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© 2003 American Society for Clinical Oncology
Summary Statement on Primary Central Nervous System Lymphomas From the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002
From the Department of Radiochemotherapy, San Raffaele H Scientific Institute, Milan, Italy; Departments of Neurology and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Neurology and Neurosurgery, Oregon Health & Science University, Portland, OR; College of Medicine, University of Nebraska Medical Center, Omaha, NE; Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA; Unité Cytokines et Cancers, Hôpital E. Herriot & Centre Léon Bérard, Lyon, France; Department of Pathology, University of Geneva, Geneva; Oncology Institute of Southern Switzerland, Division of Medical Oncology, Ospedale San Giovanni, Bellinzona, Switzerland; and Department of Cell and Animal Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. Address reprint requests to Andrés J.M. Ferreri, MD, Department of Radiochemotherapy, San Raffaele H Scientific Institute, Via Olgettina 60, 20132, Milan, Italy; email: andres.ferreri{at}hsr.it.
Under the sponsorship of the International Extranodal Lymphoma Study Group, a Multidisciplinary Workshop on primary CNS lymphoma (PCNSL) with over 50 participants from Europe, North America, Israel, and Australia was held as part of the Eighth International Conference on Malignant Lymphoma in Lugano, Switzerland (June 12 to 15, 2002). The main purposes of the Workshop were to exchange the latest scientific information, to analyze methodologic issues in the design of clinical trials, to reach a consensus on treatment recommendations and prognostic factors, to discuss clinical and molecular targets for future studies, and to establish an international collaborative group to conduct laboratory and clinical investigations in PCNSL. This article summarizes the contents of the Workshop, analyzes the current knowledge on the most relevant biologic and clinical issues in PCNSL, and focuses on fundamental challenges to be addressed in future studies.
PRIMARY CNS lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin’s lymphoma (NHL) that accounts for 4% of all primary brain tumors.1 Despite the large number of nonrandomized PCNSL trials, several fundamental therapeutic issues remain unresolved. Under the sponsorship of the International Extranodal Lymphoma Study Group (IELSG), a multidisciplinary symposium on PCNSL with over 50 participants was held as part of the Eighth International Conference on Malignant Lymphoma in Lugano, Switzerland (June 12 to 15, 2002). In addition to exchanging the latest scientific information on PCNSL, one important objective of the meeting was the establishment of an international collaborative group to conduct laboratory investigations and multidisciplinary studies. The first organizational meeting for this group was held in Philadelphia, Pennsylvania, on December 6, 2002. This article summarizes the contents of the Workshop, analyzes the current knowledge on the most relevant biologic and clinical issues in PCNSL, and focuses on the fundamental challenges to be addressed in future studies.
The large majority of PCNSLs in immunocompetent patients are Epstein-Barr virus–negative diffuse large B-cell lymphomas (DLBCL). Our current knowledge of DLBCL has been enhanced by data obtained from gene expression profiling.2 These experiments have demonstrated at least three groups of DLBCL with different prognoses; there is a germinal center (GC) type, an activated B-cell type and a third, ill-defined group. A multicenter, gene expression profiling study for PCNSL is currently underway in the United States. Most data indicate a GC origin for PCNSL. GC derivation can be demonstrated by sequence analysis of immunoglobulin genes or of other genes undergoing somatic hypermutations. The bcl-6 gene is strongly expressed in GC B cells.3 Mutations in its 5' noncoding region are specifically acquired by B-cells at the time of transition through the GC and are present in both GC and post-GC B cells but not in pre-GC B cells. bcl-6 gene mutations and bcl-6 protein expression have been reported in 50% and 100% of PCNSL, respectively.4 Additional evidence for a possible GC origin of PCNSL comes from the studies of the genes encoding the immunoglobulin (Ig) heavy and light chains.5,6 Somatic mutations among the clonally rearranged IgH genes have been observed in approximately 13% of patients, which significantly exceeds the average mutation frequency of normal B cells (5% to 6%) and other lymphomas. Analysis of V region genes demonstrates a biased use of VH; the V4–34 gene of the VH4 family is preferentially used. Intraclonal nucleotide heterogeneity was observed, indicating that the VH genes are still under the influence of the somatic hypermutation mechanism. The ratio of replacement to silent mutations showed evidence for the preservation of a functional Ig structure. Although the biologic relevance of these data is far from being completely understood, these studies indicate a GC origin for PCNSL. A centralized clinicopathologic tumor registry would allow researchers to conduct larger studies to elucidate the most relevant biologic and molecular issues in PCNSL (Table 1a  ).
