A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer

J. Tabernero1, M. A. Climent2, A. Lluch3, J. Albanell1, J. B. Vermorken4, A. Barnadas5, A. Antón6, C. Laurent7, J. I. Mayordomo8, N. Estaun1, I. Losa9, V. Guillem2, J. Garcia-Conde3, J. L. Tisaire9 and J. Baselga1,*

1 Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona; 2 Medical Oncology Service, Instituto Valenciano de Oncología, Valencia; 3 Medical Oncology Service, Hospital Clínico, Valencia; 5 Medical Oncology Service, H.U. Germans Trias i Pujol, Badalona; 6 Medical Oncology Service, H.U. Miguel Servet, Zaragoza; 8 Medical Oncology Service, H.U. Lozano Blesa, Zaragoza; 9 Aventis Pharma, Madrid, Spain; 4 Medical Oncology Service, Universitair Ziekenhuis Antwerpen, Edegem; 7 Medical Oncology Service, H. Sant-Jean, Brussels, Belgium

* Correspondence to: Dr J. Baselga, Chairman and Professor of Medicine, Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron, 119–129, 08035 Barcelona, Spain. Tel: +34-93-274-6085; Fax: +34-93-274-6059; Email: jbaselga{at}vhebron.net


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: A phase II randomised trial was conducted to evaluate the tolerability and activity of weekly or 3-weekly docetaxel in patients with metastatic breast cancer.

Patients and methods: Eighty-three patients with histologically proven metastatic breast cancer were randomised to receive either docetaxel 40 mg/m2 weekly for 6 consecutive weeks followed by 2 weeks without treatment (n=41), or docetaxel 100 mg/m2 on day 1 every 3 weeks (n=42).

Results: The incidence of all grade 3–4 adverse events was higher in the 3-weekly group than in the weekly group (96 versus 44), and the number of patients with grade 3–4 adverse events was also greater in the 3-weekly group (31 versus 20). Analysis of individual adverse events tended to favour the weekly regimen. Intent-to-treat overall response rate was 34% and 33% in the weekly and 3-weekly groups, respectively. Median time to progression was 5.7 and 5.3 months after weekly and 3-weekly docetaxel, respectively, and median time to treatment failure was 4.1 and 4.9 months, respectively.

Conclusion: Weekly docetaxel is an active regimen in metastatic breast cancer with comparable efficacy to 3 weekly docetaxel. Although both schedules were well tolerated, weekly docetaxel appears to have a more favourable toxicity profile.

Key words: docetaxel, metastatic breast cancer, randomised trial


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Docetaxel (Taxotere®; Aventis Pharmaceuticals, Antony, France), administered either alone or in combination, is possibly the most active agent available for the treatment of metastatic breast cancer [1Go, 2Go]. It is the only single agent to have demonstrated survival benefits in anthracycline-resistant patients, and improved efficacy over doxorubicin in patients previously treated with an alkylating agent [3Go].

The standard dosing regimen for docetaxel is 75–100 mg/m2 administered over 1 h every 3 weeks [4Go]. However, at the 100 mg/m2 dose, a high percentage of patients experience myelosuppression, with severe (grade 3 or 4) neutropenia being the dose-limiting toxicity [5Go, 6Go]. Previous clinical experience with paclitaxel dosed at weekly intervals in metastatic breast cancer demonstrated that toxicity could be reduced while maintaining a level of efficacy comparable to the 3-weekly regimen [7Go–9Go].

Initial phase I trials suggested that docetaxel administered over 1 h on a weekly basis was effective and produced low toxicity at doses up to 45 mg/m2 [10Go–12Go]. Hainsworth et al. [11Go] and Briasoulis et al. [12Go] also tested the hypothesis that a weekly dose of docetaxel 36–40 mg/m2 may be the most active with the least toxicity. Results of these studies suggested that weekly administration of docetaxel would be associated with a more favourable toxicity profile than an equivalent dose given every 3 weeks. Consequently, weekly docetaxel was evaluated in a series of phase II trials in patients with metastatic breast cancer. The results showed an encouraging 41–50% overall response rate with mild toxicity. The incidence of grade 3 neutropenia was <20% and no grade 4 neutropenia was reported. Additionally, no grade 3–4 oedema, neuropathy or diarrhoea was observed [13Go–16Go].

