Phase II randomised trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC)

Original article

Annals of Oncology 16: 90 –96, 2005 doi:10.1093/annonc/mdi018

Phase II randomised trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC) R. Gervais1, A. Ducolone2, J.-L. Breton3, D. Braun4, B. Lebeau5, F. Vaylet6, D. Debieuvre7, J.-L. Pujol8, J. Tredaniel9, P. Clouet10 & E. Quoix11 1

Centre Re´gional de Lutte Contre le Cancer Baclesse, Caen; 2Hoˆpital Hautepierre, Strasbourg; 3Centre Hospitalier Ge´ne´ral, Belfort; 4Centre Hospitalier Ge´ne´ral Maillot, Briey; 5Hoˆpital Saint Antoine, Paris XII; 6Hoˆpital d’Instruction des Arme´es de Percy, Clamart; 7Centre Hospitalier Paul Morel, Vesoul; 8CHU-Hoˆpital A. de Villeneuve, Montpellier; 9Hoˆpital St Louis, Paris; 10Laboratoire Aventis, Paris; 11 Hoˆpital Lyautey, Strasbourg Cedex, France

Background: Taxoterew (docetaxel) at the dose of 75 mg/m2 every 3 weeks is a standard therapy for pretreated non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety profile of two schedules of docetaxel administration (every 3 weeks versus weekly) in patients with pretreated NSCLC. Patients and methods: From February 2000 to February 2001, 125 patients with locally advanced or metastatic NSCLC were randomised after failure of a previous platinum-based regimen to receive either docetaxel 75 mg/m2 administered every 3 weeks (Dq3w) or docetaxel 40 mg/m2 given weekly for 6 weeks followed by 2 weeks of rest (Dqw). Safety evaluations focused on grade 3 – 4 neutropenia, febrile neutropenia, nausea-vomiting and asthenia. Results: Patients’ characteristics were well balanced between arms. The most common National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 – 4 toxicity was neutropenia, which occurred in 48.4% of Dq3w patients versus 15.9% of Dqw patients (P = 0.001). In addition, febrile neutropenia were observed in 6.5% of patients in Dq3w versus 0% in Dqw. Grade 3 – 4 asthenia was more frequent in Dqw. Other non-haematological toxicities were very rare. Regarding efficacy, there was a trend towards a better disease control rate in Dq3w: 32.2% versus 25.4% in Dqw. Median time to progression and survival were rather similar in both arms, respectively: 2.1 months (range 2 – 3.2) and 5.8 months (range 4.0 – 7.0) in Dq3w and 1.8 months (range 1.6– 2.3) and 5.5 months (range 3.7– 6.6) in Dqw. Conclusions: While both schedules had a favourable safety profile, a significant lower rate of severe neutropenia was observed in the weekly arm. Both regimens had similar efficacy. The weekly regimen could be considered as a good alternative for patients at risk of severe neutropenia. Key words: chemotherapy, docetaxel, non-small-cell lung cancer, second-line

Introduction Lung cancer remains a major public health concern. Nonsmall-cell lung cancer (NSCLC) accounts for approximately 75% of lung cancers and is the leading cause of cancer-related death worldwide [1]. Of patients with NSCLC, 70% have locally advanced (stage IIIB) or metastatic (stage IV) disease at diagnosis [2]. Despite the advances in the treatment of NSCLC, the prognosis for patients with stage IIIB and IV disease is disappointing, with a 1-year survival rate of 15% and a

*Correspondence to: Dr E. Quoix, Hoˆpital Lyautey, 1, Place de l’hoˆpital, 67091 Strasbourg Cedex, France. Tel: +33-3-88-11-63-02; Fax: +33-3-88-11-63-35; E-mail: [email protected] q 2005 European Society for Medical Oncology

5-year survival rate of less than 2% in a US population-based epidemiological study [3]. Platinum-based combinations remain the standard first-line chemotherapy for advanced NSCLC in good performance status patients [4]. A meta-analysis has shown that median survival improvement of 6 weeks occurs with active platinum-based combinations when compared with best supportive care (BSC) [4]. Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. American Society of Clinical Oncology guidelines recommend second-line chemotherapy for patients with a good performance status who have responded to firstline chemotherapy [5]. Since then, several chemotherapeutic

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Received 28 June 2004; revised 16 August 2004; accepted 26 August 2004