The molecular mechanisms underlying dissemination of malignant lymphocytes to and within the CNS are largely unknown. This stems, in part, from the lack of adequate in vivo experimental models. Even though animal lymphoma models with differing CNS dissemination exist,7–9 no model demonstrated ocular infiltration by the lymphoma cells. Recently, a mouse model has been developed whereby intraperitoneal inoculation of variant S49 mouse T-cell lymphoma cells into young mice resulted in specific homing of these cells (named Rev-2-T-6) into the CNS and eyes.10 The choroid plexus and the cranial nerves and ganglia constitute major sites of infiltration into the CNS, which occurs in a rostral to caudal direction.11 Once inside the CNS, the lymphoma cells may spread diffusely within the parenchyma and along myelinated tracts (corpus callosum), as well as along the optic nerve sheath into the eyes. There, tumor cells may spread into the vitreous and the anterior chamber of the eye. Visualization of Rev-2-T-6 cells within the anterior chamber of the eye is a clear indication of prior involvement of the brain.11
Now that an animal model has been established, a variety of issues may be addressed (Table 1
Current therapeutic knowledge in PCNSL results from a limited number of nonrandomized phase II trials, meta-analyses of published series, and large retrospective, multicenter series. The evaluation of new first-line chemotherapy combinations in nonrandomized trials limits comparison between studied regimens and has produced small therapeutic progress. Moreover, the use of divergent study designs and entry criteria, as well as the presence of some methodologic pitfalls, lead to incomparable results and unreliable conclusions in prospective trials.12 The inclusion of patients with relapsed disease, incomplete staging, history of a prior cancer, and a histologically unproven diagnosis limits the interpretation of some PCNSL trials.13–15 Moreover, the lack of prospectively defined age and performance status entry criteria, trial end points, and sample size, as well as low statistical power and short duration of follow-up, represent serious methodologic flaws in prior trial designs.12 Even though it has not been confirmed in a randomized trial, there is a consensus that combined chemoradiotherapy is superior to radiotherapy alone.16 Data from a large, multicenter retrospective series indicate that high-dose methotrexate (HD-MTX)-based chemotherapy followed by whole-brain radiotherapy (WBRT) should be preferred over radiotherapy alone.17 This treatment strategy is in accordance with the treatment recommendation used for the majority of localized aggressive lymphomas, for which primary chemotherapy is followed by consolidation radiotherapy. However, even with this strategy, the 5-year survival rate remains approximately 20% to 25%,16,18 and it is not known whether more-intensive combined treatment will improve outcome. Given the increased risk of treatment-related neurotoxicity, especially among elderly patients,18,19 several authorities recommend deferral of radiotherapy until relapse in this most vulnerable patient population. Although a reduction in radiation dose has also been indicated to avoid neurotoxicity risk, this strategy may be associated with decreased tumor control.20 Therefore, a dilemma in PCNSL treatment is the choice between strategies designed to increase dose-intensity to improve cure rate versus strategies of treatment de-escalation to avoid severe neurotoxicity. Ultimately, a randomized trial is necessary to definitively address this issue. Along these lines, an ongoing study comparing combined chemoradiotherapy versus chemotherapy alone, with HD-MTX as the induction chemotherapy regimen, is being conducted (E. Thiel, personal communication September 29, 2001).
