All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: a matched-control analysis by the Groupe d'Etude des Lymphomes de l'Adulte (GELA)

N. Mounier*, C. Gisselbrecht, J. Brière, C. Haioun, P. Feugier, F. Offner, C. Recher, A. Stamatoullas, F. Morschhauser, M. Macro, C. Thieblemont, A. Sonet, B. Fabiani and F. Reyes On behalf of the Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Hôpital Saint Louis, AP-HP, Paris, France

* Correspondence to: Dr N. Mounier, Groupe d'Etude des Lymphomes de l'Adulte (GELA), INSERM ERM0220, Hôpital Saint Louis, AP-HP, 1 avenue Claude Vellefaux, 75010 Paris, France. Tel: +33-1-42-49-92-96; Fax: +33-1-42-49-96-41; Email: nicolas.mounier{at}sls.ap-hop-paris.fr


    Abstract
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 Abstract
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 Patients and methods
 Results
 Discussion
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Background: Data are still conflicting on the indication of front-line autologous stem-cell transplantation (ASCT) as consolidation for aggressive lymphoma. To assess the therapeutic effect of ASCT among different aggressive lymphoma subtypes, we conducted a matched-control analysis by pooling the data from two Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials.

Patients and methods: Between October 1987 and September 1998, 330 patients received ASCT after achieving complete remission with the ACBVP induction regimen. The histological slides showed: B aggressive non-Hodgkin's lymphoma (B-NHL) in 249 patients (75%), T-NHL in 52 patients (15%) (including 23 T anaplastic) and non-classified NHL in 29 patients. The age-adjusted International Prognostic Index (aaIPI) was 2 or 3 in 66%. Patients were matched with controls from the same GELA database but treated with chemotherapy only.

Results: ASCT did not benefit non-anaplastic T-NHL patients [5-year overall survival (OS) 44% (chemotherapy) versus 49% (ASCT), P=0.87; disease-free survival (DFS) 38% versus 45%, P=0.89] in comparison with B-NHL [5-year OS 77% (chemotherapy) versus 79% (ASCT), P=0.64; DFS 67% versus 72%, P=0.13]. However, for B-NHL patients with aaIPI score 2 or 3, the benefit of ASCT was significant.

Conclusions: This cohort study confirms the high efficacy of front-line ASCT in responding aggressive B-NHL patients with adverse prognostic factors.

Key words: aggressive lymphoma, autotransplantation, B phenotype, prognostic factors, survival analysis, T phenotype


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Aggressive non-Hodgkin's lymphomas (NHLs) are highly chemotherapy-sensitive malignancies. Treatment with conventional combination chemotherapy produces complete remission (CR) rates of 50% to 70% and disease-free survival (DFS) rates of ~50% [1Go–3Go]. More intensive third-generation regimens did not prove to be better than the standard CHOP regimen of cyclophosphamide, doxorubicin, vincristine and prednisone [4Go]. However, most of those regimens were designed before the use of hematopoietic growth factor or high-dose chemotherapy (HDT) with autologous stem-cell transplantation (ASCT), and could not explore high-dose intensive treatment. Since the publication of the PARMA trial on patients with chemosensitive relapses, several studies have examined HDT with ASCT as first-line treatment for aggressive NHL and its role has been reviewed [5Go, 6Go]. ASCT is the treatment of choice for patients with relapsed aggressive NHL still responding to salvage chemotherapy, but whether ASCT has a role as front-line therapy is still a matter of debate. Until now, several randomized phase III studies have reported controversial results, several of them claiming that such an approach is beneficial at least in terms of freedom from progression in patients who achieved CR after the induction [7Go–11Go]. However, there seems to be no indication to add ASCT to the initial combination chemotherapy treatment for all patients with aggressive lymphoma [12Go–15Go]. Different patient selection and different dose intensity chemotherapy might explain these discrepancies, but there is some evidence that ASCT might be useful for selected subsets of patients.

