Annals of Oncology Advance Access originally published online on May 25, 2008
Annals of Oncology 2008 19(10):1691-1697; doi:10.1093/annonc/mdn354
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lung cancer |
A phase III randomised study of concomitant induction radiochemotherapy testing two modalities of radiosensitisation by cisplatin (standard versus daily) for limited small-cell lung cancer
1 Institut Jules Bordet, Brussels, Belgium
2 CHRU Calmette, Lille, France
3 Hellenic Cancer Institut, St-Savas Hospital, Athens, Greece
4 CH de Douai, France
5 CHU de Charleroi, Belgium
6 Hôpital de Hayange France
7 CHR St-Joseph-Warquignies, Boussu, Belgium
* Correspondence to: Prof. J. P. Sculier, Department of Critical Care & Thoracic Oncology, Institut Jules Bordet, Université Libre Bruxelles (ULB), 1, rue Héger-Bordet, B-1000 Bruxelles, Belgium. Tel: +32 2 541 31 85; Fax: +32 2 534 37 56; E-mail: sculier{at}bordet.be
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: The purpose of this study was to determine in limited small-cell lung cancer if locoregional irradiation concurrently with induction chemotherapy with cisplatin and etoposide prolongs survival when cisplatin is given daily as a radiosensitiser.
Patients and methods: Two-hundred and four eligible patients were randomised between standard radiosensitised induction chemoradiotherapy (arm A) with cisplatin (90 mg/m2 day 1) plus etoposide and daily radiosensitised induction chemoradiotherapy (arm B) with cisplatin (6 mg/m2/day) plus etoposide. Chemotherapy and chest irradiation (39.90 Gy in 15 fractions >3 weeks) both started on day 1.
Results: There was no difference in survival between both arms with respective median, 2 and 5 years of 15.5 months, 35% and 18% in arm A and 17.0 months, 38% and 21% in arm B (P = 0.50). Performance status and T status were identified as independent prognostic factors for survival. In terms of local control rate, there was a statistical trend in favour of arm A with 2% only local relapse versus 10% in arm B. Daily cisplatin radiosensitisation was associated with more oesophagitis and thrombopenia but less nephrotoxicity.
Conclusion: Induction chemoradiotherapy resulted in both arms in good long-term survival, comparable to the best reported results and without improvement by daily cisplatin administration.
Key words: small cell lung cancer, radiochemotherapy, limited disease, cisplatin
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Chemotherapy has been a major advance in the treatment of small-cell lung cancer (SCLC). However, if survival is significantly prolonged, 5-year overall survival (OS) is
5% and there are 10 times more long-term survivors in patients with limited disease (LD) than in those with extensive disease. Radiotherapy, in combination with chemotherapy, can improve survival as established by various meta-analyses [1–3]. The reduction of the risk of death in the combined group compared with the chemotherapy-alone group was estimated to 14%. The benefit in terms of OS at 3 years was 5.4%. It should be noted that those patients were mainly treated with non-cisplatin-containing chemotherapy. These results led in the nineties to a lot of questions that are still being investigated by randomised trials in order to define the optimal technique and timing for thoracic radiotherapy: Which best radiation target volume? Should radiotherapy be given concurrently, alternatingly or sequentially to chemotherapy? What fractionation type to be used for radiotherapy? How to optimise the cooperation between chemotherapy and radiotherapy by exploiting the radiosensitisation properties of some cytostatic agents?
The combination of cisplatin and etoposide can be considered as one of the most active chemotherapy regimens available today for the treatment of SCLC [4, 5]. It can be used concurrently to chest irradiation with manageable toxicity [4]. In locoregional non-small-cell lung cancer (NSCLC), a controlled trial, published in 1992, obtained improved rates of survival and control of local disease when cisplatin was given daily at small doses in combination with irradiation [6]. In addition, daily small doses of cisplatin given for 3 weeks in association with chest irradiation resulted in tolerable toxicity [7]. Taking into consideration all those data, the European Lung Cancer Working Party (ELCWP) conducted in limited SCLC, a phase III randomised study comparing induction concurrent radiochemotherapy with etoposide and standard cisplatin to etoposide and daily cisplatin.