Conventional Chemotherapy The primary chemotherapy regimen in PCNSL patients should include intravenous HD-MTX (MTX ≥ 1 g/m2), which is the most effective drug against these malignancies.19,21 HD-MTX produces a response rate of 52% to 88% as a single agent and 70% to 94% when associated with other drugs; these chemotherapeutic approaches followed by WBRT are associated with a 2-year overall survival of 58% to 72%22–24 and 43% to 73%,16,18,25–31 respectively. The efficacy of this drug depends on the duration of exposure and drug concentration,32 which are determined by the administration schedule and pharmacokinetics. Because MTX clearance from plasma is triphasic,33 an initial rapid administration to overcome the distribution phase, followed by a more prolonged infusion, seems to be the most rational schedule for this drug. However, this strategy has not been used in most published trials.13,28 The optimal duration of HD-MTX infusion is still unknown; in most trials using doses of 1 to 5 g/m2, MTX has been administered in a 4-hour infusion,20,34,35 whereas 24-hour infusions have been used for higher doses.31,36 In a study using an MTX dose of 100 mg/kg, a 3-hour infusion has been associated with a significantly higher response rate and CSF levels compared with a 6-hour infusion.37 The optimal dose of MTX has not been defined. CSF MTX concentration is strictly related to the dose administered (see Leptomeningeal Lymphoma). The best timing of MTX administration remains undefined, but no significant difference in efficacy or toxicity was observed when MTX at 3.5 g/m2 was administered every 3 weeks versus every 10 days.22 Any regimen without HD-MTX is associated with outcomes no better than with radiotherapy alone.17,19 At least partially because of their poor blood-brain barrier (BBB) penetration, the most effective drugs against NHL, doxorubicin and cyclophosphamide, are associated with unsatisfactory results.19,34,38–40 Therefore, the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is not an effective treatment against PCNSL. Corticosteroids alone may produce a rapid and substantial tumor regression in up to 40% of PCNSL patients. Thus, the concurrent use of corticosteroids and investigational agents should be avoided in phase II trials because it may not be clear which drug caused tumor regression. Moreover, because many patients with brain masses are treated with corticosteroids before definitive therapy, the baseline cranial magnetic resonance imaging scan should be obtained immediately before the initiation of the experimental treatment. Several drugs have been added to HD-MTX to improve outcome. These drugs were selected based on their capacity to penetrate the BBB and on their demonstrated efficacy against systemic NHL. However, none of these drugs had been previously evaluated as effective single agents in patients with relapsed or refractory PCNSL. Preliminary results from small pilot studies in relapsed patients are now available with topotecan, rituximab, temozolomide, and the procarbazine, lomustine, and vincristine regimen.41–43 A recently reported survival improvement resulting from the addition of high-dose cytarabine immediately after HD-MTX17,44 deserves to be prospectively confirmed. Although there is no proven benefit of additional drugs, it is likely that an MTX-based polychemotherapy regimen will emerge as the standard combination for PCNSL. The identification of new active drugs and combinations in phase I/II trials in relapsed or refractory PCNSL should receive high priority.
BBB Disruption (BBBD) BBBD may also be an effective strategy in PCNSL patients who have experienced relapse after initial treatment with HD-MTX. Carboplatin-based chemotherapy in conjunction with BBBD produced a 36% response rate and a median survival after relapse of 6.8 months (range, 1 to 91 months); 16% of patients survived beyond 3 years from salvage therapy without cognitive loss in the absence of prior radiotherapy.47 Finally, the technique of BBBD may prove most useful in the delivery of agents unlikely to traverse an intact BBB, such as unconjugated or radiolabeled monoclonal antibodies, which deserves to be assessed in future trials.
High-Dose Chemotherapy With Autologous Peripheral-Blood Stem-Cell Transplantation (APBSCT) The preliminary results from these trials using high-dose chemotherapy with APBSCT clearly indicate that this strategy is feasible in patients with PCNSL. It is possible that the patients treated at relapse who previously received WBRT will have a higher risk of neurotoxicity. As with conventional therapy, cytostatic drugs for induction and conditioning chemotherapy have been selected on the basis of their safety, efficacy against systemic lymphomas, and ability to cross the BBB. The lack of cross-resistance with MTX has been an advantage when this strategy has been used as salvage therapy.50 The role of high-dose chemotherapy and APBSCT in PCNSL remains to be defined considering that the worldwide experience is still limited, and further studies will need to be performed to identify the optimal induction and high-dose chemotherapy regimens.
