Randomised, multicentre phase II study assessing two doses of docetaxel (75 or 100 mg/m2) as second-line monotherapy for non-small-cell lung cancer

E. Quoix1,*, B. Lebeau2, A. Depierre3, A. Ducolone4, D. Moro-Sibilot5, B. Milleron6, J. L. Breton7, E. Lemarie8, J. L. Pujol9, J. M. Brechot10, G. Zalcman11, D. Debieuvre12, F. Vaylet13, A. Vergnenegre14 and P. Clouet15

1 Hôpital Lyautey, Strasbourg; 2 Hôpital Saint Antoine, Paris; 3 Hôpital Jean Minjoz, Besançon; 4 Hôpital Hautepierre, Strasbourg; 5 DMAS Thoracic Oncology, CHU Grenoble, Grenoble; 6 Hôpital Tenon, Paris; 7 Centre Hospitalier Général, Belfort; 8 Hôpital Bretonneau, Tours; 9 CHU-Hôpital A. de Villeneuve, Montpellier; 10 Hôtel-Dieu, Paris; 11 Institut Curie, Paris; 12 CHI de la Haute-Saône, Vesoul; 13 Hôpital d’Instruction des Armées de Percy, Clamart; 14 CHU-Hôpital du Cluzeau, Limoges; 15 Laboratoire Aventis, Paris, France

Received 30 June 2003; accepted 13 August 2003


    ABSTRACT
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

The survival benefit associated with first-line chemotherapy in advanced lung cancer led to the need for second-line chemotherapy. Docetaxel (Taxotere®) has proven efficacy in both settings. This study evaluated the safety and efficacy of two doses of docetaxel in patients with non-small-cell lung cancer who had failed first-line platinum-based chemotherapy.

Patients and methods:

In total, 182 patients from 24 French centres were randomised and treated with either docetaxel 75 mg/m2 (arm A) or 100 mg/m2 (arm B) every 3 weeks. Baseline characteristics were well balanced, except more patients in arm A had metastatic disease (91.4% versus 78.7%) and therefore the median number of sites involved for arm A was three compared with two for arm B.

Results:

Median time to treatment failure was 1.34 months [95% confidence interval (CI) 1.28–1.64] for arm A and 1.64 months (95% CI 1.34–2.62) for arm B. Median overall survival was 4.7 months (95% CI 3.8–5.9) for arm A versus 6.7 months (95% CI 4.8–7.1) for arm B. According to a blinded expert panel, disease control was achieved in 35 (43.8%) patients in arm A and 39 (49.4%) patients in arm B. More patients in arm B experienced grade 3–4 neutropenia (B: 72.7% versus A: 44.0%), asthenia (B: 20.2% versus A: 10.8%) and infection (B: 6.7% versus A: 2.2%). Three treatment-related deaths were reported in each arm.

Conclusions:

The optimal docetaxel dosage in this second-line setting is 75 mg/m2, as it has a more favourable safety profile and on balance a similar efficacy to the 100 mg/m2 dose.

Key words: chemotherapy, docetaxel (Taxotere®), non-small-cell lung cancer, randomised


    Introduction
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Lung cancer continues to be a major public health concern. Non-small-cell lung cancer (NSCLC) accounts for approximately three-quarters of all lung cancer cases and is the leading cause of cancer-related death worldwide [1, 2]. The majority of patients have advanced/metastatic disease at diagnosis. Cisplatin-based combination chemotherapy has been shown to provide a modest but significant survival benefit in advanced NSCLC compared with best supportive care; median survival was extended by 1.5 months and there was a 10% absolute improvement in the 1-year survival rate [3].