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patients and methods |
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selection criteria
Patients with pathologically proven SCLC were eligible for the study if they fulfilled the following criteria: existence of an LD (i.e. a disease without distant metastases and that can be included in a single irradiation field incorporating primary tumour, mediastinum and ipsilateral supraclavicular lymph nodes), ability to tolerate a radiation course, absence of contralateral supraclavicular nodes and malignant pleural effusion, no prior treatment with chemotherapy, radiotherapy or surgery, Karnofsky performance status (PS)
60, age 
75 years and the other criteria commonly used in prior ELCWP trials [8]. Informed consent had to be provided. The protocol, fully available on the public website www.elcwp.org, had to be approved by the ethical committee of each participating centre. The trial is an academic study according to the definition of the Belgian law on the basis of the European directive (2001/20/CE).
treatment
Eligible patients were randomised between standard induction chemoradiotherapy (arm A) with cisplatin (90 mg/m2 day 1) plus etoposide (100 mg/m2 days 1–3) and daily radiosensitised induction chemoradiotherapy (arm B) with cisplatin (6 mg/m2 days 1–5, days 8–12, days 15–19; 90 mg/m2 day 1) plus etoposide (100 mg/m2 days 1–3). Chemotherapy and chest irradiation (39.90 Gy in 15 fractions >3 weeks) both started on day 1.
Daily cisplatin was given i.v. >15 min in 100 ml NaCl 0.9% 1 h before chest irradiation. Patients had to take daily 2 l of fluid. Cisplatin and etoposide were administered as previously reported [9]. The target volume of radiotherapy included the primary tumour and the entire regional lymphatic drainage which consisted of the ipsilateral hilum, the mediastinum and both supraclavicular fossae. After 11 fractions, only the areas with known disease were treated to the full dose which was 39.90 Gy with daily fractions of 2.66 Gy, five times a week. The treatment could be divided in two parts: a large field for 11 fractions and a boost for the last four fractions. The first part, carried out with anterior and posterior large fields, covered the primary lung tumour with 1–1.5 cm margins of normal lung tissue, the ipsilateral hilum, the mediastinum and both supraclavicular fossae. For the second part of the treatment, only the area where tumour was considered to be present was treated, using oblique fields to avoid the spinal cord. Megavoltage equipment was recommended with energies of at least 4 MV. Computed tomography (CT) scan-based treatment planning was mandatory. If the treatment needed to be interrupted for <1 week for toxicity or technical problems, the treatment had to be completed to the prescribed doses. If the interruption exceeded 1 week, radiotherapy had to be disregarded.
A second course of chemotherapy (standard schedule) was given on day 29 and then 3 weekly if haematological function has recovered and for a total of six courses. The rules for drug dose adaptation were similar to previous ones. If serum creatinine recovered after a peak >2.0 mg/dl, cisplatin dosage was reduced to 50%; otherwise, the drug was discontinued. If serum creatinine increased during daily cisplatin, patient received 500 ml normal saline. If creatinine level did not decrease, patient received 3–4 l i.v. rehydration and cisplatin was withhold until creatinine recovery. Cisplatin was stopped if neutrophils felt <500/mm3 and given again when neutrophils increased >500/mm3.
Evaluation of response was carried out after three and six courses of chemotherapy. In case of no response, patients went off trial. At relapse, if the delay since the last course of chemotherapy was >6 months, chemotherapy with cisplatin and etoposide was given again. Otherwise, patients went off trial.
workups
The initial workup comprised the standard tests previously reported [10] including chest CT scan, fibreoptic bronchoscopy with biopsy, upper abdomen CT scan or echography, pulmonary function tests and brain CT scan.
Complete blood cell counts and serum creatinine were carried out twice weekly during the first course and then weekly. Blood chemistry, chest X-rays and clinical examination were repeated before each course. Restaging on the basis of all tests carried out at the initial workup was repeated after the first three courses and at the end of the treatment.