These encouraging efficacy results and low incidence of neutropenia were confirmed by four other studies [17Go–20Go], and suggest that although weekly docetaxel 35 mg/m2 did not offer increased dose density when compared with 3-weekly 100 mg/m2 administration, it could potentially produce a better toxicity profile. This would be of importance in elderly or pretreated patients, where a weekly docetaxel schedule with good clinical tolerability may result in a better risk:benefit ratio [19Go]. Additionally, a weekly regimen could allow more flexibility for combinations than with other cytotoxic agents [21Go].

The present study was conducted to evaluate weekly docetaxel and the conventional 3-weekly regimen. The primary objective of this study was to assess the safety profile of docetaxel administered either weekly or every 3 weeks in patients with anthracycline- and/or alkylating agent-resistant metastatic breast cancer. The main secondary objectives were to assess the relative dose intensity and the overall tumour response rate in the two arms, and to estimate the duration of response, time to progression, time to treatment failure, and overall survival. Quality of life assessments were prospectively specified in the study protocol, but these results will be presented elsewhere.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
This was a prospective, multicentre, randomised phase II study conducted at 10 centres in Europe between November 1999 and October 2001. Patients were randomised by hospital centre and stratified according to whether or not they had received previous chemotherapy for metastatic disease or had been pretreated with paclitaxel. Randomisation was centrally conducted, with stratification for each participating hospital. The study was approved by an independent ethics committee and institutional review board at each of the participating centres, and all patients gave written informed consent before participation.

Women aged 18–75 years with histologically or cytologically confirmed metastatic breast cancer and one or more measurable lesion were eligible for enrolment. Patients were eligible if they had received previous chemotherapy with an anthracycline and/or alkylating agent either in the adjuvant/neoadjuvant or the metastatic setting, or one previous chemotherapy schedule for metastatic disease, except for patients who had relapsed in a period <1 year after completion of adjuvant chemotherapy treatment. Additionally, they were allowed previous radiotherapy, paclitaxel and/or hormonal therapy for metastatic disease. A period of ≥4 weeks was required to have elapsed since the administration of the final chemotherapy cycle (≥6 weeks if nitrosourea or mitomycin C was received) or any radiotherapy. Adequate general health status [Eastern Cooperative Oncology Group (ECOG) performance status <2, absence of any other disease or serious medical disorder], bone marrow reserve (leukocytes ≥4 x 109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l and haemoglobin ≥10 g/dl) and laboratory evaluation [total bilirubin <1xupper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5x ULN, and alkaline phosphate <5x ULN except in the presence of bony metastasis, and the absence of any hepatic disorder; creatinine <1.6 mg/dl] were required. Menopausal status was assessed using standard clinical criteria (time from last menstrual discharge).

Patients with symptomatic peripheral neuropathy of grade ≥2 according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 1.0 were excluded. Other exclusion criteria included pregnancy, use of inadequate contraceptive measures, concomitant treatment with other antineoplastics, previous treatment with docetaxel, and a contraindication for the use of corticosteroids.

Treatment plan
Patients in the weekly treatment group received docetaxel 40 mg/m2 as a 30-min i.v. infusion once a week for 6 weeks followed by 2 weeks without treatment for each cycle (one cycle lasted 8 weeks). The 3-weekly group received docetaxel 100 mg/m2 as a 1-h i.v. infusion on day 1 every 21 days for each treatment cycle. The estimated dose density was 30 mg/m2/week in the weekly group and 33.3 mg/m2/week in the 3-weekly group. Patients continued treatment until they experienced either disease progression or unacceptable toxicity.

Premedication for the weekly group consisted of oral dexamethasone 8 mg taken on the morning of, 1 h before, and on the evening of the treatment day (total dose of 24 mg/week). Premedication for the 3-weekly group consisted of oral dexamethasone 8 mg administered the night before infusion, the morning of, 1 h before, and the evening of the infusion, as well as on the morning and evening of the day following the infusion (total dose of 48 mg every 3 weeks). Anti-emetics were prescribed as required. No other concurrent oncologic therapy or prophylactic hematopoietic growth factor therapy was allowed.

