemotherapy. In none of the patients was the bladder the sole site of disease; almost two-thirds of the population had lymph-node metastases, and almost one-third had either liver or bone involvement.


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Table 1. Patient characteristics at baseline
 
Response
In the intention-to-treat analysis, the objective response rate was 65.6% [23/35 patients; 95% confidence interval (CI) 47.8% to 80.9%]. Complete response was achieved in 10 patients (28.5%, 95% CI 14.6% to 46.3%) and partial response in 13 (37.1%, 95% CI 21.5% to 55.0%). An additional six patients met the criteria for disease stabilisation, and three patients had progressive disease. The three patients who were not assessable for response were also classed as having progressive disease (Table 2). Responses by disease site are shown in Table 3. Some complete responses were noted in patients with metastases at all disease sites except for bone. The patient with pleural effusion who achieved complete remission also had lymph-node and lung metastases.


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Table 2. Response rates (n = 35)
 

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Table 3. Response by disease site
 
The median duration of response was 10.2 months (range 3.1 to 24.8 months), the median time to progression was 8.9 months (range 4.2 to 22.6 months) and the median survival time was 15.5 months (range 1.8 to 24.8 months). At a median follow-up of 12.9 months, 18 patients were still alive.

Treatment administration
The median number of cycles per patient was five (range 1–8). The median relative dose intensities were 0.87 for docetaxel, 0.88 for gemcitabine and 0.89 for cisplatin. Despite the prophylactic use of haematopoietic growth factors, dose reduction was required in seven patients (20%), three of whom required two reductions. Five patients required dose reductions of cisplatin because of renal toxicity, but no cisplatin doses were omitted or delayed. All dose reductions were due to neutropenia, thrombocytopenia or renal toxicity, with no dose reduction or treatment delay for any other grade 3/4 toxicity.

Toxicity
The main toxicity was myelosuppression (Table 4). Grade 4 neutropenia occurred in four patients (11.4%) and grade 3 neutropenia in six (17.1%) patients. Five patients were hospitalised with febrile neutropenia, which was treated with broad-spectrum antibiotics. Grade 3/4 thrombocytopenia occurred in nine patients (25.7%). Nine patients required hospitalisation (five because of febrile neutropenia and four for platelet transfusions). None of the patients who underwent platelet transfusions had evidence of bleeding.


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Table 4. Incidence of toxicity
 
Grade 3/4 nephrotoxicity occurred in five patients (14.3%) and resulted in dose reduction in all five. Fluid retention grade >=2 occurred in six patients (17.2%) but was easily managed with oral diuretics. No patient had general skin changes, but erythema, rash, pruritus, desquamation and nail changes were observed in more than one-third of patients. Peripheral neuropathy was experienced by four patients (11.4%), usually after two or three treatment cycles. Infusion-related allergic reactions occurred in five patients (14.3%), but all resolved within 5–10 min. Two of these patients showed evidence of hypersensitivity reaction (chest tightness, dyspnoea, cough and flushing) that required treatment with adrenaline, antihistamines and corticosteroids; these events did not recur after the patients were treated with a 2 h infusion of docetaxel and gemcitabine.

Nausea and vomiting grade >=2 occurred in 22 patients (62.8%), grade 2/3 diarrhoea in seven patients (20%) and mucositis grade >=2 in 12 patients (34.3%). Ten patients (28.6%) developed grade 2/3 fatigue that did not require dose modification, but one patient who experienced grade 3 fatigue withdrew from treatment after the first cycle. Alopecia was universal but reversible. Constipation was not a problem. There were no instances of cardiac toxicity and no treatment-related deaths during the study or follow-up.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This phase II study of a combination of docetaxel, gemcitabine and cisplatin (the first reported for this drug combination) given weekly was well tolerated and highly effective as a first-line treatment for metastatic TCC, as demonstrated by the response rate, median time to progression and median survival. The overall response rate of 65.6% is one of the highest reported to date; it is superior to response rates with the three agents alone [3–6, 15–20] and matches or exceeds response rates achieved with combinations of cisplatin/gemcitabine [2932] or cisplatin/docetaxel [2628].

Methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) remains the standard treatment for many patients with advanced TCC (10). Recently, M-VAC regimen was compared in a randomised, multinational, multicentre phase III study with gemcitabine 1000 mg/m2 given on days 1, 8 and 15 and cisplatin 70 mg/m2 day 2 [38]. The response rate (46% versus 49%), median time to progression (7.4 months for both arms) and median survival (14.8 versus 13.8 months) were similar in both arms. More gemcitabine plus cisplatin than M-VAC patients had grade 3/4 anaemia and thrombocytopenia, while more M-VAC than gemcitabine plus cisplatin patients had grade 3/4 neutropenia, neutropenic fever, neutropenic sepsis and toxic death. More patients on gemcitabine plus cisplatin faired better regarding weight, performance status and fatigue. The need exists, therefore, to develop new combinations for the treatment of patients with metastatic TCC in order to find more effective and less toxic combinations. During the last few years a number of new chemotherapeutic agents have been shown to be active against advanced TCC, including paclitaxel [3941], docetaxel [15, 16, 25], gemcitabine [18, 19], vinorelbine [4244], liposomal doxorubicin [45] and gallium nitrate [4648].

This triple combination was also well tolerated, showing only moderate toxicity—28.5% of patients developed grade 3/4 neutropenia and 25.7% thrombocytopenia; only nine patients required hospitalisation. These figures compare well with the findings of dual combinations of cisplatin/gemcitabine or cisplatin/docetaxel. In a phase II study of cisplatin/gemcitabine, 55% of patients experienced grade >=3 thrombocytopenia [32]. In recent phase I/II studies, the incidence of neutropenia was 56% in patients receiving docetaxel/cisplatin [27] and as high as 71% in those receiving cisplatin/gemcitabine [38]. No major infections occurred in this study, compared with an incidence of febrile neutropenia of 41% reported in one study using M-VAC [3] and 38% grade 3/4 neutropenia reported in a study using paclitaxel, gemcitabine and cisplatin every 3 weeks [34]. Nausea and vomiting grade >=3 occurred in approximately one-quarter of our patients, despite the use of ondansetron premedication, a finding that compares well with incidences seen in studies of gemcitabine/cisplatin [38] or docetaxel/cisplatin [27] in combination. Mucositis grade 3/4 occurred in 11.4% of patients, which is comparable with incidences reported with M-VAC [3] and a combination of gemcitabine/cisplatin [32]. Fatigue grade >=3 also occurred in 11.4% of patients, comparing well with reports for M-VAC [3] and a combination of gemcitabine/cisplatin [32]. Neurotoxicity grade >=2 was observed in 11.4% of patients, but was reversible during the follow-up period. Grade 2/3 cutaneous toxicity and fluid retention were limited by the use of premedication and a low dose of docetaxel. Hypersensitivity reactions were generally mild to moderate and resolved within 5–10 min. Premedication was given to reduce the risk of allergic reactions. Prophylactic haematopoietic growth factor was used to maintain the dose and weekly administration, although 20% of patients required a dose reduction and 8.6% required two reductions.

Our study was designed on the basis that paired combinations of docetaxel, gemcitabine and cisplatin, which represent three of the most active single agents in advanced TCC, have been shown to achieve higher response rates than any of the three agents alone. Combination chemotherapy offers the potential to optimise response rates and survival by using agents with complementary mechanisms of action. In vivo and in vitro studies of cisplatin plus gemcitabine have shown both synergistic and additive effects [49]. Cisplatin and docetaxel are not synergistic in vivo, but seem to be non-cross-resistant clinically and have a predominantly non-overlapping toxicity profile, and this combination may have at least an additive effect clinically [50]. Gemcitabine and docetaxel have different cellular targets (DNA synthesis and microtubules, respectively) and act at different phases of the cell cycle (S phase and mitosis, respectively). The interaction between gemcitabine and paclitaxel has also been studied in cell-line models (A 549, lung; MCF 7, breast; and P-SW pancreas) [51]. Antagonism was noted for all three cell lines when gemcitabine and paclitaxel were administered concurrently, while additive effects were seen when gemcitabine preceded or followed paclitaxel [51]. However, simultaneous and sequential combination schedules of gemcitabine and paclitaxel in human bladder cancer cell lines showed additive cytotoxic properties [52]. In addition, it seems that a schedule of weekly administration of these agents is probably better tolerated than schedules in which these agents are given every 3–4 weeks [53]. Also, considerable experience has been accumulated with weekly or rapidly repeated regimens. Results clearly indicate that this strategy is feasible in many oncological settings, with manageable toxicity and a limited number of toxicity-related deaths when therapy is adequately monitored by well trained oncologists. Response rates are impressive and a benefit in disease-free survival or overall survival has been reported in a number of malignances [54]. We therefore administered the triple combination of docetaxel, gemcitabine and cisplatin to investigate whether incorporating a third agent would prove superior in terms of response rate, median survival and/or toxicity. The sequence of agents was chosen on the basis of previous experience with combination studies [26–32, 35, 38]. We administered the three agents on a weekly basis in the following sequence: docetaxel, gemcitabine and cisplatin.