After the completion of treatment, patients were followed every 2 months for the first 6 months and then every 3 months with clinical examination, chest X-rays and biochemical tests. Chest CT scan and bronchoscopy were repeated every 6 months for 2 years and then every year.
criteria of evaluation
Patients were evaluated for response after the completion of three courses of chemotherapy. Responses were assessed by at least three independent observers during regular meetings of the group.
Criteria for complete remission, partial response, progression and no change were previously reported [8]. Early death due to disease progression before evaluation and toxic death due to chemotherapy, or early chemotherapy discontinuation because of toxicity, were considered as treatment failures and the patients were incorporated in the evaluable patient population.
Progression-free survival (PFS) and survival times were calculated from the day of registration until the first event, progression for the first item and death for the second item. World Health Organization criteria were used to assess toxicity.
primary end point and sample size determination
The primary end point was to determine if locoregional irradiation concurrently with induction chemotherapy with cisplatin and etoposide prolonged survival when cisplatin was given daily as a radiosensitiser compared with a standard schedule. Secondary end points were the assessment of response, local control and toxicity.
The sample size evaluation was on the basis of the primary end point. On the basis of the experience of our group about a combination of chemotherapy with cisplatin and etoposide and chest irradiation for limited SCLC patients, we expected in the standard arm a 2-year survival rate of 10%. In order to have with the experimental treatment (daily cisplatin) an increase of this rate to 20%, 198 events were needed and we estimated that this number of events could be reached with the randomization of 116 patients [11] in each arm of the study (alpha = 5%; beta = 20%; one-sided log-rank test).
registration and randomisation procedure
Registration and randomisation were centrally carried out by calling the ELCWP central office. The ELCWP central office for the study coordination and analysis (including the study coordinator, the biostatistician and the data manager) was located at the Jules Bordet Institute (ULB), in Brussels.
Randomisation was carried out using the minimisation technique and patients were stratified according to the centre, Karnofsky PS (<80 versus 80) and stage (I–IIIA versus IIIB).
statistical methodology
Survival curves were estimated by the method of Kaplan and Meier. The log-rank test was used to compare survival curves. P values for testing differences between proportions were calculated with chi-square tests or with Fisher's exact tests. A multivariate analysis for adjustment of the treatment effect taking into account prognostic factors was carried out by fitting the data with a Cox model for duration of survival and a logistic regression model for objective response. Statistical results were considered as significant when the P value was <0.05. All reported P values are two-sided.
Chemotherapy intensity was estimated by calculating absolute dose intensity (ADI). The ADI was defined as the ratio of the received dose per square metre of body surface to the actual duration of treatment: it was expressed in mg/m2/3 weeks, as previously published [12]. Comparisons of the distributions of the dose intensity variables between regimens were done by using Mann–Whitney tests.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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A total of 214 patients were registered in the trial from March 1993 to March 2006. Ten (4.7%) were ineligible to the study (three in arm A and seven in arm B) for the following reasons: extensive non-metastatic (three) or metastatic (four) disease, existence of another cancer (one), NSCLC histology (one) and no informed consent (one). Characteristics of the 204 eligible patients (104 in arm A and 100 in arm B) are shown in Table 1. Both arms were well balanced. Median follow-up duration for the alive patients at the time of analysis was 54 months (range: 4–147); 83% were randomised before 2002. There were 79 deaths in each arm.
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response assessment
Seven patients (3.4%) were not assessable for response for the following reasons: major protocol violation (four), treatment refusal for reason unrelated to disease or treatment (one) and early death due to unrelated disease (two). They were included in the intent to treat analysis reported here (Table 2). Objective response rates were 87 of 104 (84%) in the control arm A and 80 of 100 (80%) in the experimental arm B (P = 0.59). The difference between both arms was 4% (95% CI = –8% to 15%). There was no difference in response rate between arms in the subgroup analyses carried out according to the main characteristics (age, sex, PS and stage). A univariate prognostic factor analysis for response revealed as significant Karnofsky PS and platelets. In multivariate analysis, platelets were the only covariate kept in the model (odds ratio = 0.31 for abnormal platelets count; 95% CI = 0.11–0.87; P = 0.03).