Despite the survival benefit associated with first-line chemotherapy, the majority of patients will eventually relapse or present progressive disease. American Society of Clinical Oncology (ASCO) guidelines suggest that for patients with a good performance status who have responded to first-line chemotherapy, second-line chemotherapy should be considered [4]. Several chemotherapeutic agents have been investigated in the second-line setting but the most extensively studied has been docetaxel (Taxotere®; Aventis Pharma, Antony, France) [5]. Docetaxel is a semi-synthetic taxoïd derived from baccatin II, which is obtained from the needles of the European yew tree. Docetaxel monotherapy, at a dose of 100 mg/m2 administered once every 3 weeks, has shown promising activity as a second-line treatment for NSCLC, yielding an objective response rate (ORR) of 20% [6]. Neutropenia is the main dose-limiting adverse event for NSCLC patients treated with docetaxel. Grade 3 or 4 neutropenia was observed in 89% of patients who received docetaxel 100 mg/m2; however, the duration of neutropenia was short, with blood counts recovering in a median of 7 days [6]. Results of previous studies have suggested that docetaxel at a dose of 75 mg/m2 has a better benefit–risk ratio than the 100 mg/m2 dose, particularly with regard to febrile neutropenia. This has been confirmed in two randomised phase III trials, which compared docetaxel, as second- or third-line therapy, with best supportive care [7] and vinorelbine–ifosfamide [8].

The present multicentre, randomised study was designed to confirm these previous results, which suggest that docetaxel 75 mg/m2 has similar efficacy but a better safety profile than docetaxel 100 mg/m2 in patients with NSCLC who have failed first-line chemotherapy.


    Patients and methods
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 Introduction
 Patients and methods
 Results
 Discussion
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Patient eligibility
All patients had histologically confirmed locally advanced (non-irradiable) or metastatic NSCLC, with failure of first-line platinum-based chemotherapy. Before study entry, at least 4 weeks must have elapsed since any prior chemotherapy. Patients had to have measurable or evaluable disease, a World Health Organization (WHO) performance status ≤2, and be aged between 18 and 70 years.

Adequate renal (serum creatinine level <140 µmol/l), hepatic (normal bilirubin level; serum alanine aminotransferase, serum asparate aminotransferase and alkaline phosphatase <2.5 x upper limit of normal) and haematological (granulocyte count, ≥2 x 109 cells/l; platelet count, ≥100 x 109 cells/l; and haemoglobin, >10 g/l) parameters were required. Patients with symptomatic brain metastases, symptomatic peripheral neuropathy grade ≥2, or who had been previously treated with taxanes were excluded. Previous radiotherapy was not an exclusion criterion provided that it had been completed >4 weeks prior to study entry, that <25% of the bone marrow had been irradiated and that the target lesion was not within the radiation therapy field. All patients signed a written informed consent form approved by the Institutional Committee for Protection of Patients Involved in Clinical Trials.

Study design and treatment
Patients were stratified by centre and randomised to receive either docetaxel 75 mg/m2 (arm A) or docetaxel 100 mg/m2 (arm B) once every 3 weeks, for up to six cycles. Administration was performed intravenously as a 1-h infusion on day 1 of each cycle. Premedication consisted of oral prednisolone 50 mg b.i.d. or equivalent for 3 days, starting the day before docetaxel infusion. Anti-emetic treatment was permitted with corticotherapy. The prophylactic use of haematopoietic growth factors was forbidden; however, they could be administered therapeutically.

In the event of grade 4 neutropenia lasting for >7 days, grade 4 thrombocytopenia or febrile neutropenia, the docetaxel dose must be reduced in subsequent treatment cycles (dose reduction steps: 100 to 75 mg/m2 and 75 to 60 mg/m2). Appropriate dose modifications (dose reduction in arm A: 75 to 60 mg/m2; in arm B: 100 to 75, then 60 mg/m2 if necessary) or end of treatment were also performed in case of grade ≥3 non-haematological toxicities, with the exception of alopecia, observed in the previous cycle. Subsequent cycles were delayed for a maximum of 2 weeks if granulocytes were <1.5 x 109 cells/l or if the platelet count did not return to a minimum of 100 000/mm3 on the day of infusion. Other toxicities were required to be either grade 0 or 1 before another cycle could be started (with a maximum delay of 2 weeks).

Study treatment was discontinued after the planned six cycles or was terminated early in the event of tumour progression, grade 4 haematological toxicity, despite up to two dose reductions, no haematological recovery at day 35 of a cycle or after up to two dose reductions, any unacceptable toxicity, or withdrawal of patient consent. Treatment could be continued beyond six cycles, at the discretion of the treating physician, if it was considered that patients would obtain clinical benefit from further cycles.