Recent studies have also evaluated the efficacy of other triple combination regimens in advanced TCC. Again, overall response rates and median survival were similar to those reported with our triple regimen, but these regimens appeared to give rise to higher levels of toxicity. In a previous phase II study we investigated a combination of epirubicin (40 mg/m2) i.v. push, docetaxel (75 mg/m2) in a 1-h infusion and cisplatin (75 mg/m2), every 3 weeks in patients with advanced TCC [55]. Overall response rate was 67% and median survival was 14.5 months. However, 53% of patients experienced grade >=3 neutropenia and, despite the use of haematopoietic growth factors, 53.3% of patients required dose reduction due to myelosuppression (16.7% required two reductions). In another phase II study evaluating cisplatin 70 mg/m2 on day 1, and paclitaxel 80 mg/m2 and gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks in patients with previously untreated locally unresectable or metastatic TCC, Bellmunt et al. [34] reported an overall response rate of 77.6% (27.6% complete response) and median survival of 24 months. Again, however, toxicity was higher [main toxicity grade >=3 neutropenia and thrombocytopenia (55% and 22%, respectively)] than that seen with the triple regimen described in the present study. Frassoldati et al. [35] evaluated the combination of cisplatin 70 mg/m2, gemcitabine 800 mg/m2 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks in chemotherapy-naïve patients with metastatic or unresectable locally advanced TCC. Although overall response rate was somewhat lower than that reported with our triple regimen (33%; intention-to-treat response rate 26.6%; median time to progression of 4 months), grade >=3 neutropenia and thrombocytopenia occurred in only 14% and 8% of patients, respectively. The authors consider that pharmacokinetic interaction due to the sequence of the drugs could be responsible for this low response rate.

A recent triple regimen study, based on carboplatin rather than cisplatin, has shown similar findings. A combination of paclitaxel (200 mg/m2), carboplatin (target AUC of 5) on day 1, and gemcitabine (800 mg/m2 on days 1 and 8), every 3 weeks, gave a response rate of 68% (95% CI 56.26 to 82.86; 32% complete response) and a median survival of 14.7 months (1-year survival 59%) [56]. However, neutropenia and thrombocytopenia grade >=3 occurred in 73% and 43% of patients, respectively.

The response rate achieved with our triple regimen, administered weekly, was therefore similar to those reported with other triple combination regimens administered every 3 weeks [34, 35, 55]. In addition, our findings compare favourably with those seen with M-VAC, also administered every 3 weeks [3], and a combination of cisplatin/gemcitabine when both agents were given weekly (65.6% in our study versus 40%) [29] or 3-weekly (65.6% in our study versus 49.4%) [38].

In conclusion, the weekly triple combination of docetaxel, gemcitabine plus cisplatin investigated in this study is a highly active regimen in patients with previously untreated advanced TCC, and gives rise to moderate toxicity. Despite the need for co-administration of G-CSF, its weekly regimen is attractive because of its outpatient administration, high response rate and median survival duration. Before a definite conclusion can be made, prospective randomised studies are needed to compare this triple regimen with the standard M-VAC regimen or other combinations using novel agents.


    Footnotes
 
+ Correspondence to: 51 Botassi Street, 18537 Piraeus, Greece. Tel: +30-1-6008610; Fax: +30-1-6008610; E-mail: pectasid@otenet.gr Back


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 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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