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survival
Median survival times were 15.5 months (95% CI = 12.0–18.9) in arm A and 17.0 months (95% CI = 13.9–20.0) in arm B. At 2 and 5 years, rates, respectively, were 35% (25%–45%) and 18% (10%–26%) in arm A and 38% (28%–48%) and 21% (13%–29%) in arm B (log-rank test: P = 0.50). The hazard ratio (HR) for comparing the two survival curves (Figure 1) is 0.89 (95% CI = 0.65—1.22; P = 0.48; control arm used as reference). There was no difference in survival between arms in the subgroups analyses carried out according to the main characteristics (age, sex, PS and stage).
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Univariate prognostic factors analysis revealed as significant variables (Table 3) age, PS, T status, neutrophils and haemoglobin. In the multivariate model (Table 3), taking into account 186 patients (141 events), two factors were independently predicting survival: T status and Karnofsky PS. When treatment comparison was adjusted for these two factors, we got an HR of 0.99 (95% CI = 0.71–1.38; P = 0.99).
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PFS and local control
Progression was documented in 118 patients (60 in arm A and 58 in arm B). Table 4 shows the first documented mode of progression: local, cerebral, local + cerebral and distant with or without brain relapse. Excluding the two patients with unknown site of progression, there is a trend for heterogeneity among the two treatment arms (P = 0.09). In the 33 complete responders, initial brain relapse was documented in seven patients, including two with concomitant local failure. Cumulative rates of local relapse (using first relapse sites only and censoring patients having died without documented relapse) at 1, 2 and 3 years were 16%, 30% and 30% in the standard arm and 19%, 29% and 32% in the daily arm, respectively. For brain relapse, they were, respectively, 26%, 37% and 43% and 26%, 26% and 36%.
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PFS median times were, respectively, for arms A and B, 10.3 (95% CI = 8.5–12.2) and 10.1 (95% CI = 9.0–11.2) months (log-rank test: P = 0.51) with respective 2-year rates of 23% (95% CI = 15% to 31%) and 26% (95% CI = 18% to 34%) and 5-year rates of 16% (95% CI = 8% to 24%) and 19% (95% CI = 11% to 27%). The HR between the two distributions was estimated to be 0.90 (95% CI = 0.67–1.22; P = 0.51; reference = arm A).
treatment received and dose intensity
The rates of patients having received the planned six courses of chemotherapy were not statistically different between both arms: 78% in arm A and 70% in arm B (P = 0.21). For the first course, the rates of patients with a dose of cisplatin close to the planned one (>85 mg/m2) were statistically different between arms A (92%) and B (65%) (P < 0.001). There was no difference for the dose of etoposide (P = 0.16). Concerning radiotherapy, the rates of adequate doses (between 38 and 42 Gy) were 90% in arm A and 96% in arm B (P = 0.17). Irradiation was stopped early in six and four patients, respectively. For further cycles of chemotherapy, there was no difference between both arms in terms of dose reduction (49% and 50% in arms A and B) or treatment postponement (33% and 32%, respectively).
When the full cycles of treatment were considered, there was no detectable difference in delivered dose intensity between treatment arms, neither for cisplatin (P = 0.67) nor for etoposide (P = 0.70).
toxicity
Toxicity is summarised in Table 5. The only statistically significant difference between both arms was more severe thrombopenia with daily cisplatin treatment. There was also a trend for more oesophagitis with that regimen. During the first cycle, nephrotoxicity was observed in 9% of the patients in arm A and in 2% in arm B.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The present randomised trial failed to show that daily radiosensitisation by small doses of cisplatin can improve survival in comparison to the standard administration of the full dose of cisplatin on the first day of induction chemoradiotherapy. Nevertheless, both arms were associated with quite good long-term survival: 18% and 21% 5-year survival rates, respectively, for the standard and experimental arms. Those results were much better than expected: the objective was to improve the 2-year survival rate of 10% obtained in our prior trials to 20% and in fact we obtained respective 35% and 38% 2-year rates.