Treatment evaluation
Response was to be assessed every two cycles, according to WHO criteria [9]. In case of partial or complete response, a new assessment to confirm the response must be performed ≥4 weeks later. Investigators’ assessments were reviewed by an expert panel of clinicians. This expert panel was blinded to which treatment arm the patients were on and to the investigators’ assessments.

Drug safety was based on laboratory tests and on clinical signs and symptoms experienced during the treatment period. Safety was assessed in all patients who had received at least one docetaxel infusion, according to National Cancer Institute–common toxicity criteria (NCI–CTC), at each cycle.

Statistical considerations
The primary objective of this phase II study was to assess the time to treatment failure. The main secondary objectives were to assess the relative dose intensity in the two arms, identify risk factors leading to severe or serious toxicity, assess the dose–response relationship and estimate the time to progression and overall survival. The planned sample size was 80 patients per treatment arm (160 patients in total).

For the statistical analysis, three populations were defined: intention-to-treat (ITT; all randomised patients who received at least one docetaxel infusion), evaluable population according to the investigators’ assessment, evaluable population according to the expert panel’s assessment. Patients who received at least two cycles of docetaxel and patients who terminated therapy due to disease progression (irrespective of the number of treatment cycles received) were considered evaluable.

The main outcome criterion, time to treatment failure, was assessed in the ITT population (for each arm) and was defined as the time from the first docetaxel infusion until treatment failure. Treatment failure was defined as disease progression, treatment discontinuation due to toxicity, consent withdrawal or death; or during the follow-up period, as disease progression or death in the absence of any other antitumour treatment.

Secondary outcome criteria were as follows: response rate; response duration (partial response, time from the first treatment day until disease progression; complete response, time from the first day of complete response until disease progression or relapse); time to progression/relapse (time from the first infusion until progression/relapse onset); overall survival (time from first infusion until death); median follow-up time; relative dose intensity; and incidence of grade 3–4 toxicities.

Statistical analysis was descriptive. Quantitative parameters were summarised by mean, standard deviation, median, minimum and maximum, and qualitative parameters by frequencies and percentages. The primary outcome measure, time to treatment failure, and some secondary outcome measures, time to progression, overall survival and response duration were analysed using the Kaplan–Meier method and a 95% confidence interval (CI) was calculated for each treatment arm.


    Results
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 Introduction
 Patients and methods
 Results
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Patient characteristics
From January 19, 1998 to October 11, 1999, 183 patients at 24 French centres were enrolled in the trial. The cut-off date for follow-up was September 14, 2000. The median follow-up time was 16.1 months (range 10.7–30.8) in arm A and 17.0 months (range 10.2–30.9) in arm B.

One patient died before the first drug administration; therefore, 182 patients received at least one cycle; 93 patients in arm A (docetaxel 75 mg/m2) and 89 patients in arm B (docetaxel 100 mg/m2) (Table 1). Four patients did not meet major eligibility criteria (three, arm A; one, arm B): two patients did not have locally advanced or metastatic disease, one patient had a broncho-alveolar carcinoma and one patient had no measurable or evaluable target lesion.


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Table 1. Patient populations
 
Baseline patient characteristics were well balanced between the two groups (Table 2), except more patients in arm A had metastatic disease at study inclusion (91.4% versus 78.7%) and therefore the median number of sites involved for arm A was three (range 1–6) compared with two (range 1–4) for arm B. The median duration between diagnosis and first treatment cycle was 6.6 months (range 1–81). The median duration between the last cycle of first-line chemotherapy and first infusion of the study drug was 5.3 months (range 1.0–24.9) in arm A and 5.9 months (range 0.9–56.2) in arm B. First-line chemotherapy was palliative in 140 patients (76.9%), neo-adjuvant in 27 patients (14.8%), adjuvant in 13 patients (7.1%) and both neo-adjuvant and adjuvant in two patients (1.1%). With respect to prior non-chemotherapeutic treatment, 22.0% of patients had previous surgery and 31.3% had previous mediastinal radiotherapy. Thirty-one [17.0% (A, 14.0%; B, 20.2%)] patients were sensitive (no disease progression within 6 months after the end of platinum-based chemotherapy). Forty-nine patients (52.7%) in arm A and 39 patients (43.8%) in arm B were resistant to prior cisplatin-based chemotherapy (i.e. having had a complete or partial response, or stable disease within the 6 months before disease progression). The numbers of cisplatin-refractory patients (i.e. having never had an objective response or stable disease) were equally balanced between both arms: 31 patients (33.3%) in arm A and 32 patients (36.0%) in arm B.