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Patients and methods Eligibility To be included in the study approved by the Institutional Review Board of Strasbourg, patients had to have histologically or cytologically proven stage IIIB or IV NSCLC, at least one bi-dimensionally measurable or evaluable lesion outside a previously irradiated area and to have received only one prior platinum-containing chemotherapy. Furthermore, patients had to be aged 18–75 years with a WHO performance status (PS) < _ 2 and adequate biological functions: hepatic [normal bilirubin level, _ 1.5  upper limit of aspartate aminotransferase, alanine aminotransferase < _ 5  ULN], renal (serum creatinormal (ULN) and alkaline phosphatase < _ 1.5  ULN) and haematological (absolute neutrophil count nine level <

> _ 2  109/l, platelet count > _ 100  109/l, haemoglobin > _ 10 g/dl). Patients were not enrolled if they presented symptomatic brain metastases, periph_ 2 or prior treatment with taxanes. Prior radiothereral neuropathy grade > apy was not a reason for exclusion provided that it had been completed more than 3 weeks before enrolment. All patients signed a written informed consent form approved by the Institutional Review Board of Strasbourg.

Pretreatment evaluation Before initiation of chemotherapy, patients were evaluated as follows: medical history and physical examination, determination of PS, tumour evaluation, a complete blood cell and platelet count and serum levels of a-1 glycoprotein, creatinine, transaminases, alkaline phosphatase and bilirubin. Chest X-ray, chest, abdominal and brain computed tomography scans and/or ultrasound were also required. Bone scan was performed only if clinically indicated.

Treatment plan Patients were stratified by centre and randomised to receive either docetaxel 75 mg/m2 every 3 weeks (Dq3w) or docetaxel 40 mg/m2 weekly for six consecutive weeks, followed by 2 weeks of rest (Dqw). Duration of treatment was six cycles in Dq3w and two sequences in Dqw. When clinical benefit was shown in the absence of unacceptable toxicity, treatment was permitted to continue. Docetaxel was administered intravenously as a 1-h infusion. Prophylactic oral corticosteroid premedication (prednisolone 50 mg, methylprednisolone 40 mg or dexamethasone 8 mg) was below the recommended schedule and given three times over 2 days (the evening before the day of treatment, the following morning and evening) instead of six times over 3 days. Prophylactic use of haematopoietic growth factors was not authorised at cycle 1. Anti-emetic prophylaxis was given according to each institution’s guidelines.

Dose adjustments In the event of grade 4 neutropenia lasting more than 7 days, grade 4 _ 3 non-haematothrombocytopenia or febrile neutropenia and/or grade > logical toxicities (except alopecia), a dose reduction was implemented in subsequent treatment cycles, i.e. by 20% in Dq3w and by 25% in Dqw. _ 100 109/l _ 1.5 109/l and platelets > Patients had to have neutrophils > before any infusion. Other toxicities were required to be below grade 2 before next infusion. Docetaxel infusion could be delayed for a maximum of 2 weeks before patient discontinuation.

Treatment evaluation Patients were evaluated for efficacy according to WHO criteria [15]. Tumour response was assessed using the same procedures described in pretreatment evaluation. Patients were assessed every three treatment cycles (9 weeks) in Dq3w and at the end of each treatment sequence (8 weeks) in Dqw. A confirmatory assessment was also performed in responding patients at least 4 weeks after the initial determination of response. All responses were reviewed by a panel of investigators. Toxicities were assessed in all patients who had received at least one docetaxel infusion according to the NCI CTC version 1, based on clinical signs and symptoms and laboratory tests evaluated during the treatment period.

Statistical analysis The primary objective was to evaluate the safety of the two treatment schedules in the intention-to-treat population (ITT) defined as all randomised patients who received at least one docetaxel infusion. The primary