These good results can be explained for several reasons. First, a better patient selection has probably been carried out because chest radiotherapy was started on day 1 of treatment, which requires that the irradiation field is calculated from the initial tumour presentation and not after tumour volume reduction by chemotherapy as it can be the case when radiotherapy is delivered later. In our previous trials, radiotherapy was often used as a consolidation treatment [12–14]. Secondly, we used as chemotherapy regimen cisplatin and etoposide which are associated with better survival than the regimens without those drugs as shown by a meta-analysis of the literature [15] and by a subgroup analysis of a randomised trial with concurrent chemoradiotherapy [16]. In addition, cisplatin is a strong radiosensitiser which is one of the reasons why guidelines recommend this particular drug in the management of limited SCLC [4, 5]. Thirdly, early concurrent chemoradiotherapy seems to be associated with better long-term results than late irradiation as indicated by various meta-analyses [17–21]. All are on the basis of published papers, taking into account seven or eight randomised trials for a total of >1500 patients and using different definitions for early and late irradiation. All but one [21] are in favour of early irradiation, although in the De Ruysscher et al. meta-analysis, statistically significant 5-year survival improvement is only obtained in favour of radiotherapy when it was finished within 30 days after the start of chemotherapy and if chemotherapy was cisplatin-based [20]. In the four analysed randomised trials [19], 5-year survival ranged between 20% and 30%, a rate similar to those we obtained in our trial. In a subgroup meta-analysis taking into account the completion or not of the planned chemotherapy, Spiro et al. [21] demonstrated that survival was improved by early irradiation only if full chemotherapy cycles were provided, which was the case in about half of the patients in our trial. Two studies [22, 23], but all [24, 25], indicate that hyperfractionated radiotherapy improves the median survival time. The 5-year survival rates obtained with this technique appear similar to the results reported in the recent trials by Spiro et al. [21] and by our group, carried out with standard irradiation. That irradiation modality needs thus further controlled data before being considered as the new standard.
Although there is no difference in overall delivered dose intensity, the dose of cisplatin administered during the first cycle was reduced in the daily arm. This may perhaps explain why in terms of local control rate, there was a statistical trend in favour of standard dosage with 2% only local relapse versus 10% with the daily regimen (Table 4). Daily cisplatin radiosensitisation was associated with more oesophagitis and thrombopenia but less nephrotoxicity that was nevertheless never severe. Lung toxicity was similar in both arms.
Our trial was designed before the meta-analysis was carried out on prophylactic cerebral irradiation (PCI) [26] and, mainly for that reason, PCI was not part of the treatment plan. Today, the ELCWP guidelines [5] recommend to propose prophylactic cranial irradiation in patients with LD SCLC, in cases with complete response to treatment if the response assessment and the assessment workup are similar to those used in the relevant trials and if a similar definition of complete response is used. An intriguing observation in the present report was a low rate of initial relapse in the brain (with or without concomitant other sites) despite the lack of PCI: 60 of 204 (29%) in the overall population and 8 of 33 (24%) in the complete responders. All our patients had brain CT scan before chemoradiotherapy. In the meta-analyses on the role of PCI [26, 27], the rates of initial brain relapse in complete responders were 27% in case of PCI and 48% without PCI. In the four trials where the patients had a brain CT scan in the initial workup, the rates were, respectively, 28% and 49%. Although the trial was not designed for that purpose, our data indicate that the exact place of PCI in the management merits further investigations, taking into account the initial assessment of brain metastatic involvement by adequate imaging.
