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Annals of Oncology Advance Access originally published online on October 17, 2007
Annals of Oncology 2008 19(2):362-369; doi:10.1093/annonc/mdm474
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© 2007 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

lung cancer

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

R. Rosell1,*, G. Robinet2, A. Szczesna3, R. Ramlau4, M. Constenla5, B. C. Mennecier6, W. Pfeifer7, K. J. O'Byrne8, T. Welte9, R. Kolb10, R. Pirker11, A. Chemaissani12, M. Perol13, M. R. Ranson14, P. A. Ellis15, K. Pilz16 and M. Reck17

1 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
2 Institut de Cancérologie, CHU Morvan, Brest, France
3 Mazowieckie Centrum Chorob Pluc i Gruzlicy, III Oddzial Chorob Pluc, Otwock
4 Wielkopolskie Centrum Chorob Pluc i Gruzlicy, Oddzial Onkologii, Poznan, Poland
5 Unidad de Oncología, Hospital de Pontevedra, Spain
6 Service de Pneumologie, Pavillon Laennec, Hôpitaux Universitaires, Strasbourg, France
7 Abt. f. Atem-u. Lungenkrankheiten, A.ö. Krankenhaus d. Stadt Linz, Linz, Austria
8 Department of Oncology, St James' Hospital, Dublin, Ireland
9 Abt. Pneumologie, Medizinische Hochschule Hannover, Hannover, Germany
10 Abteilung f. Lungenkrankheiten, Klinikum Kreuzschwestern Wels, Wels
11 Klinische Abteilung für Onkologie, Univ.-Klinik f. Innere Medizin I, Wien, Austria
12 Lungenklinik Köln-Merheim, Köln, Germany
13 Service de Pneumologie, Hôpital de la Croix Rousse, Lyon, France
14 Department of Medical Oncology, Christie Hospital, University of Manchester, Manchester
15 Department of Medical Oncology, Guy's Hospital, London, UK
16 Medical Sciences Oncology, Clinical Research & Development, Merck Serono, Darmstadt
17 Onkologischer Schwerpunkt, Zentrum für Pneumologie und Thoraxchirurgie, Krankenhaus Großhansdorf, Wohrendamm, Grosshansdorf, Germany

* Correspondence to: Dr R. Rosell, Medical Oncology Service, Scientific Director of Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona, Barcelona, Spain. Tel: +34-93-497-89-25; Fax: +34-93-497-89-50; E-mail: rrosell{at}ico.scs.es


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics.

Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m2, followed by 250 mg/m2 weekly thereafter).

Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated.

Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.

Key words: cetuximab, cisplatin, epidermal growth factor receptor, first-line, NSCLC, vinorelbine


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
The majority of patients with non-small-cell lung cancer (NSCLC) present with locally advanced or metastatic disease that is incurable with existing treatment modalities [1]. Platinum-based chemotherapy constitutes standard first-line treatment for patients with stage IIIB and IV disease and good performance status [1]. For a number of years, four doublets have been in common use in this setting: cisplatin/vinorelbine, cisplatin/gemcitabine, cisplatin/docetaxel and carboplatin/paclitaxel. In randomized phase III trials, these regimens produced remission rates of 17%–44%, median progression-free survival (PFS) times of 3–5 months and median overall survival (OS) times of 7–11 months [2–5].

The epidermal growth factor receptor (EGFR) is expressed in 40%–80% of NSCLC [6, 7] and has been shown to play a role in processes linked to tumor growth and progression, including cell proliferation, angiogenesis, invasion, metastasis and the inhibition of apoptosis [7–11]. Two classes of EGFR-targeting agents are currently under extensive clinical investigations: the small molecule EGFR tyrosine kinase inhibitors (TKIs) and EGFR-targeted monoclonal antibodies (mAbs). Both types of agent inhibit EGFR downstream signaling and induce tumor cell apoptosis [12].