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agents have been evaluated in the second-line setting and the efficacy of second-line chemotherapy has been shown. One of the agents most extensively studied, and approved by regulatory authorities in this setting, has been docetaxel [6]. In four phase II trials when used as a single-agent, docetaxel 100 mg/m2 every 3 weeks provided response rates ranging from 16% to 22% whilst grade 3–4 (National Cancer Institute Common Toxicity Criteria, NCI-CTC) neutropenia was the primary dose-limiting event [6 –9]. Then, docetaxel at a dose of 75 mg/m2 was recommended by two phase III trials which compared docetaxel 75 or 100 mg/m2 as second- or third-line therapy with BSC [10] or to vinorelbine/ifosfamide [11] in which the best overall survival was obtained at this dose level. Docetaxel 75 mg/m2 was also shown to have reduced the risk of febrile neutropenia (2% to 8%) compared with higher doses while providing increased survival and quality of life benefits. Grade 3–4 neutropenia was observed in 54% –67% with the 75 mg/m2 dose and the main non-haematological toxicities included asthenia, alopecia, skin reaction, hypersensitivity reaction and fluid retention. These results were confirmed by a French randomised phase II trial [12]. In phase I trials, a weekly dose of docetaxel was examined. This regimen consists of the administration of docetaxel 35 –40 mg/m2 weekly for six consecutive weeks followed by 2 weeks of rest [13]. The weekly schedule of docetaxel was active and well tolerated. The incidence of grade 3–4 leucopenia ranged from 14% to 20%. The administration of weekly docetaxel at low doses (25 mg/m2) was reported recently. Both acceptable efficacy [partial response (PR) 10.5% and median survival 12.8 weeks] and a good safety profile was demonstrated with this low dose [14]. Regarding toxicity, fluid retention was docetaxel-specific but well managed by corticosteroid premedication given around docetaxel infusion. In the two phase III trials discussed above [10, 11], the cumulative dose reached using the 3-weekly schedule ranged from 225 to 300 mg/m2 further below those in which fluid retention syndrome appears. This raises the question that it may be possible to decrease corticosteroid premedication. For these reasons, we started a randomised phase II study to evaluate the incidence of grade 3 and 4 toxicities of weekly docetaxel administration and docetaxel every 3 weeks in patients with NSCLC who had failed after first-line platinum-based chemotherapy.

92 criteria were the incidence per patient of four principal parameters: incidence of grade 3–4 neutropenia, febrile neutropenia, nausea/vomiting and asthenia. In order to evaluate the percentage of patients who developed at least one grade 3–4 of the above toxicities with a confidence interval of 95%, it was arbitrarily decided to include 60 patients per arm (total 120 patients). Response rate, disease control, incidence of other toxicities, time to progression (TTP) and overall survival were secondary objectives. In addition, subgroup analysis of disease control (objective response and stable disease) was conducted stratifying patients according to their response to the prior cisplatin-containing chemotherapy and baseline a-1 glycoprotein levels (below or above 1.5 ULN a-1 glycoprotein).

Regarding treatment administration, relative dose intensity (RDI) was evaluated as the ratio between given cumulative dose intensity per patient and per week and the planned cumulative dose intensity per patient and per week. No comparison analysis was planned. Statistical tests regarding the primary objective were allowed per protocol for exploratory purposes only.

Results Patient characteristics From February 2000 to February 2001, 125 patients were enrolled in the study by 22 French centres. Overall, 62 patients were randomised in Dq3w and 63 patients in Dqw. Patient characteristics (presented in Table 1) were well balanced between the two arms in terms of age, performance status, histological type (with a predominance of adenocarcinoma) and cisplatin-refractory patients (i.e. never had an objective response or stable disease with cisplatin treatment). Eighteen patients (14%) were considered sensitive to platinum-based therapy (disease progression beyond 6 months after the end of platinum-based chemotherapy). The remaining patients (62) who responded or remained stable for less than 6 months were called ‘resistant’. Certain disease characteristics slightly favoured patients receiving Dq3w: 40% of patients had three or more involved organs versus 51% in Dqw; 19% of patients had asymptomatic brain metastasis in Dq3w versus 25% in Dqw.

Treatment exposure A total of 628 docetaxel infusions were administered: 214 in the Dq3w arm and 414 in the Dqw arm. The median number of cycles was three cycles per patient (range 1 –8) for Dq3w and six infusions (range 1–12) for Dqw. The median cumulative dose was 223.3 mg/m2 in Dq3w and 235.5 mg/m2 in Dqw. The median RDI per patient was similar in both treatment arms; 0.99 (range 0.77 –1.04) in Dq3w and 0.91 (range 0.35 –1.07) in Dqw.

Characteristics

Patients enrolled

3-weekly docetaxel

Weekly docetaxel

n

%

n

%

62

100

63

100

Age (years) Median

59

58

Range

37–72.5

26.8–74.3

Sex Male

50

80

51

81

Female

12

19

12

19

0

9

15

8

13

1

40

65

42

67

2

13

21

13

21

Performance status (WHO)

Histological type of cancer Adenocarcinoma

27

44

29

46

Squamous carcinoma

25

40

23

37

Other

10

15

11

17

Locoregional (stage IIIB)

21

34

21

33

Metastatic (stage IV)