The probability of being cured by the initial treatment depends on the presence or absence of adverse prognostic factors such as age, Eastern Cooperative Oncology Group (ECOG) performance status, tumor stage, lactate dehydrogenase (LDH) level and the number of sites of extranodal disease. These factors are incorporated in the International Prognostic Index (IPI) [16Go]. While waiting for the better characterization of the respective impact of gene-expression signatures and clinical characteristics on prognosis [17Go], major interest still focuses on the IPI factors for identifying patients at increased risks for standard treatment failure, in whom ASCT would be appropriate.

When the IPI was retrospectively applied to the Groupe d'Etude des Lymphomes de l'Adulte (GELA) LNH-87 and the Italian trials, a failure-free and overall survival (OS) benefit from ASCT was demonstrated for the high/intermediate-risk and high-risk patients [7Go, 8Go, 10Go]. This was prospectively confirmed by the recent GOELAMS study [11Go]. In addition, recent studies focused on the impact of the immunophenotype on outcome after ASCT. Rodriguez and others [18Go–21Go] have found a comparable outcome for peripheral T-cell lymphomas to that for B-cell lymphoma, despite the fact that patients with peripheral T-cell lymphoma are known to have a worse prognosis compared with B-cell NHL.

Therefore, to establish whether or not ASCT has the same impact between different lymphoma subtypes, we conducted a matched-control analysis using a case population from the two GELA trials that incorporated a full course of CHOP-like induction (ACVBP) followed by front-line consolidative ASCT and a control population receiving the same induction regimen but a sequential consolidation.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
The study population was entered in two prospective multicentric trials conducted by the GELA, between October 1987 and September 1998: trials LNH-87 (n=916) and LNH-93 (n=718). Approval for these trials was obtained from our institutional review board. Informed consent was provided in accordance with the Declaration of Helsinki.

Treatment
The LNH-87 trial
Details regarding the design and data management of the trial have already been published [7Go, 8Go]. Briefly, 916 patients were eligible from October 1987 to February 1993. The aim of the trial was to compare consolidation with ASCT and with sequential chemotherapy. Patients were adults <55 years old with newly diagnosed aggressive NHL and at least one of the following adverse factors: performance status of 2–4, two or more extranodal sites, a largest tumor of at least 10 cm in diameter, and bone marrow or central nervous system involvement. Patients who had lymphoblastic or Burkitt's lymphoma with meningeal or bone marrow involvement or had primary cerebral NHL were excluded. Patients were randomized to receive four courses of two of the following CHOP-like regimens every 2 weeks: doxorubicin 75 mg/m2, cyclophosphamide 1200 mg/m2 given intravenously on day 1, vindesine 2 mg/m2 given intravenously on days 1 and 5, bleomycin 10 mg given intravenously on days 1 and 5, prednisone 60 mg/m2 given orally on days 1–5 and intrathecal methotrexate 15 mg on day 2 (ACVB arm); or the same regimen with the substitution (randomly assigned at diagnosis) of mitoxantrone 12 mg/m2 for doxorubicin, given intravenously on day 1 (NCVB arm). Patients who achieved CR were subsequently randomized to be given sequential chemotherapeutic consolidation at 2-week intervals, with two cycles of methotrexate 3 g/m2 plus leucovorin rescue, four cycles of etoposide 300 mg/m2 and ifosfamide 1500 mg/m2, and two cycles of cytarabine 100 mg/m2 subcutaneously for 4 days, or a consolidative HDT with the CBV regimen consisting of carmustine 300 mg/m2, cyclophosphamide 6000 mg/m2 and etoposide 1000 mg/m2, followed by ASCT with bone marrow stem cells collected at the time of remission.

The LNH-93 trial
Details regarding the design and data management of the trial have already been published [12Go, 22Go]. Briefly, 718 patients were eligible from March 1993 to September 1998. The aim of the first part of the trial was to compare the results of shortened induction plus ASCT to those of full course induction plus sequential consolidation; the aim of the second part was to confirm the efficacy of full course induction plus ASCT reported in the LNH-87 trial. Patients were adults aged between 15 and 60 years with newly diagnosed aggressive NHL, and at least two of the following adverse prognostic factors, as defined by the IPI: an elevated LDH level, performance status >1 and Ann Arbor stage III–IV. Patients who had lymphoblastic or Burkitt's lymphoma with meningeal or bone marrow involvement, or primary cerebral NHL, were excluded.