The EGFR TKIs gefitinib and erlotinib have been the most extensively studied of the targeted agents in NSCLC [13–21]. After the failure of chemotherapy, they were shown to induce remissions in 8%–19% of patients, and median PFS and OS times of 2–3 months and 6–8 months, respectively [13–17]. These results led to four large randomized phase III trials using gefitinib or erlotinib in combination with either cisplatin/gemcitabine or carboplatin/paclitaxel as first-line treatment for unresectable stage IIIB and stage IV NSCLC. Unfortunately, all of these studies failed to show superiority over the particular chemotherapy regimens plus placebo in terms of response rates, median PFS times and median OS times [18–21].

Although both types of agent can suppress EGFR-mediated downstream signal transduction, several studies indicate that the small molecule EGFR TKIs and EGFR-directed mAbs may have different spectrums of activity [12, 22, 23]. For example, a recent study showed that EGFR mutations were associated with gefitinib sensitivity in vitro, but this was not the case for the EGFR-targeted mAb, cetuximab (Erbitux®, ImClone Systems Inc. licensed Merck KGaA) [22]. For the Lung Cancer Cetuximab Study (LUCAS), we selected the standard chemotherapy regimen of cisplatin/vinorelbine as a combination partner for cetuximab.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
eligibility criteria
Chemotherapy-naive patients with histologically or cytologically proven NSCLC, stage IV or stage IIIB with documented malignant pleural effusion, according to American Joint Committee on Cancer criteria, and immunohistochemical evidence of EGFR expression in the primary tumor and/or metastases, were enrolled. If at least 1% of malignant cells were EGFR detectable with respect to a positive control (according to Dako EGFR pharmDxTM Kit assays [24]), the sample was considered to be EGFR expressing. Other enrollment criteria included the following: measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), age ≥18 years, Karnofsky performance status ≥70, life expectancy of ≥3 months, neutrophil count ≥1.5 x 106/l, platelet count ≥100 x 109/l, hemoglobin ≥9 g/dl, serum creatinine ≤1.25 x the upper limit of normal (ULN) or creatinine clearance ≥60 ml/min, bilirubin <1.5 x ULN, aspartate aminotransferase and alanine aminotransferase ≤3 x ULN (≤5 x ULN in the case of liver metastasis), recovery from toxicities due to prior treatment and use of effective contraception. The most important exclusion criteria were proven or symptomatic brain metastasis, prior treatment with mAbs or other EGFR-targeting treatments, and pregnancy.

treatment plan
Patients were randomly assigned 1 : 1 to receive either cisplatin/vinorelbine or cetuximab plus cisplatin/vinorelbine. Patients in both arms received: vinorelbine, given as a 25 mg/m2 i.v. infusion over 10 min on days 1 and 8; plus cisplatin, 80 mg/m2 i.v. over 1 h on day 1, together with adequate hydration. Antihistamine premedication was administered to patients scheduled to receive cetuximab, which was given at an initial dose of 400 mg/m2 i.v. (including a ‘test dose’ of a 20 mg (10 ml) infusion administered over 10 min followed by an observation period of 30 min after administration for signs of anaphylaxis) over 2 h on day 1. From day 8 onwards, cetuximab was administered weekly at a dose of 250 mg/m2 i.v. over 1 h—cisplatin and vinorelbine were administered 1 h after completion of the cetuximab infusion.