41

66

42

67

1

15

24

9

14

2

22

36

22

35

> _3

25

40

32

51

12

19

15

25

Site of relapse at inclusion

Number of involved organs

Asymptomatic brain metastases

Response to prior platinum-based chemotherapy Resistant disease

30

48

32

51

Refractory disease

22

36

23

37

Sensitive

10

16

8

13

Safety Treatment delays (more than 7 days) were applied in five patients (2.4% of cycles) in Dq3w. One delay occurred due to appendicular syndrome with fever (considered as related to the treatment by the investigator) and four delays were not related to treatment (one phlebitis, three personal convenience). In Dqw, delays occurred for nine patients (2.2% of infusions) mainly due to related haematological toxicity: three grade 3 and one grade 2 neutropenia, one grade 2 anaemia and one grade 3 cutaneous toxicity. Two delays in the Dqw arm were not related to treatment: one pulmonary disorder and one Clostridium difficile infection. Also, one patient omitted the last infusion of the first sequence for unknown reasons. Dose reduction was applied in three patients (1.4% of cycles) in Dq3w due to haematological toxicity (two patients for febrile neutropenia and one for grade 4 neutropenia) and in five patients (1.1% of infusions) in Dqw due to haematological

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For statistical analyses, quantitative parameters were summarised by mean, standard deviation, median, minimum and maximum and qualitative parameters by frequencies and percentages. Time dependent variables (TTP, overall survival and duration of disease control) were analysed using the Kaplan–Meier method and a 95% confidence interval (CI) was calculated for each treatment arm. The date of entry for TTP and overall survival was the first day of treatment and the date of point was 30 December 2001.

Table 1. Patient characteristics (ITT population)

93 (two grade 3 neutropenia, one grade 2 anaemia) and non-haematological toxicities (one patient had his infusion interrupted for laryngeal spasm, the other had a grade 3 skin toxicity). Eleven patients discontinued study treatment due to toxicity: three (5%) patients in Dq3w (one respiratory distress, one grade 3 diarrhoea and one grade 3 paraesthesia) and eight (13%) patients in Dqw (two grade 3 stomatitis, two grade 3 neutropenia, one grade 3 myalgia, one grade 3 anaemia, one grade 4 laryngeal spasm and one grade 3 inguinal abscess). Nineteen patients discontinued study treatment due to death; amongst them only one was imputable to treatment (septic shock related to febrile neutropenia) in Dq3w. The main grade 3–4 toxicities are summarised in Table 2. More patients treated in Dq3w experienced grade 3–4 neutropenia: 48.4% (35.9% to 68.4%) versus 15.9% (6.8% to 24.9%) in Dqw (exploratory test, P = 0.0001). In addition, febrile neutropenia was observed in 6.5% of patients in Dq3w versus 0% in Dqw. The frequency of non-haematological related adverse events was similar in both arms (Table 2), except for asthenia, which

was less common in the Dq3w arm (4.8%) than in the Dqw arm (11%). The only grade 3 peripheral oedema in Dqw was not related to the treatment. One severe hypersensitivity reaction was observed in Dqw (laryngeal spasm that occurred during perfusion). Three patients were reported with grade 3–4 respiratory events related to the treatment. These events included a respiratory insufficiency and a severe pneumonia with a febrile neutropenia in one patient; a dyspnoea along with a neutropenia, anaemia and asthenia; a respiratory distress together with a fever; and an impaired general status that led to death. Other grade 3–4 toxicities were rare. Sixteen patients experienced treatment-related serious adverse events, 11 patients in Dq3w (mainly due to haematological toxicity) and five patients in Dqw (due to non-haematological toxicity).

Disease control (objective response and stable disease) in the ITT population was achieved in 32.2% of patients in Dq3w and in 25.4% of patients in Dqw. Most of these patients had stable disease. Response rate was of 4.8% in the D3qw arm and of 3.2% in the Dqw arm. Among the patients who were resistant or refractory to prior cisplatin-based chemotherapy, disease control was achieved in 32.7% and 23.6% of patients in Dq3w and Dqw, respectively. Disease control was more frequent for patients who had an a-1 glycoprotein level measured below or equal to 1.5 ULN, considering that only 80% of patients in each arm had this examination performed (Table 3). Both median TTP and overall survival were similar in the two treatment arms. At the time of the analysis, the median follow-up time (delay between the date of first infusion and the date of analysis) was 17.0 months (range 10.0 –22.5) and the median time of participation (delay between the date of first infusion and the date of last contact or death) was 5.8 months (range 0.2–20.9) in Dq3w and 5.5 months (range 0.3–19.4) in Dqw. A median TTP of 2.1 months (95% CI 2.0–3.2) was achieved in patients receiving 3-weekly docetaxel and 1.8 months (95% CI 1.6–2.3) in those receiving