Radiotherapy alone is rarely curative in PCNSL patients because response is usually short-lived, with a median survival of 12 to 14 months.21,51 Consolidation after chemotherapy may represent the best role for radiotherapy, although the optimal field and doses have not been identified.51,52 Because PCNSL is often multifocal, the target for radiotherapy is the whole brain, whereas the added value of the tumor-bed boost is questionable.53 The inclusion of the posterior two thirds of the eyes into the radiation field is advisable.54 The radiation dose should be decided on the basis of response to primary chemotherapy, and, until definitive conclusions from well-designed trials are available, radiotherapy parameters should follow the widely accepted principles used for other aggressive NHLs.51 Doses of ≥ 40 Gy or 36 to 40 Gy may be advisable in patients with or without residual disease, respectively, after primary chemotherapy. Combined chemoradiotherapy is associated with severe neurologic impairment in 40% of patients and a neurotoxicity-related mortality of 30%,16,23 especially in patients older than 60 years of age. In fact, a direct relationship between age and risk of neurotoxicity has been reported,55 and female sex, MTX dose more than 3 g/m2, intrathecal chemotherapy, and higher tumor radiation dose have also been proposed as risk factors for this complication.17 Avoiding radiotherapy in patients older than 60 years of age in complete remission after primary chemotherapy has been proposed as a strategy to minimize neurotoxicity (see Chemotherapy as Exclusive Treatment). New strategies to improve the tolerance and efficacy of radiotherapy should be investigated in future trials. An important issue will be to define the risk of neurotoxicity in younger patients. In a recently published study,16 HD-MTX–based chemotherapy, followed by WBRT (45 Gy) and postradiation cytarabine, has been associated with severe neurotoxicity in 15% of patients; this complication was seen as frequently in patients younger than 60 years as in those who were 60 years or older. Interestingly, in the same study,16 the use of hyperfractionated WBRT (1.2 Gy/fraction twice daily; total dose, 36 Gy) did not seem to reduce the risk of neurotoxicity. Substantial dose reduction or WBRT withdrawal in patients younger than 60 years should be critically discussed considering that a detrimental survival effect has been reported with a WBRT dose reduction from 45 Gy to 30.6 Gy in these patients in a nonrandomized trial.20 A major question in older patients will be to define whether reduced radiation doses and restricted treatment fields may reduce the incidence of neurotoxicity without compromising efficacy.
As described above, the use of chemotherapy alone is of particular importance in PCNSL patients over the age of 60 years who achieve a complete remission after HD-MTX–based chemotherapy. In small series, this strategy has produced response rates in excess of 90%, and patients who relapsed were effectively treated with additional salvage chemotherapy or radiotherapy.56 In published prospective trials, HD-MTX alone produced a 52% to 100% response rate and a 2-year survival rate of 61% to 63%,29,31,57 whereas HD-MTX–based polychemotherapy regimens resulted in a 65% to 100% response rate and 2-year survival rate of 65% to 78%.13,58 In a comparison of older patients treated with or without WBRT after HD-MTX–based chemotherapy,18 chemotherapy alone markedly reduced the risk of neurotoxicity, and although there was a higher relapse rate in patients treated without WBRT, there was no difference in survival (median, 32 months) between these two subgroups. In a retrospective analysis of 378 patients, it was observed that WBRT did not improve survival in patients achieving complete remission after HD-MTX.17 These data seem to indicate that it is feasible to treat PCNSL using chemotherapy alone. Given the extremely high risk of treatment-related neurotoxicity, chemotherapy alone should be considered in patients over the age of 60 years. Future studies, in larger series, should validate the chemotherapy-alone strategy, as well as other strategies to dose-intensify chemotherapy and eliminate the need for WBRT (BBBD, APBSCT, and prolonged-maintenance MTX).