Dose reductions were performed based on NCI-CTC toxicity grading (version 1.0). Adjustments of dose for myelosuppression were based on haematological data from day 1 of each cycle and at the nadir. Docetaxel dose was reduced by 25% for grade ≥2 cutaneous reactions (rash or localised eruption but excluding nail toxicity) or peripheral neuropathy, grade 3 mucositis or grade 3–4 diarrhoea, increases of ≥2.5x ULN of AST and/or ALT and/or ≥5x ULN alkaline phosphate values, neutrophils <0.5 x 109/l for a duration of >7 days and/or in the case of neutropenia or documented infection, or platelets <25 x 109/l. Discontinuation of treatment occurred if the patient had severe neutropenia that did not recover after dose reduction, grade 3–4 hypersensitivity reactions, grade 3 peripheral neuropathy, grade 4 cutaneous reactions or mucositis, grade 3–4 constipation, and other grade 3 or 4 non-haematological toxicities. Colony-stimulating factors were allowed for treatment of neutropenic fever or infection associated with neutropenia. Antibacterial agents were not administered for prophylaxis against infection. Treatment for infection or complications with sepsis was performed according to standard practice guidelines at each centre.

Treatment assessments
The primary objective of the study was to evaluate the toxicity profiles of weekly and 3-weekly docetaxel, and the proportion of patients with grade 3–4 adverse events. Toxicity was classified according to NCI-CTC version 1.0 criteria [22Go]. Grade 1–2 events were considered non-serious and grade 3–4 events were classified as serious. Toxicity assessments were made before each drug infusion; once a week for the weekly group and twice every 3 weeks for the 3-weekly group.

Secondary objectives included assessment of relative dose intensity, overall response rate according to World Heath Organization (WHO) criteria [23Go], response duration, time to progression, time to treatment failure, and overall survival. Patients who experienced complete or partial responses, and those who had stable disease, were included in duration of response assessments. Response duration was measured from the time an objective response or disease stabilization was observed until time to progression or death. Time to progression was measured from the date of inclusion into the study until the time at which disease progression was observed or death occurred. Time to treatment failure was measured from the date of inclusion into the study until disease progression, death, or withdrawal due to toxicity. Response was evaluated every 9 weeks; patients who received docetaxel weekly were assessed after the first infusion of the second cycle, while those receiving 3-weekly docetaxel had their assessment after the third cycle. Patients who demonstrated a complete or partial response were re-assessed according to WHO criteria at least 4 weeks later for confirmation of clinical response.

Statistical analysis
The primary objective of this randomised phase II study was to evaluate the safety profile of two docetaxel regimens. The sample size was predetermined to differentiate a grade 3–4 adverse event rate between 30% and 60%, and the planned sample size was 40 patients per treatment arm (80 patients in total). The statistical analysis was descriptive and grade 3–4 adverse event rates are expressed as percentages. The main secondary objectives were to assess the relative dose intensity and the overall tumour response rate in the two arms, and to estimate the duration of response, time to progression, time to treatment failure, and overall survival. Relative dose intensities are expressed as median and range. Overall tumour response rates are presented as percentages and 95% confidence intervals (CIs). Kaplan–Meier curves [24Go] and 95% CIs are used to describe duration of response, time to progression, time to treatment failure, and overall survival for each of the two treatment groups. All randomised patients who received one or more treatment dose were included in the safety analysis. Efficacy outcomes were analysed for all randomised patients (intent to treat).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 83 patients were enrolled in the study. Forty-one patients were randomised to weekly therapy with docetaxel and 42 patients were randomised to 3-weekly docetaxel. Patient characteristics are listed in Table 1. The median age of patients was 56 years for the weekly group and 55 years for the 3-weekly group, and 33 patients on each arm were post-menopausal. The groups were well balanced at baseline. The median number of metastatic sites in each treatment group was two. Sixty-seven (81%) patients had previously been treated with anthracyclines and/or taxanes. Only one patient in each treatment group had not received chemotherapy previously.