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Table 2. Baseline patient and disease characteristics (ITT population)
 
Treatment administered
In total, 612 cycles were administered, 300 in arm A and 312 in arm B. The median number of cycles per patient was two (range 1–21) for arm A and three (range 1–9) for arm B. The median cumulative dose was 151.2 mg/m2 in arm A and 297.3 mg/m2 in arm B. The median relative dose intensity was similar in both arms: 0.99 (range 0.76–1.14).

In the 155 patients (85.2%) [78 patients (83.9%) in arm A and 77 patients (86.5%) in arm B] who received more than one cycle of docetaxel, 18 (2.9%) cycles were delayed for >7 days (arm A, 11; arm B, seven). Docetaxel dose was reduced in a total of 14 cycles, mainly due to haematological toxicity: five (1.7%) cycles were reduced in arm A and nine (2.9%) in arm B.

Response and survival
The median time to failure (main efficacy end point) for the ITT population was 1.34 months (95% CI 1.28–1.64) for arm A (75 mg/m2 group) and 1.64 months (95% CI 1.34–2.62) for arm B (100 mg/m2 group) (Figure 1). Median time to disease progression (ITT population) was 1.5 months (95% CI 1.3–2.0) for arm A and 2.1 months (95% CI 1.3–2.7) for arm B. There was a trend towards longer survival in patients treated in arm B. Median overall survival for arm A was 4.7 months (95% CI 3.8–5.9) versus 6.7 months (95% CI 4.8–7.1) for arm B (Figure 2).



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Figure 1. Time to treatment failure. Arm A, docetaxel 75 mg/m2; arm B, docetaxel 100 mg/m2.

 


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Figure 2. Overall survival. Arm A, docetaxel 75 mg/m2; arm B, docetaxel 100 mg/m2.

 
Response data for the evaluable population, as assessed by the investigators and the expert panel, are provided in Table 3. According to the investigators’ assessments, disease control (i.e. either an objective response or stable disease) was achieved in 37 patients (45.7%) in arm A and in 45 patients (57.0%) in arm B. The expert panel’s assessment was more conservative but yielded similar results: disease control was evident in 35 patients (43.8%) in arm A and in 39 patients (49.4%) in arm B. The median duration of response according to the expert panel was 8.8 months for arm A and 4.1 months for arm B.


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Table 3. Response rate (evaluable population)
 
Considering efficacy according to previous response to first-line chemotherapy, disease control was obtained in 61% of the sensitive population in both arms, 37% and 36% of the resistant and refractory population, respectively, in arm A, and 56% and 38% of the same population, respectively, in arm B.

Toxicity
The most common grade 3–4 haematological and non-haematological toxicities (by patient) are summarised in Table 4. More patients in arm B experienced grade 3–4 neutropenia: 72.7% versus 44.0% in arm A. Analysis by treatment cycle also indicated that grade 3–4 neutropenia occurred more frequently in arm B: 57.3% versus 30.4% in arm A. However, febrile neutropenia occurred at a similar frequency in both arms (six patients in each arm).


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Table 4. Main treatment-related grade 3 and 4 toxicities
 
The frequency of grade 3–4 non-haematological toxicities was similar in both arms, except for asthenia which seemed to be less common in arm A (8.6%) than in arm B (19.1%) as well as for diarrhoea (A: 1.1% versus B: 4.5%) and for related infections that occurred only in arm B (5.6%). Grade 3–4 treatment-related respiratory symptoms (dyspnoea, cough) and pulmonary infiltration were observed at a similar frequency and severity in both arms.