The interim analysis, conducted after the first part of the trial, showed negative results for the shortened induction arm with ASCT compared with the results for ACVB arm with sequential consolidation. Consequently, the Data and Safety Monitoring Committee recommended that the randomization be stopped on 15 September 1995 (n=370) [12Go].

In the second part of the trial, patients were to be treated as in the LNH-87 trial with full course induction, i.e. four cycles of ACVB followed, in patients achieving CR, by consolidative HDT with the CBV or BEAM regimen (carmustine 300 mg/m2, etoposide 800 mg/m2, aracytine 800 mg/m2 and melphalan 140 mg/m2) and then ASCT with peripheral stem cells collected after three or four cycles of ACVB (n=348) [22Go]. Only this group of 348 patients was included in the present analysis.

Staging and follow-up
Morphology and immunophenotype were reviewed by two independent pathologists from the GELA for 80% of the study population, and lymphomas were reclassified according to the WHO classification [23Go]. Consensus for discordant cases was reached using a two-head microscope.

The stage of the disease was evaluated by physical examination, computed tomography (CT) scan of the chest and abdomen, cerebrospinal fluid examination, bone marrow biopsy, and other investigations depending on the clinical symptoms. Patients were staged according to the Ann Arbor classification. ECOG performance status was assessed and LDH was expressed as the maximum/normal value ratio.

Tumor responses were assessed after the four cycles of ACVBP or NCVBP were classified as CR, unconfirmed CR (CRu), partial response, stable disease or progressive disease according to the International Workshop criteria [24Go]. These classifications were defined as follows. CR was defined as the disappearance of all lesions and of radiological or biological abnormalities observed at diagnosis and the absence of new lesions. CRu was CR, but with the persistence of some radiological abnormalities, which must have regressed in size by ≥75%. Partial response was the regression of all measurable lesions by >50%, the disappearance of non-measurable lesions and the absence of new lesions. Stable disease was the regression of measurable lesions by ≤50%, or no change for the non-measurable lesions, and no progression of >25% of existing lesions or appearance of new lesions. Progressive disease was the appearance of new lesions, growth of the initial lesions by >25% or growth of measurable lesions that had regressed during treatment by >50% of their smallest dimensions.

Follow-up procedures included physical examination every 3 months for the first 2 years, then every 6 months for 3 years, and then annually thereafter. Thoracic and abdominal CT scans were performed every 6 months during the first 2 years, and then at the discretion of the treating physician.

Patient selection and matching
To obtain a homogeneous group, we only included in the present analysis patients aged <60 years, who achieved CR/CRu after induction with the ACVB or NCVB regimen and were consolidated with HDT and ASCT. In the LNH-87 trial (n=916), 541 patients were eligible and achieved CR/CRu after ACVB or NCVB. Of these, 273 were randomized in the sequential chemotherapy arm and 268 in the ASCT arm. However, only 198 were actually given ASCT. In the non-randomized second part of the LNH-93 trial (n=348), 236 were eligible and achieved CR/CRu after ACVB. However, only 132 were actually given ASCT. In all, 330 patients were included in the present analysis: 198 from LNH-87 trial and 132 from the LNH-93 trial.

To assess the therapeutic effect of ASCT among different aggressive lymphoma subtypes, a case-controlled study was performed by matching this ASCT population (case group) with sequential chemotherapy patients (control group) selected from the LNH-87 and LNH-93 trials. Case and control CR/CRu patients were fully matched (1:1) on treatment protocol, histology, age-adjusted IPI (aaIPI) score, marrow involvement and number of extranodal sites.

Statistical methods
Patient characteristics were compared by the {chi}2-test and Fisher's exact test. DFS was measured from the date of graft to that of disease progression, relapse or death from any cause or to the stopping date (1 January 2002). OS was measured from the date of graft to either death from any cause or the stopping date. When the stopping date was not reached, the data were censored at the date of the last follow-up evaluation. Survival functions were estimated by the Kaplan–Meier method and compared by log-rank test [25Go]. We controlled for the effects of prognostic factors on outcome due to sampling fluctuation using multivariate analysis with a Cox model [26Go]. Differences between the results of comparative tests were considered significant if the two-sided P value was <0.05. All statistical analyses were performed using SAS 8.2 (SAS Institute, Cary, NC, USA) and Splus 2000 (MathSoft, Cambridge, MA, USA) software.