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Table 1. Patient characteristics

 
Patients in the weekly group received a total of 114 cycles of docetaxel comprising 684 weekly infusions. The median number of delivered cycles and weeks on therapy were two (range 1–10 cycles) and 16 (range 8–80 weeks), respectively, for the weekly group, with 27 (66%) patients completing two or more cycles, and one (2%) patient receiving 10 cycles. Patients in the 3-weekly group received a total of 268 infusions of docetaxel administered over 804 weeks. The median number of delivered cycles and weeks on treatment were 6 (range 1–12 cycles) and 18 (range 3–36 weeks), respectively, for the 3-weekly group, with 30 (72%) patients completing six or more cycles of therapy.

The mean administered cumulative dose of docetaxel was 620 mg/m2 (range 80–2400 mg/m2) and 614 mg/m2 (range 100–1200 mg/m2) in the weekly and 3-weekly groups, respectively. Median relative dose intensity was 95% (range 54–107%) after weekly docetaxel and 96% (range 68%–100%) after the 3-weekly regimen. The number of cycles with dose reduction was similar between the groups: 7.9% in the weekly and 7.1% in the 3-weekly group. A total of six patients (15%) in the weekly group and 17 patients (42%) in the 3-weekly docetaxel group required dose reduction. The proportion of delayed cycles in the weekly and 3-weekly docetaxel groups were 11% and 3%, respectively; however, the number of patients who had delayed cycles was equivalent (17% in each group). Reasons for discontinuing the trial were disease progression (34 patients), grade 3–4 toxicity (34 patients), withdrawal of patient consent (10 patients) and investigator discretion (one patient).

Toxicity
One patient in the 3-weekly group was not included in the toxicity evaluation because of incomplete data.

Grade 3–4 haematological and non-haematological toxicities occurring in ≥5% of patients in either arm are listed in Table 2. Overall, 20 (49%; 95% CI 4.6–51.2%) patients in the weekly group and 31 (76%; 95% CI 73.6–77.7%) in the 3-weekly group experienced grade 3–4 adverse events. There was a total of 44 grade 3–4 adverse events in the weekly group and 96 in the 3-weekly group. Analysis of individual adverse events tended to favour the weekly regimen. The incidence of grade 3–4 adverse events in the weekly and 3-weekly groups, respectively, was as follows: neutropenia without fever, 2% (95% CI 1.7–3.2%) and 17% (95% CI 15.3–18.9%); neurotoxicity, 2% (95% CI 1.7–3.2%) and 17% (95% CI 15.3–18.9%); febrile neutropenia, 5% (95% CI 3.8–5.9%) and 20% (95% CI 17.6–21.4%); and stomatitis, 7% (95% CI 6.1–8.6%) and 17% (95% CI 15.3–18.9%). The weekly and 3-weekly regimens, respectively, had similar rates of other clinically relevant toxicities, such as fatigue (68% and 81%), nail toxicity (56% and 56%), tearing or watery eyes (53% and 39%), alopecia (78% and 87%) and oedema (33% and 33%).


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Table 2. Grade 3–4 treatment-related toxicity

 
Nineteen (46%) patients receiving weekly docetaxel and 15 (37%) patients receiving 3-weekly docetaxel withdrew from the study due to toxicity (Table 3). Two patients from each group died during treatment. Of these patients, two died from toxicity probably related to treatment (one case of neutropenic sepsis in the weekly group and one case of toxic shock attributed to neutropenia in the 3-weekly group, both in the first cycle of treatment) and two died from other causes that were probably not related to treatment (one case of cardiac failure after the third cycle in the 3-weekly group and one case of pulmonary thromboembolism in the first cycle in the weekly group).


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Table 3. Patient withdrawals due to toxicity

 
Response
Responses to treatment with weekly and 3-weekly docetaxel are summarized in Table 4. In both treatment groups, two patients showed complete and 12 showed partial responses, to give an overall response rate of 34% (95% CI 21–51%) in the weekly group and 33% (95% CI 20–50%) in the 3-weekly group. Four (10%) patients in the weekly group and two (5%) patients in the 3-weekly group presented unconfirmed partial responses. Ten (24%) patients in the weekly group and 15 (36%) in the 3-weekly group had stable disease. Progressive disease was seen in 12 (29%) and 10 (24%) patients, respectively, receiving weekly or 3-weekly docetaxel.