One treatment cycle comprised a period of 3 weeks (21 days). Patients received a maximum of eight cycles in both treatment arms, unless disease progression or unacceptable toxicity was observed. After completion of the scheduled cycles, patients in the cetuximab plus cisplatin/vinorelbine arm were allowed to receive cetuximab monotherapy until disease progression or the occurrence of unacceptable toxicity.

chemotherapy dose adjustments
Chemotherapy was repeated every 21 days, provided blood counts (neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l, hemoglobin ≥9 g/100 ml), serum bilirubin <1.5 ULN and creatinine clearance ≥60 ml/min were adequate and patients had recovered from all clinically relevant non-hematological toxicities; represented by National Cancer Institute–Common Toxicity Criteria (NCI–CTC) defined adverse events (AEs) resolving to grade 1 or base line. If patients did not meet these criteria, chemotherapy was delayed for up to 2 weeks. If longer delays were required, chemotherapy was discontinued. Dose adjustments for vinorelbine based on neutrophil and serum bilirubin values were on day 8 of a cycle. On this day, vinorelbine was omitted for neutrophils <1 x 109/l, platelets <75 x 109/l and serum bilirubin ≥1.5 x ULN. For patients who experienced neutropenic fever in the previous cycle, subsequent doses of vinorelbine and cisplatin were reduced to 20 mg/m2 and 60 mg/m2, respectively.

cetuximab dose adjustments
In the case of grade 4 skin reactions, cetuximab was discontinued. If grade 3 skin reactions occurred, cetuximab administration was delayed for up to two consecutive infusions until resolution of the reaction to grade 2. Cetuximab was resumed at the planned dose (for a first skin reaction) or at a reduced dose (200 and 150 mg/m2, for second and third occurrences, respectively). Cetuximab treatment was discontinued in the event of a delay of three consecutive infusions or a fourth occurrence of a grade 3 skin reaction. Grade 1 or 2 hypersensitivity reactions were managed by prolongation of the infusion time of cetuximab to 2 h for this and all subsequent infusions. If this was not effective, discontinuation of cetuximab was considered. In the case of grade 3 or 4 hypersensitivity reactions, treatment with cetuximab was discontinued.

pretreatment and follow-up assessments
Baseline evaluation and staging consisted of physical examination, electrocardiogram, chest X-ray, chest and abdominal computed tomography or magnetic resonance imaging, complete blood count, serum chemistry and bone scan (if clinically indicated). A physical examination, complete blood counts and serum chemistry were obtained before each cycle. In addition, complete blood counts and serum bilirubin analyses were carried out on day 8 of each cycle. Patients were evaluated radiologically every two cycles and assessed by investigators for tumor response using RECIST criteria. AEs were assessed according to NCI–CTC version 2. Study follow-up was every 2 months.

study design and sample size
This open-label, randomized phase II study compared cetuximab in combination with cisplatin/vinorelbine with the same chemotherapy regimen as an active control arm. The main purpose of this study was to assess the add-on activity of cetuximab. The primary objective was to determine the best overall response rate (ORR), based on the number of patients in each treatment arm achieving a partial or complete response as best overall response. The planned sample size was fixed without test power consideration at 80 patients with EGFR-expressing tumors. Due to the limited sample size, no conclusions can be drawn in the case of nonsignificant statistical efficacy results. Therefore, statistical analysis focused on estimation, including corresponding confidence intervals (CIs) (e.g. median survival time and hazard ratio). Assuming a response rate of 30% in the cetuximab plus cisplatin/vinorelbine arm allowed for a lower limit of the 95% CI of the best ORR of 15%.

statistical methods
The efficacy analysis was based on the intent to treat population defined as all randomized patients. The safety analysis was based on all patients who had received any dose of study treatment. The primary efficacy end point was best ORR. Secondary efficacy end points were survival time, PFS time, time to treatment failure (TTF) and duration of response. Estimates for the best ORR, including two-sided Clopper–Pearson 95% CIs, were calculated. Time to event variables (OS, PFS, TTF and duration of response) were determined using Kaplan–Meier methods [25] (product-limit estimates) including estimates for the median and corresponding two-sided 95% CI.