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ASCT patients cases
The study population of 330 patients comprised 197 males and 133 females. The median age was 39 years (range 16–60).

Pathological and phenotypical characteristics
The cohort included 249 (75%) cases of B-NHL. Of these, 1.5% exhibited follicular large cells, 55% diffuse B large cells, 15% Burkitt's or Burkitt-like and 2.5% immunoblastic. There were 52 (16%) cases of T-NHL. Of these, 4% exhibited lymphoblastic subtype, 5% peripheral T cells and 7% anaplastic (two primary cutaneous). In 29 (9%) cases, large-cell NHL could not be otherwise classified, because of the lack of an immunohistochemical study. Pathological and phenotypical characteristics were well balanced among the LNH-87 and LNH-93 trials.

Clinical and treatment characteristics
The main hematological characteristics are shown in Table 1. Two-thirds of the study population comprised high-risk patients with an aaIPI >1. However, in the LNH-93 trial only patients with IPI >1 could be included. Of the total study population of 330, 160 (48%) had mediastinal localizations, only 50 (15%) had gastrointestinal involvement and 12 (4%) had meningeal or cranial nerves involvement. The anthracycline was doxorubicin for 246 patients and mitoxantrone for 84. Two hundred and two (61%) patients achieved CR and 128 (39%) CRu. The CBV conditioning regimen was given to 243 (74%) patients and the BEAM regimen to 79 (24%). The source of stem cells was bone marrow for 201 (61%) patients and peripheral blood stem cells for 129 (39%).


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Table 1. Patients' characteristics

 
Survival analysis
The median follow-up was 6.5 years (range 0.5–12.1). The 2-year OS was estimated at 82 ± 5% in the LNH-87 trial and 81 ± 7% in LNH-93. As these estimates were identical, we pooled the data for the two cohorts, which led us to estimate 2-year OS at 82 ± 4% and 5-year OS at 75 ± 5%. The 2-year DFS was 73 ± 6% for the LNH-87 trial and 74 ± 8% for LNH-93, leading to pooled estimations of 74 ± 5% for 2-year DFS and 67 ± 5% for 5-year DFS. The aaIPI score [0–1 (n=108) versus 2–3 (n=211)] had no prognostic value (5-year OS 76% versus 74%, P=0.48; DFS 65% versus 66%, P=0.67). Survival estimates according to the different lymphoma subtypes are given in Table 2.


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Table 2. Univariate analysis: survival after ASCT according to pathological characteristics

 
Pair-matched analysis
To assess the prognostic value of different lymphoma subtypes, the histology was classified according to non-anaplastic T-NHL versus others, because, as shown in Table 2, B-NHL and anaplastic T-NHL exhibited the same survival, in contrast to the low survival for non-anaplastic T-NHL (Figure 1). Then, B-NHL and non-anaplastic T-NHL patients treated with ASCT were fully matched (1:1) with control CR/CRu patients treated with consolidative chemotherapy in the same LNH-87 and LNH-93 trials.



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Figure 1. (A) Overall survival (OS) and (B) disease-free survival (DFS) according to the main pathological subtypes: B aggressive non-Hodgkin's lymphoma (B-NHL) patients (n=249), anaplastic T-NHL (n=23) and non-anaplastic T-NHL (n=29).