Serious adverse events (SAEs) related to treatment were reported for 10 patients (13 SAEs) in arm A (docetaxel 75 mg/m2) and for 19 patients (32 SAEs) in arm B (docetaxel 100 mg/m2). Six treatment-related deaths were reported: three in arm A (one respiratory failure in a patient with a past history of pulmonary tuberculosis and chronic obstructive pulmonary disease; one febrile neutropenia with septic shock; and one diffuse interstitial pneumopathy) and three in arm B (one septic shock; one diffuse interstitial pneumonia; and one febrile pneumonia in a context of leukopenia).


    Discussion
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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Due to the efficacy of first-line platinum-based chemotherapy in advanced NSCLC, there are more candidates for second-line treatment at time of progression or relapse [4]. Many phase I/II trials have been performed with docetaxel in the second-line setting but at this time only two randomised studies have been published [7, 8]. These studies established that second-line docetaxel provides survival and quality-of-life benefits [7, 8]. Docetaxel 100 mg/m2 was initially proposed in this second-line setting; however, results from a phase III study by Shepherd et al. [7] indicated that the efficacy of docetaxel at a 75 mg/m2 dose was similar to that of the 100 mg/m2 dose, while the safety profile (in particular with respect to febrile neutropenia) was clearly better at 75 mg/m2 than at 100 mg/m2. Fossella et al. [8] conducted a large phase III study comparing docetaxel 75 mg/m2 and 100 mg/m2 versus ifosfamide or vinorelbine; results of this study led to similar conclusions, favouring docetaxel 75 mg/m2. On the basis of these studies, the recommended dose of docetaxel in this setting was set at 75 mg/m2 every 3 weeks. The present study was designed to confirm whether 75 mg/m2 is indeed the optimal dose of docetaxel for second-line treatment of NSCLC and, in particular, to evaluate whether the toxicities observed previously [7, 8] with the 100 mg/m2 dose were abnormally severe and frequent, especially with respect to toxic deaths [7], compared with what was reported in previous phase II studies [6, 1013].

The efficacy results in our study suggest a slight advantage for docetaxel 100 mg/m2: median time to treatment failure, the principal efficacy end point, was slightly longer (1.64 months) in arm B (docetaxel 100 mg/m2) than in arm A (docetaxel 75 mg/m2) (1.34 months) and median overall survival was 6.7 months in arm B and 4.7 months in arm A. Interestingly, although the response rate was low in both arms as expected, disease control was achieved in almost half of the patients treated with docetaxel (43.8% in arm A and 49.4% in arm B).

Before any definite conclusions can be drawn, the baseline populations of the two arms of the study should be compared carefully. The two arms were well balanced for age, gender and WHO performance status. Response to previous platinum-based chemotherapy is also a factor that may possibly influence response to second-line chemotherapy. In our study, approximately one-third of patients were refractory in each arm, but there were more resistant patients in arm A (52.7%) than in arm B (43.8%). Disease control was obtained more frequently in the sensitive population in both arms but the numbers were low (13 patients in arm A and 18 patients in arm B). As a matter of fact, it is well known in small-cell lung carcinoma that patients with refractory disease do not respond to second-line therapy [14]; however, in NSCLC, this is still a matter of controversy [5]. Moreover, at this time, there is no consistent definition of sensitive and refractory patients throughout the literature.

There was a higher proportion of patients with metastatic disease in arm A (91.4%) than in arm B (78.7%). Thus, the median number of involved sites was three for arm A and two for arm B. The higher number of patients with metastatic disease in arm A (docetaxel 75 mg/m2) may well account for the trend towards longer survival observed in patients treated with the 100 mg/m2 dose. Although histological type is not a strong prognostic factor [15], it is interesting to note that there were more patients with adenocarcinoma in the 75 mg/m2 arm than in the 100 mg/m2 arm (46.2% versus 34.8%). These slightly unbalanced baseline characteristics, to the detriment of arm A, suggest that the possibility of a true dose–response relationship cannot be derived.