Table 2. Main grade 3 and 4 toxicities per patient 3-weekly docetaxel (n = 62)

Weekly docetaxel (n = 63)

Total (n = 125)

30 (48.4)a

10 (15.9)a

40 (32)

Haematological, n (%) Neutropenia Febrile neutropenia

4 (6.5)

Anemia

6 (9.7)

– 8 (12.7)

14 (11.2)

4 (3.2)

Asthenia

3 (4.8)

7 (11.1)

10 (8)

Nausea/vomiting

2 (3.2)

3 (4.8)

Diarrhoea

1 (1.6)

2 (3.2)

Non-haematological, n (%)

Hypersensitivity reaction

–

Respiratory system

2 (3.2)

5 (7.9) –

1 (1.6)

1 (0.8)

1 (1.6)

3 (2.4)

a

Exploratory test, P = 0.0001.

Table 3. Disease control rate Populations ITT

Disease control (%) Median duration (months) (95% CI) a

Refractorya/resistant+b to prior platinum

According to level of a-1 glycoprotein at inclusion > _ 1.5  ULN

Dq3w

Dqw

Dq3w

Dqw

<1.5  ULN

n = 62

n = 63

n = 52

n = 55

Dq3w

Dqw

Dq3w

n = 33

n = 31

n = 17

n = 19

32.2 4.6 (4.4–12.2)

25.4 3.6 (3.4–5.7)

Dqw

32.7

23.6

39.4

25.8

17.6

15.8

–

–

–

–

–

–

Patient who never had an objective response or stable disease. Patients who had a complete response or partial response, or stable disease within the 6 months before progressive disease after previous platinum therapy. CL, confidence interval; Dq3w, docetaxel 75 mg/m2 administered every 3 weeks; Dqw, docetaxel 40 mg/m2 given weekly for 6 weeks followed by 2 weeks of rest; ITT, intention-to-treat; ULN, upper limit to normal. b

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Efficacy and time-related parameters

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Figure 1. Overall survival.

Discussion Two phase III studies [11, 12] involving docetaxel demonstrated a survival benefit in the second-line setting for advanced NSCLC patients. The recommended schedule of docetaxel was set at 75 mg/m2 every 3 weeks. Weekly administration of chemotherapy has been extensively studied in NSCLC, especially with newer agents (e.g. vinorelbine, gemcitabine and the taxanes) [16 –18]. Such a weekly schedule can reduce toxicity by dividing the dose over time, intensifying the dose without increasing adverse effects allowing also for concomitant radiotherapy [19]. Our study was designed to evaluate, as a primary objective, the safety of two docetaxel schedules: every 3 weeks versus a weekly administration. In both arms, prophylactic corticosteroid premedication was administered for a reduced period of time (three times over 2 days instead of twice a day for 3 days). With respect to haematological toxicity, grade 3–4 neutropenia was observed in only 16% (grade 4, 3.2%) of patients treated with weekly docetaxel schedule compared with 48% (grade 4, 24.2%) when docetaxel was administered every 3 weeks. No febrile neutropenia was observed with weekly administration of docetaxel. Two phase II studies of weekly schedules performed in a small number of NSCLC patients showed similarly low incidence of haematological toxicities [20, 21]. These findings are also consistent with the preliminary results of phase III trials [23, 24]. This low incidence in haematological toxicities could be an advantage for patients at high risk of severe neutropenia, as defined by Alexandre et al. [25] using the Nutritional and Inflammatory Status. Grade 3– 4 asthenia was the main non-haematological toxicity in both arms, with a higher incidence observed in the weekly dosing schedule (11% in Dqw versus 5% in Dq3w). Pulmonary toxicity related to treatment was observed only in three patients (2.4%), of which two had had previous radiotherapy. This incidence is low compared with the Shepherd et al. phase III trial (20.0%) [10] and similar to the incidence of 2.5% observed by Fossella and colleagues [11]. The good

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weekly docetaxel. Median overall survival was 5.8 months and 5.5 months in Dq3w and Dqw, respectively (Figure 1). At the time of analysis, 15 (12%) patients were still alive. The 1-year survival rate was 18% in Dq3w versus 6% in Dqw.