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Table 4. Response to therapy (intent-to-treat population)

 
The median follow-up time was 10.0 months (95% CI 0.5–24.0 months) and 10.2 months (95% CI 0.3–26.7 months) in the weekly and 3-weekly groups, respectively. The median time to progression for patients treated with weekly docetaxel was 5.7 months (95% CI 4.0–7.5 months), while for those treated with 3-weekly docetaxel it was 5.3 months (95% CI 4.3–6.2 months) (Figure 1). The median overall survival was 29.1 months (95% CI 23.9–34.3 months) and 20.1 months (95% CI 15.0–25.2 months) for patients treated in the weekly and 3-weekly groups, respectively (Figure 2). The median duration of response was 7.7 months (95% CI 6.1–9.3 months) in the weekly group and 6.3 months (95% CI 6.1–6.6 months) in the 3-weekly group (Figure 3). The corresponding time to treatment failure was 4.1 months (95% CI 2.5–5.7 months) and 4.9 months (95% CI 4.4–5.4 months), respectively (Figure 4).



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Figure 1. Kaplan–Meier plot of time to progression for weekly (black line) and 3-weekly (grey line) docetaxel.

 


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Figure 2. Kaplan–Meier plot of overall survival for weekly (black line) and 3-weekly (grey line) docetaxel.

 


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Figure 3. Kaplan–Meier plot of duration of response for weekly (black line) and 3-weekly (grey line) docetaxel.

 


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Figure 4. Kaplan–Meier plot of time to treatment failure for weekly (black line) and 3-weekly (grey line) docetaxel.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The present study was conducted to assess the tolerability and activity of weekly and 3-weekly docetaxel in patients with anthracycline-resistant metastatic breast cancer. Weekly docetaxel 40 mg/m2 and 3-weekly docetaxel 100 mg/m2 produced overall response rates of 34% and 33%, respectively. The mean cumulative dose of docetaxel was similar for both treatment groups (620 and 614 mg/m2 for the weekly and 3-weekly schedules, respectively). Although both schedules were well tolerated, the weekly regimen appears to have a more favourable toxicity profile than 3-weekly docetaxel with respect to grade 3–4 neutropenia, neurotoxicity, febrile neutropenia and stomatitis.

The results of the present study indicate that weekly and 3-weekly docetaxel schedules may have similar antitumour activity as assessed by time to progression, time to treatment failure, overall survival, and duration of response. The overall tumour response rate was 34%, with ~5% of patients in each group having a complete response and ~29% having a partial response. These response rates compare favourably with other phase II studies of weekly docetaxel in patients with metastatic breast cancer, which reported overall response rates of 34–41% [16Go, 19Go, 20Go].

Docetaxel is usually administered at a dose of 75–100 mg/m2 every 3 weeks for metastatic breast cancer. However, 90–95% of patients report grade 3–4 neutropenia and/or leukopenia [25Go–27Go]. In the current study, weekly docetaxel 40 mg/m2 was not associated with any grade 3–4 leukopenia, and the incidence of febrile neutropenia and grade 3–4 neutropenia without fever was <5%. It is notable that the incidence of grade 3–4 neutropenia in the 3-weekly docetaxel 100 mg/m2 group (37%) was much lower than has generally been reported with this dosage schedule. Although colony stimulating factor support was not administered prophylactically in our study, ~95% of patients in both treatment groups had an ECOG performance status of 0–1, which may have contributed to the lower incidence of toxicity.