PFS time was defined as the time from randomization to the date of disease progression or death (due to any cause when occurring within 60 days after last tumor assessment). For patients with no progression date and death not within 60 days after the last tumor assessment, PFS was censored on the date of last tumor assessment. OS was defined as the time between randomization and death. TTF was defined as the time from randomization to the first occurrence of one of the following events: discontinuation of study treatment due to an AE, progressive disease, death within 60 days after last tumor assessment or withdrawal of consent.

pharmacokinetics
Blood samples to measure cetuximab were drawn at the following time points:

cycle 1: day 1—just before and after the initial dose of cetuximab; week 3—just before, at the end of and 1, 2, 4, 48, 96 and 168 h after the start of the third dose of cetuximab;
cycle 2: week 4—just before, at the end of and 1, 2, 4, 48, 96 and 168 h after the start of the fourth cetuximab infusion.

The plasma concentration time data were analyzed using noncompartmental and compartmental standard methods. The following pharmacokinetic parameters were determined: Cmax (µg/ml), AUC{tau} (µg/ml), t1/2 (h), CLss (l/h), Vss (l).


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
patients
From February 2002 to May 2003, one hundred and twenty-nine patients were prescreened for study participation. EGFR test results were available for 114 patients, 103 of whom had tumors that expressed EGFR. Of these, 86 patients from 16 centers in six European countries met all protocol eligibility criteria and were randomly assigned to receive either cisplatin/vinorelbine alone (43 patients) or in combination with cetuximab (43 patients). The two arms were well balanced in terms of patients and disease characteristics (Table 1).


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  		Table 1 Patient and disease characteristics at baseline

 
efficacy
Efficacy data are summarized in Table 2. The best ORRs for cetuximab plus cisplatin/vinorelbine and cisplatin/vinorelbine were 35% (95% CI: 21% to 51%) and 28% (15% to 44%), respectively. The addition of cetuximab improved the median duration of response by 1.6 months (6.1 versus 4.5 months). The median PFS time for cetuximab plus cisplatin/vinorelbine was 5.0 (4.5–5.8) months compared with 4.6 (2.5–6.0) months for cisplatin/vinorelbine (Figure 1A). The hazard ratio was 0.71 (0.4–1.2), representing a risk reduction for disease progression of 29% and a trend towards the prolongation of PFS in favor of the cetuximab-containing regimen. There was also a trend towards a higher 12-month PFS rate for the cetuximab plus cisplatin/vinorelbine arm [15% (1–29) versus 0%; Figure 1A]. The median TTF was 3.4 months for cetuximab plus cisplatin/vinorelbine and 2.9 months for cisplatin/vinorelbine.


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  		Table 2 Efficacy data for the ITT population

 

Figure 1
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  		Figure 1. Kaplan–Meier plots for PFS (panel A) and overall survival (panel B). PFS, progression-free survival; Med, median; CTX, chemotherapy (cisplatin/vinorelbine); Cet, cetuximab; Surv, survival.

 
The median survival time was 8.3 (6.1–9.9) months for patients who received cetuximab plus cisplatin/vinorelbine and 7.3 (5.6–9.5 months for those who received chemotherapy alone (Figure 1B). The hazard ratio of 0.71 (0.5–1.1) indicates a risk reduction for death of 29% and a trend for improved survival for cetuximab plus cisplatin/vinorelbine. The 1- and 2-year survival rates were 33% (19–47) and 16% (5–27) in the cetuximab plus cisplatin/vinorelbine arm and 26% (13–40) and 0% in the chemotherapy alone arm.

Analysis of the subgroup of patients experiencing skin toxicities in the cetuximab plus cisplatin/vinorelbine arm showed response rates of 100% (five of five patients) and 17% (one of six patients) for patients with grade 3 skin toxicity and no skin toxicity, respectively (Table 3).