 
First, we performed the analysis for B-NHL. Among the 249 B-NHL patients treated with ASCT, only 221 had complete data for matching. These 221 B-NHL patients treated with ASCT were fully matched (1:1) with 221 control patients treated with consolidative chemotherapy in the same trials. As expected from the matching method, the case and control groups of patients did not show any statistical significant differences in the main clinical characteristics (Table 3). In each group, 126 patients came from the LNH-87 and 95 from the LNH-93. The median age was 39 years. As shown in Figures 2A and 3A, the present study confirmed the good prognosis of B-NHL [5-year OS 77% (chemotherapy) versus 79% (ASCT), P=0.64; DFS 67% versus 72%, P=0.13]. However, as shown in Figures 2B and 3B, the benefit of ASCT was significant only for B-NHL patients with two or three aaIPI factors [5-year OS 72% (chemotherapy) versus 78% (ASCT), P=0.04; DFS 63% versus 75%, P=0.001].


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Table 3. Pair-matched analysis: characteristics of the case and control populations

 


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Figure 2. Overall survival (OS) according to the matching groups for (A) all B aggressive non-Hodgkin's lymphoma (B-NHL) patients (n=221), (B) age-adjusted International Prognostic Index (aaIPI) 2–3 B-NHL patients (n=152) and (C) non-anaplastic T-NHL (n=28). ACST, autologous stem-cell transplantation; Chemo, chemotherapy.

 


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Figure 3. Disease-free survival (DFS) according to the matching groups for (A) all B aggressive non-Hodgkin's lymphoma (B-NHL) patients (n=221), (B) age-adjusted International Prognostic Index (aaIPI) 2–3 B-NHL patients (n=152) and (C) non-anaplastic T-NHL (n=28). ACST, autologous stem-cell transplantation; Chemo, chemotherapy.

 
Next, we performed the same analysis for non-anaplastic T-NHL. Among the 29 non-anaplastic T-NHL patients treated with ASCT, only 28 had complete data for matching. Again, case and control groups of patients did not show any statistical significant differences in the main clinical characteristics (Table 3). In each group, 17 patients came from the LNH-87 and 11 from the LNH-93. The median age was 36 years. In univariate analysis, Figures 2C and 3C confirm the poor prognosis of non-anaplastic T-NHL [5-year OS 44% (chemotherapy) versus 49% (ASCT), P=0.87; DFS 38% versus 45%, P=0.89]. Moreover, in a Cox model and after controlling for the aaIPI score, ASCT versus chemotherapy had no significant effects on OS (relative risk 0.93; P=0.83) or DFS (relative risk 0.86; P=0.61).


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 Abstract
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 Patients and methods
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The report of the International Consensus Conference on ASCT in aggressive NHL held in 1999 stated that only a subset of this population would benefit from front-line ASCT [6Go]. In fact, while waiting for the achievement of molecular response profile studies, physicians mainly focus on the IPI score to make the decision as to whether or not to perform ASCT. Therefore, to help decision making, the central theme of the present study was to assess whether or not ASCT given as consolidation in CR patients has the same impact between different lymphoma subtypes.

In order to obtain a homogenous group and to avoid the influence of chemotherapy regimens, we retained only patients <60 years old and treated with a ACVBP-type regimen. Although this was a selected study population, the main interest of the present study was to focus only on patients who achieved CR or CRu, and who underwent HDT with ASCT. The number of the patients (n=330) and the diversity of the 30 study centers give a broadly representative population. OS and DFS were the only end points, because cause-specific survival could not be assessed in our database. As we used previously published data, due to the retrospective design of the present study, the median follow-up could not improve upon 6.5 years. Here, the matched-pair analysis performed with patients treated with chemotherapy only and achieving CR confirmed, on an enlarged population, the results already published in the LNH-87 trial. There is a significant benefit for patients with B-cell lymphoma and more than one adverse IPI factors submitted to a consolidation with ASCT. On the other hand, ASCT seems to have a lower impact for patients without adverse IPI factors and no impact for non-anaplastic T-NHL patients.