PCNSL infiltrates the subarachnoid space in up to 40% to 50% of patients.23,26,59 This indicates the necessity of meningeal treatment, which may be achieved by craniospinal radiation, high-dose systemic chemotherapy, or intrathecal chemotherapy. The first strategy is associated with relevant myelotoxicity, whereas the indications and efficacy of the other two strategies are debatable. Therapeutic MTX concentrations (10 µmol/L) can be achieved in CSF using intravenous doses of 3 g/m2 or greater,60 whereas lower doses resulted in unpredictable levels.61,62 Intrathecal administration produces drug levels 10-fold higher than those obtained with systemic chemotherapy.60,63 MTX, cytarabine, and corticosteroids are the drugs most commonly delivered by intrathecal route, mostly using an intraventricular Ommaya’s reservoir, which affords more reliable CSF distribution compared with lumbar injection. A sustained-release formulation of cytarabine (liposomal cytarabine) for intrathecal injection is available and allows dosing once every 14 days.64 Intrathecal chemotherapy is associated with increased risks of neurotoxicity and chemical meningitis,17,20,22 whereas its efficacy in PCNSL patients has not been prospectively assessed. Even if only a minority of relapsed patients are routinely assessed for meningeal recurrence, the majority of meningeal relapses seem to occur in patients with positive CSF cytology at diagnosis.17,22,34 This has led some authorities to indicate that, to minimize toxicity, intrathecal chemotherapy should be reserved for patients with positive CSF cytology.22,39 However, this recommendation could result in undertreatment because CSF cytology examination is associated with a finite false-negative rate.65,66 Some prospective22,29,34 and retrospective17,67 studies indicate that intrathecal chemotherapy does not improve outcome in patients who receive HD-MTX–based chemotherapy. Moreover, preliminary data indicate that systemic HD-MTX is associated with eradication of neoplastic cells from CSF,28,31 which deserves to be investigated in future trials. The optimal treatment for meningeal lymphoma remains undefined. Leptomeningeal relapse is associated with brain recurrence in more than 90% of patients. Relapse in the brain constitutes the cardinal prognostic event in PCNSL, obscuring the effect of concurrent leptomeningeal relapse on survival and, consequently, the potential benefit of intrathecal chemotherapy. Furthermore, the high local relapse rate observed in PCNSL patients indicates the inadequacy of primary chemotherapy and radiotherapy, and improvements in these strategies should be considered as priorities.
Promising anecdotal results in small series of patients with concurrent brain and ocular lymphoma treated with chemotherapy have been reported.68 The efficacy of chemotherapy is dependent on intraocular pharmacokinetics, which are not well understood, although some data from one case series indicate that micromolar concentrations of MTX are achieved in the aqueous and vitreous humor when the drug is given at a dose of 8 g/m2.69 Better disease control combining ocular irradiation with MTX-based chemotherapy has been reported.54 Thus, the use of chemotherapy alone should be the subject of experimental protocols and not considered a standard approach in patients with ocular disease. Improved outcome with intraocular drug injections has also been reported,70,71 but the role of this strategy should be addressed in future studies.
The identification of clinically relevant prognostic factors in PCNSL may allow the separation of patients into risk groups, which could result in the application of risk-adjusted therapeutic strategies, and the comparison of therapeutic results from prospective studies. Two major categories of prognostic factors influence the survival of PCNSL patients, namely the classical prognostic factors for NHL and specific prognostic factors for PCNSL. Among the parameters used for the International Prognostic Index (IPI), age, Eastern Cooperative Oncology Group performance status,18,29 and serum lactate dehydrogenase level72 are generally correlated to survival in retrospective series. However, the use of the IPI does not discriminate between low- and intermediate-low–risk groups in PCNSL series.73 This could be because of the relatively small number of patients in these studies compared with the IPI series or because of the influence of more specific prognostic variables. A significant association between survival and involvement of deep structures of the brain (periventricular areas, corpus callosum, basal ganglia, brainstem, and cerebellum) and elevated CSF protein concentrations has been reported.17,19,74 In the IELSG series of 378 patients,17 both classical prognostic factors (age, Eastern Cooperative Oncology Group performance status, and serum lactate dehydrogenase level) and PCNSL-specific predictors (CSF protein level and tumor location) have been established as independent predictors of response and survival.74 These variables have been used to develop a prognostic scoring system that distinguishes three different risk groups based on the presence of zero to one, two to three, or four to five unfavorable features (Fig 1 ).74 The clinical relevance of this prognostic score should be validated in further studies. Histopathologic,75 biologic, and molecular76 markers with potential prognostic value are currently under investigation.