In terms of haematological toxicity, whilst the incidence of febrile neutropenia was similarly low in both arms (A: 6.7% versus B: 6.8%), the incidence of grade 3–4 neutropenia occurred more frequently in arm B (A: 44.0% versus B: 72.7%). These data indicate that any potential efficacy benefit obtained with the 100 mg/m2 dose is out-weighed by a higher incidence of grade 3–4 neutropenia. Non-haematological grade 3–4 toxicities were similar in both arms, except for asthenia (A: 8.6% versus B: 19.1%), diarrhoea (A: 1.1% versus B: 4.5%) and infection (A: 0% versus B: 5.6%), which again occurred more frequently with the 100 mg/m2 dose. Toxic deaths were observed in 6/182 patients (three in each arm), which is acceptable in this type of population. This compares favourably with the 6/104 patients in Shepherd’s phase III trial [7] and is higher than the observed rate (2/250 patients) in the Fossella phase III trial [8]. Diffuse interstitial disease has rarely been reported as a complication of docetaxel treatment [16]. It is impossible to compare our rate to that observed in the phase III studies as the treatment-related toxicities are not reported as such in these studies [7, 8]. Overall grade 1–4 respiratory symptoms were observed in 50 (54%) patients in arm A and in 55 (62%) patients in arm B (data not shown). In the study by Shepherd et al. [7], 38% of patients treated with 75 mg/m2 and 53% of patients treated with 100 mg/m2 developed pulmonary toxicity (grade 1–4), but also 50% of patients receiving only best supportive care developed pulmonary toxicity, demonstrating that most of the events may well be due to the disease and are not treatment-related.

On the basis that docetaxel 75 mg/m2 has a more favourable safety profile, particularly with respect to haematological toxicity, and that on balance it probably has a similar efficacy to the 100 mg/m2 dose, we can conclude that the optimal dosage of docetaxel in this setting is indeed 75 mg/m2, as suggested in previous studies [7, 8]. Our results, together with those from other phase II and III trials, have established that docetaxel is an effective treatment for patients with advanced NSCLC who have been pretreated with platinum-based chemotherapy and docetaxel 75 mg/m2 is actually a standard for those patients. New agents or alternative schedules of docetaxel [17] developed in the second-line setting should therefore be compared to docetaxel 75 mg/m2 every 3 weeks.


    Acknowledgements
 
The authors would like to thank all their colleagues who participated in this study: L. Moreau and J.P. Oster (CHU Lyautey, Strasbourg); N. Paillot (CHU Notre Dame, Metz); A.C. Neidhart and P. Bombaron (CH Muller, Mulhouse); M. Mornet (CH J Coeur, Bourges); C. Clary-Meinesz (Hôpital Pasteur, Nice); R. Poirier and F. Mouysset (CH Pays d’Aix, Aix-en-Provence); H. Bourgeois and J.C. Meurice (CHU Poitiers-La Miletrie, Poitiers); D. Braun and B. Remignon (CHG Maillot, Briey); C. Boaziz and A. Kanoui (Hôpital Privé–Nord Parisien, Sarcelles); J. Trédaniel (Hôpital Saint Louis, Paris); D. Levy (CHG Pasteur, Colmar); X. Quantin (CHU A de Villeneuve, Montpellier); M. Clavel (CHU Hôpital du Cluzeau, Limoges); P. Jacoulet, V. Westeel and A. Madroszyk (CHU Minioz, Besançon); A. Livartowski (Institut Curie, Paris); P. Diot (CHU, Tours); M.A. Massiani, J.M. Naccache and L. Rosencher (Hôpital Tenon, AP-HP, Paris); J.P. Gury (CHG Morel, Vesoul); and all members of the teams who participated in this study. Special thanks to L. Mussak for his assistance with the statistical analyses.


    FOOTNOTES
 
* Correspondence to: Dr Elisabeth Quoix, Hôpital Lyautey, 1 Place de l’Hôpital, 67091 Strasbourg Cedex, France. Tel: +33-3-88-11-63-02; Fax: +33-3-88-11-63-35; E-mail: elisabeth.quoix{at}chru-strasbourg.fr Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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