Some independent prognostic factors were identified: platelets for response and PS and T status for survival. In a prior analysis of our trials database [28], in addition to the key prognostic role of disease extent, we had found as additional independent prognostic factors for response to chemotherapy gender, neutrophils count and haemoglobin level and for OS, Karnofsky PS, gender and neutrophils count. In the present analysis, restricted to LD eligible for induction chemoradiotherapy, in addition to PS, we found the importance of the T status, reflecting probably the role of the tumour volume when the local treatment is on the basis of irradiation.
Due to a progressive low accrual rate since 1998, we decided to close the trial in 2006. For that reason, we did not obtain the requested number of randomised patients. Twenty-eight patients were missing to reach the number required in the statistical considerations. This lack of accrual is not explained by another competing protocol but by the progressive rarefaction of patients with SCLC and LD, possibly related to better workup detecting more metastatic disease and to a diminution of the prevalence of the disease as indicated by epidemiological data [29]. This lower prevalence explains probably why there are very few randomised trials published during the last years about SCLC LD: only three since 2000 [21, 23, 24].
In conclusion, induction chemoradiotherapy with the cisplatin–etoposide regimen and chest irradiation administered during the first cycle of chemotherapy resulted in good long-term survival, comparable to the best reported results. Daily cisplatin administration failed to improve the results, perhaps due to a lower local control rate. In addition to PS, T status appeared to be an independent prognostic factor for survival, reflecting probably the role of the tumour volume when the local treatment is on the basis of irradiation. On the basis of those results, initial concurrent chemoradiation has become the ELCWP standard for the management of LD SCLC [5].
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The following institutions participated to the trial: Institut Jules Bordet, Brussels, Belgium (J. P. Sculier, T. Berghmans, A. P. Meert, P. Van Houtte, M. Roelandts, M. Paesmans, N. Leclercq), CHRU Calmette, Lille, France (J. J. Lafitte, A. Scherpereel), Centre Oscar Lambret, France (B. Prevost), Hellenic Cancer Institut, St Savas Hospital, Athens, Greece (A. P. Efremidis, G. Koumakis), CH de Douai, Douai, France (M. C. Florin, E. Maetz, S. Desurmont), CHU de Charleroi, Charleroi, Belgium (J. Lecomte, J. Thiriaux), Hôpital de Hayange, Hayange, France (M. C. Berchier, P. Botrus), CHR St-Joseph-Warquiginies, Boussu, Belgium (M. Richez), Klinika radioterapie a onkologie, Kosice, Slovaquia (J. Baumöhl), RHMS, Clinique Louis Caty, Baudour, Belgium (V. Richard, D. Diana, B. Vanderschueren), CH de Roubaix, Hôpital Victor Provo, Roubaix, France (F. Kroll, F. Steenhouwer, F. Salez, A. Strecker), Groupe médical St Rémy, Reims, France (G. Bureau, J. M. Faupin), Hôpital Ambroise Paré, Mons, Belgium (P. Wackenier, S. Holbrechts), Clinique de La Louvière, Lille, France (F. Fortin), CHU André Vésale, Montigny-le-Tilleul, Belgium (D. Brohée), CH Tivoli, La Louvière, Belgium (J. Michel), RHMS, Hôpital de la Madeleine, Ath (P. Ravez), Cabinet Médical Dampierre, Anzin, France (J. P. Roux, B. Stach), CHG de Tourcoing, Tourcoing, France (X. Ficheroulle), Hôpital Erasme, Brussels, Belgium (S. Luce, F. Branle), CHI Le Raincy, Montfermeil, France (T. Collon), CHU Saint-Pierre, Brussels, Belgium (V. Ninane, R. Sergysels, T. Bosschaerts), CH Dr. Schaffner "Ameuille", Lens, France (J. Amourette, C. Bergoin), Hôpital Saint-Joseph, Gilly, Belgium (B. Colinet), Hôpital Brugmann, Brussels, Belgium (A. Drowart, T. Prigogine), CH d'Arras, Arras, France (J. P. Bervar) and CH Etterbeek-Ixelles, Brussels, Belgium (G. Plat).
Received for publication March 13, 2008. Revision received April 21, 2008. Accepted for publication April 22, 2008.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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