Controversies still exist as to the impact of ASCT in first-line treatment of aggressive lymphoma. Several aspects of the various studies published could be responsible for the discrepancies reported. The most obvious one is the difference in inclusion criteria, where the IPI was generally not the basis of selection, although most of the patients belonged to the high/intermediate-risk or high-risk group. In positive studies on front-line ASCT, patients with those clinical features had an improvement of survival [7Go–10Go]. Recently, Milpied et al. [11Go] reported a randomized trial in 197 patients comparing CHOP with a more intensive regimen with HDT in patients with more than one adverse prognostic factors. They showed an advantage for the HDT arm in 5-year event-free survival (EFS) (55% versus 36%, P=0.037), but the advantage in survival was restricted to the 105 intermediate/high-risk patients (5-year OS 74% versus 43%, P=0.005). These results are similar to our LNH-87 trial when reporting only the subset of patients with two or more adverse prognostic factors [8Go]. In a report of the European Organization for Research and Treatment of Cancer, there was no difference between the two arms with or without ASCT, but only 60 patients with two aaIPI factors were randomized, with a considerable drop-out of 40% [27Go].

In conclusion, it should be pointed out that even if ACVBP is able to induce better EFS than CHOP in several randomized trials, the CR rate is only 65% in patients with adverse prognostic factors, and needs to be improved if one is to take advantage of this type of consolidation with HDT [28Go, 29Go]. For B-cell lymphoma, rituximab associated with chemotherapy is likely to improve the CR rate, and will be used in future trials with ASCT [30Go]. For non-anaplastic T-cell lymphoma, alternative strategies with other monoclonal antibodies or allogeneic transplantation should be tested. For lymphoblastic lymphoma patients, many would advocate treatment with therapy for acute lymphoblastic leukemia.


    Acknowledgements
 
The authors thank Olive Eccleston for editing the English and Sylvie Corre for secretarial assistance. They also thank the Editor of Annal of Oncology and referees for helpful comments and suggestions. This study was supported in part by research funding from the Ministère de la Sante (PHRC-AOM 95061) and from the Délégation à la Recherche Clinique de l'Assistance Publique-Hôpitaux de Paris (AP-HP) to the GELA.

The following clinicians actively participated in the LNH-87 and LNH-93 trials: N. Albin, C. Allard, M. Aoudjane, D. Assouline, M. Attal, B. Audhuy, M. Azagury, J. C. Barats, C. Beaumont, E. Baumelou, P. Biron, M. Blanc, D. Bordessoulle, R. Bouabdallah, C. Bouleuc, P. Bourquard, P. Bourquelot, F. Boué, O. Boulat, P. Brice, J. Brière, G. Brun, D. Caillot, O. Casasnovas, P. Carde, S. Castaigne, S. Chèze, B. Christian, P. Colin, C. Collet, T. Conroy, T. Cosnard, B. Corront, H. Curé, A. Delmer, V. Delwail, L. Detourmignies, A. Devidas, H. Dombret, J. F. Dor, C. Doyen, F. Dreyfus, S. Dront, G. Dupont, B. Dupriez, J. C. Eisenmann, M. Fabbro, C. Fermé, G. Fillet, M. Flesch, C. Fruchart, J. Gabarre, C. Haioun, R. Herbrecht, O. Hermine, A. Huyn, F. Huguet, M. Janvier, E. Jourdan, J. M. Karsenti, Y. Kerneis, F. Kohser, V. Leblond, P. Lederlin, S. Lefort, P. Lenain, G. Lepeu, S. Lepretre, X. Levaltier, A. Le Rol, G. Marit, C. Martin, F. Mayer, C. Nouvel, P. Morel, M. Moriceau, J. N. Munck, G. Nedellec, F. Offner, J. M. Pavlovitch, I. Plantier, P. Y. Péaud, A. M. Peny, J. Pico, C. Platini, J. P. Pollet, B. Quesnel, O. Reman, B. Richard, R. Riou, P. Rodon, B. Salles, G. Salles, C. Sarazin, D. Schlaifer, C. Sebban, M. Simon, P. Solal-Céligny, J. J. Sotto, A. Stamatoullas, C. Soussain, G. Tertian, A. Thyss, J. D. Tigaud, G. Tobelem, P. Travade, A. Van Hoof, A. Zaniboni and J. M. Zini.

The following members of GELA performed the histological review: T. Molina, J. Brière, J. Diebold, B. Fabiani, P. Gaulard, C. Guettier, T. Petrella and L. Xerri.

Received for publication May 19, 2004. Revision received July 10, 2004. Accepted for publication July 13, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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