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  		Table 3 Subgroup analysis of patients experiencing skin toxic effects in the cetuximab plus cisplatin/vinorelbine arm for response rate

 
treatment exposure
The extent of exposure to cisplatin and vinorelbine was similar in both treatment groups, with a median exposure time of 13.6 and 12 weeks for the cetuximab plus cisplatin/vinorelbine and chemotherapy alone arms, respectively. The percentages of patients receiving ≥4 cisplatin or ≥7 vinorelbine infusions were 74% in each case for the cetuximab plus cisplatin/vinorelbine arm and 54% and 56% for the cisplatin/vinorelbine arm, respectively. The relative dose intensity of cisplatin was ≥90% for 90% of patients in both treatment groups for cycles 1–3; but during this time, the percentage of patients who received >90% of the planned vinorelbine dose decreased from cycle 1 to 3 from 93% to 72% in the cetuximab plus chemotherapy arm and from 95% to 74% in the chemotherapy arm.

The median exposure time to cetuximab was 13.6 weeks with a median number of 13 infusions per patient. The median cetuximab dose intensity was 240 mg/m2/week (range 172–251 mg/m2/week) and the relative dose intensity was ≥80% for 93% of patients. Ten patients continued on cetuximab monotherapy following the cessation of chemotherapy, for a median duration of 8 weeks.

safety
Forty-two patients in the cetuximab plus cisplatin/vinorelbine arm (one patient was randomly allocated to the study but never treated) and 43 patients in the chemotherapy alone arm were assessable for safety. The frequencies of grade 3/4 non-hematological AEs and grade 3/4 laboratory abnormalities are summarized in Table 4. The incidence of most of the non-hematological grade 3/4 AEs was similar between regimens. Differences in the rates of occurrence in the range of 10%–17% were noted for grade 3/4 asthenia (19% versus 2%), respiratory symptoms (12% versus 2%) and skin toxicities (10% versus none); all more frequent in the cetuximab plus cisplatin/vinorelbine arm. Skin toxicities included acne-like rash (7% versus none). Any acne-like rash was reported in 32 (76%) patients in the cetuximab plus cisplatin/vinorelbine arm, of which 27 patients experienced their first acne-like rash during the first 3 weeks of study treatment. In the cetuximab plus cisplatin/vinorelbine arm, one patient experienced a grade 3 hypersensitivity reaction at the first infusion and was withdrawn from the study.


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  		Table 4 Most common non-hematological grade 3/4 AEs and grade 3/4 laboratory abnormalities reported for ≥5% of the safety population

 
The most common grade 3/4 hematological laboratory abnormalities included anemia and thrombocytopenia, which were seen with a similar frequency in both treatment arms; however, the addition of cetuximab was associated with an increase in the frequency of grade 4 neutropenia from 37% to 50%.

cetuximab pharmacokinetics
Thirty-three patients, who had received cetuximab plus cisplatin/vinorelbine within the framework of this study contributed to the pharmacokinetic profile after administration of single-agent cetuximab in week 3 and of cetuximab in combination with cisplatin/vinorelbine in week 4. The mean values of the obtained pharmacokinetic parameters (Table 5) were in good agreement between week 3 and 4, indicating that cisplatin/vinorelbine did not have a significant influence on the pharmacokinetics of cetuximab.


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  		Table 5 Mean pharmacokinetic parameters in week 3 and 4 for cetuximab (PK population)

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
This randomized phase II trial was designed to investigate the activity and safety of cetuximab in combination with cisplatin/vinorelbine as first-line treatment in patients with EGFR-expressing advanced NSCLC. The addition of cetuximab increased the response rate from 28% to 35% and led to an apparent prolongation of median PFS time (5.0 versus 4.6 months) and median survival time (8.3 versus 7.3 months), compared with cisplatin/vinorelbine alone. There was also a clear trend for the combination of cetuximab plus cisplatin/vinorelbine to improve the 12-month PFS rate (15% versus 0%) and the 1- and 2-year survival rates (33% versus 26% and 16 versus 0%, respectively). The median OS times achieved in both arms of the current study are low, but are nevertheless within the range of 7–11 months reported for platinum doublets of other randomized NSCLC studies [4, 26–30]. It may be that the relatively high percentage of stage IV patients (91%) enrolled in LUCAS or a more limited use of second-line therapies [47% (cetuximab plus cisplatin/vinorelbine) and 33% (cisplatin/vinorelbine) of patients received no post-treatment anticancer therapy contributed to the shorter than expected median OS times.