The tolerability data for weekly docetaxel in this phase II study are consistent with those reported in previous phase I trials. Lück et al. [10Go] reported that docetaxel up to 45 mg/m2 administered weekly did not produce any grade 3–4 haematological or non-haematological toxicity in a limited phase I study with 16 heavily pretreated patients with metastatic breast cancer. Similarly, the two separate phase I studies of Hainsworth et al. [11Go] and Briasoulis et al. [12Go] found that weekly docetaxel doses up to 43 mg/m2 produced few grade 3–4 haematological effects, with a total of three episodes of grade 3 leukopenia being reported. The incidences of neutropenia and leukopenia reported in this study compare with those of other phase II trials of weekly docetaxel in patients with metastatic breast cancer [13Go, 14Go, 17Go]. Burstein et al. [16Go] showed that weekly docetaxel 40 mg/m2 produced a higher incidence of grade 3 neutropenia (14% versus 3%), but a similar incidence of grade 3 asthenia/fatigue compared with our study. It should be noted that our phase II study is not highly powered and further investigation in phase III studies is required to allow formal statistical comparisons of the two treatment regimens.

Toxicities related to cumulative dose, such as peripheral oedema, developed despite oral administration of dexamethasone 8 mg in the weekly and 3-weekly groups. One patient in the weekly group with grade 4 oedema, and two patients in the 3-weekly group with grade 3 oedema withdrew. The 33% incidence of oedema is consistent with reports from other studies [16Go, 26Go–28Go]. However, conclusive data are lacking regarding whether a different dexamethasone dosing schedule may reduce the incidence of oedema.

Recent phase II trials, including those involving elderly patients, support the findings from this study [19Go, 27Go, 28Go]. In 41 elderly patients, weekly docetaxel 36 mg/m2 produced grade 3–4 neutropenia in only 0.4% of treatment courses and no other grade 3–4 haematological toxicity was observed [28Go]. Consistent with results reported by Aihara et al. [29Go] in a recent trial of weekly docetaxel in patients with metastatic breast cancer, severe haematological toxicity also appears to be lower with weekly rather than 3-weekly administration in the current study. In this study, 37 patients were treated with weekly docetaxel 40 mg/m2 and seven patients (19%) had grade 3–4 neutropenia. By contrast, only one (2.5%) case of grade 3–4 neutropenia was reported in the weekly group in the current study. Nevertheless, non-haematological toxicities occurred with similar incidence and severity in both studies. The incidence of toxic deaths in the present study (2.4% for each group) is consistent with the rate reported in previous phase II/III studies of 3-weekly docetaxel in metastatic breast cancer (1.4–3%) [25Go, 26Go, 30Go]. In other phase I/II studies of weekly docetaxel in metastatic breast cancer, no deaths due to toxicity have been observed during the study period [16Go–19Go, 27Go–29Go], although the results of these studies are very limited due to the short follow-up.

Preliminary reports from a phase III study of weekly versus 3-weekly docetaxel in advanced non-small-cell lung cancer support our observations in patients with metastatic breast cancer; docetaxel could be administered at equivalent dose intensities, and response rates and survival were similar for the two treatment schedules [31Go].

In conclusion, weekly docetaxel is active in anthracycline-resistant metastatic breast cancer and appears to have similar efficacy to the 3-weekly regimen. The reduction in acute toxicity for the weekly docetaxel schedule compared with the 3-weekly schedule must be considered from a balanced perspective as it requires an increased number of clinic visits for therapy. However, the reduction in haematological toxicity associated with weekly docetaxel may translate into quality-of-life advantages for certain groups of patients, particularly those with metastatic disease, and the elderly or those with poor performance status. Weekly docetaxel offers promising options for future investigations into combinations with other novel biological and cytotoxic agents.


    Acknowledgements
 
The authors would like to thank all their colleagues who participated in this study and who are not included in the list of authors: J. R. Mel and S. E. Vázquez (H. Xeral-Calde, Lugo, Spain), M. Constela (H. Montecelo, Pontevedra, Spain), L. Dirix (A. Z. St Augustinus, Wilrijk, Belgium) and M. Lambrechts (Aventis Pharma, Brussels, Belgium). The authors also wish to thank A. Contijoch for editorial assistance and J. L. Sanz for statistical analysis. The results were presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, USA, 18–21 May 2002. This work was supported by an unrestricted grant from Aventis Pharma, Spain.

Received for publication February 13, 2004. Revision received April 28, 2004. Accepted for publication May 4, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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