safety profile of the weekly schedule observed in our trial supports the results from other studies [20, 21, 24, 26]. In these four phase II trials, docetaxel was administered at a dose of 35–43 mg/m2 for six consecutive weeks, followed by 2 weeks of rest. One grade 4 neutropenia was reported, grade 3 neutropenia was reported in a range of 0% to 12%, grade 3 asthenia and diarrhoea in a range of 0% to 14%, grade 3 nausea/vomiting in one patient in three of the four studies, and grade 3 fluid retention syndrome was reported in 0% to 11%. However, the rate of discontinuation for toxicity doubled in the Dqw arm. This could be because the schedule did not leave enough time for the patient to improve between two infusions. In keeping with the results of the previous phase III studies [10, 11], the cumulative doses observed in the present study were rather similar; 223.3 mg/m2 with docetaxel administered every 3 weeks and 235.5 mg/m2 with weekly docetaxel, showing that even with a slightly higher rate of discontinuation for toxicity in Dqw, the doses received are similar in the two arms. The median number of cycles (three in Dq3w) was also similar to those observed in the two phase III studies [10, 11]. The absence of oedema suggests that a prophylactic corticosteroid premedication schedule administered over 2 days is feasible in either weekly or 3-weekly docetaxel schedules. The two treatments arms had similar efficacy profiles, with a trend towards greater efficacy regarding disease control with docetaxel administered every 3 weeks (disease control: 32% versus 25%) with a median duration of 4.6 months with docetaxel administered every 3 weeks and 3.6 months with weekly docetaxel. Both median TTP and overall survival were similar between the two treatment arms: 2.1 months versus 1.8 months and 5.8 months versus 5.5 months in the 3-weekly and the weekly treatment regimens, respectively. The disease control rate appears interesting but overall response rate were low in the two arms. However, they were in the range of those obtained in previous phase III studies: overall response rate (ORR) 5.5% in the Shepherd study [10] and 6.7% (range 3.1%–13.1%) in the Fossella study [11]. As previously demonstrated, the level of a-1 glycoprotein is predictive of the response to docetaxel; all responders and 75% of patients with stabilisation of disease had an a-1 glycoprotein level below 1.5 ULN [27]. This did not differ between the two treatment arms. These efficacy results are notable, considering this poor prognosis population with a high proportion of metastatic patients at inclusion (66%) with three or more sites involved (46%) and with asymptomatic brain metastases (22%). Furthermore, 86% of patients were resistant or refractory to prior platinum-based chemotherapy. Preliminary results of on going phase III trials [22, 23] have also shown similar results with a weekly versus 3-weekly schedule. Both the 3-weekly and weekly docetaxel regimens provide clinical benefit in poor-prognosis stage IIIB –IV NSCLC patients who have failed prior platinum-based treatment. Several factors should be taken into account when choosing the best schedule of chemotherapy for a given patient. First, several new agents have demonstrated an efficacy benefit with

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Acknowledgements The authors would like to thank all their colleagues who participated in this study: Dr A. Rivie`re and G. Lemoel (Centre anticance´reux Baclesse, Caen); Dr L. Moreau, Dr G. Fourgaut and Dr R. Stenger (CHU Lyautey, Strasbourg); Dr J. P. Gury (CHG Morel, Vesoul); Dr X. Quantin (CHU A de Villeneuve, Montpellier); Dr R. Poirier and Dr F. Mouysset (CH Pays d’Aix, Aix-en-Provence); Dr M. Mornet, A. Levy, Dr G. Adam (CH J. Coeur, Bourges); Dr N. Paillot (CHU Notre Dame, Metz); Dr E. Lemarie´ (CHU Hoˆpital Bretonneau, Tours); Dr P. Carre´ (CHG Pasteur, Colmar); Dr A. Vergnene`gre, Dr B. Melloni, Dr F. Touraine (CHU Hoˆpital du Cluzeau, Limoges); Dr A. Monnier, Dr X. S. Sun, J. Plaza, N. Sakek (CHG, Montbe´liard); Dr D. Moro-Sibilot, Dr O. Oliarguet (CHU, Grenoble); Dr A. Livartowski, Dr G. Zalcman (Institut Curie, Paris); Dr C. Clary-Meinesz (Hoˆpital Pasteur, Nice); Dr J. M. Vannetzel, Dr G. Jebrak, Dr A. Marceau (Hoˆpital Beaujon – AP-HP, Paris); Dr L. Gaucher, (Clinique Fleming, Tours); Dr A. C. Neidhart and V. Zengerling (CH Muller, Mulhouse) and all members of the teams who participated in this study. Special thanks to L. Mussak for his assistance with the statistical analyses.

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