The relative dose intensity of >80% for >90% of the patients demonstrates the feasibility of administering the planned dose of cetuximab in combination with cisplatin/vinorelbine. Slightly higher frequencies of certain grade 3/4 AEs compared with cisplatin/vinorelbine alone were seen. These were asthenia and skin toxicities, which represent known side-effects of cetuximab. Skin toxicities (including acne-like rash) are also typical for other EGFR-inhibitory agents. Respiratory symptoms were mainly dyspnea, and none of these grade 3 or 4 AEs was related to cetuximab. Reasons for the increase in frequency of grade 4 neutropenia from 37% to 50% could not be found. The ongoing phase III study might clarify whether this represents a chance finding. No influence of cisplatin/vinorelbine on the pharmacokinetics of cetuximab was detected. Together, these findings indicate that the addition of cetuximab may improve the efficacy of cisplatin/vinorelbine with an acceptable safety profile.

Currently, there is no evidence indicating that the addition of EGFR-targeting agents improves the efficacy of the two most widely used platinum-based regimens in the first-line setting of advanced NSCLC. The EGFR TKIs gefitinib and erlotinib and the EGFR-targeted mAb panitumumab failed to improve overall efficacy in four large randomized phase III and one randomized phase II trial when added to either paclitaxel/carboplatin or gemcitabine/cisplatin in terms of response rate, median PFS time or median survival time compared with the same chemotherapy alone [18–21, 31]. The reasons for the lack of additive antitumor activity of the EGFR TKIs and panitumumab in this setting are still puzzling, although variations in the levels of EGFR expression are unlikely to be involved. Possible explanations include patient selection parameters, inadequate dosing or scheduling and suboptimal sequencing with cytotoxic agents. A further possible explanation for the failure of panitumumab to improve the efficacy of the first-line paclitaxel/carboplatin combination is that this immunoglobulin G2 mAb has a low capacity for eliciting antibody-dependent cellular cytotoxicity (ADCC) reactions. In contrast, cetuximab, an immunoglobulin G1 mAb, has the capacity to elicit ADCC [32]. Furthermore, in contrast to the situation in relation to EGFR TKIs, [33] cetuximab efficacy in NSCLC appears to be independent of sensitizing EGFR mutations [23, 34].

Two nonrandomized phase I/II studies have examined cetuximab in combination with either paclitaxel/carboplatin [35] or gemcitabine/carboplatin [36] in the first-line treatment of 31 and 35 stage IV NSCLC patients, respectively. Both regimens were reported to be well tolerated and response rates of 26% and 29% and median OS rates of 11.0 and 10.2 months, respectively, hinted at improved efficacy for cetuximab plus chemotherapy over chemotherapy alone.

In summary, to our knowledge, this is the first randomized trial demonstrating that combination treatment with cetuximab plus cisplatin/vinorelbine enhances the response rate and improves PFS and survival time with an acceptable safety profile compared with cisplatin/vinorelbine alone. To validate these results a large, randomized phase III trial of first-line Erbitux in lung cancer (FLEX) to evaluate cetuximab plus cisplatin/vinorelbine as first-line treatment is underway in patients with EGFR-expressing stage IIIB or IV NSCLC. Recruitment of 1125 patients in the FLEX study was completed in February 2006.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
We thank the monitors, nurses, other support staff and the patients participating in the study; Isil Montaner, Thomas Goddemeier, Marc-Ulrich Haeusler and Yvonne Schnaars.

Received for publication June 1, 2007. Revision received August 22, 2007. Accepted for publication September 10, 2007.


   References
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 patients and methods
 results
 discussion
 Acknowledgements
 References
 
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