A number of fundamental therapeutic issues remain unresolved in the management of PCNSL (Table 1  ). Because causal inferences regarding these questions can only be made in the context of a randomized study, there is considerable interest in this approach. However, several fundamental challenges must be addressed before initiation of a study that would require substantial financial resources as well as several years for accrual and follow-up. These challenges include the identification of one to two fundamental questions for a single randomized trial; the limited use of some specialized procedures (plasma MTX concentration and BBBD) in community-based hospitals, whose participation is vital for an adequate accrual; the lack of a clear consensus on a chemotherapy regimen to be used as a control arm; and the role of emerging strategies against systemic NHL, which may be applicable to PCNSL in the near future. Given the lack of consensus surrounding these questions, short-term prospects for a randomized clinical trial in PCNSL are not good. However, two promising clinical research strategies deserve immediate mention. The first involves the creation of a shared historical database that would pool information from multiple studies with identical patient entry criteria. These data could then be used for comparison to outcomes obtained in future, prospective nonrandomized trials in which the same entry criteria and prognostic factors were applied. Second, randomized phase II trials may be an alternative method of acquiring comparative information between different therapeutic strategies. Other critical end points for PCNSL patients include cognitive function and quality of life. The design of instruments to measure such outcomes in this patient population should receive high priority. In addition to these clinical research issues, it is critical that investigators share archival tumor tissue, which is especially important for frozen tissue because this is a rare resource in PCNSL. An international, multidisciplinary, multicenter collaborative group is an ideal setting in which to address some of the fundamental clinical and biologic research questions for PCNSL. In the years ahead, it is hoped that the International PCNSL Study Group established at the Lugano Conference will assume a prominent role in such investigations.
Lauren Abrey, Department of Neurology, and Joachim Yahalom, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; James Armitage, College of Medicine, University of Nebraska Medical Center, Omaha, NE; Tracy Batchelor, Brain Tumor Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; Edward A. Neuwelt and Nancy Doolittle, Department of Neurology, Oregon Health Sciences University, Portland, OR; Jean-Yves Blay, Hopital Edouard Herriot & Centre Leon-Berard, Lyon; Francoise Berger, Service de Pathologie, Centre Hospitalier Lyon–Lyon-Sud; Philippe Colombat, Service d’Oncologie Médicale, CHU Bretonneau, Tours; Khé Hoang-Xuan, Clinique Neurologique et INSERM, Division Mazarin, Hopital la Salpetriere, Paris; Carole Soussain, Service d’Hematologie, Hopital de Meaux, Meaux, France; Eric Bessell, Department of Clinical Oncology, Nottingham City Hospital, Nottingham; Tony Child, National Cancer Research Institute, Leeds, United Kingdom; Bettina Borisch, Department of Clinical Pathology, University Hospital of Geneva, Geneva; Roger Stupp, CHUV, Lausanne, Switzerland; Franco Cavalli, Emanuele Zucca and Salvatore Grisanti, Istituto Oncologico della Svizzera Italiana, Bellinzona; Andrés J.M. Ferreri and Michele Reni, Department of Radiochemotherapy, and Maurilio Ponzoni, Department of Pathology, San Raffaele H Scientific Institute, Milan, Italy; Jürgen Finke, Gerald Illerhaus, and Roland Guttenberger, Department of Hematology and Oncology, Medizinische Klinik Albert Ludwigs Universität, Freiburg; Axel Glasmacher, Department of Internal Medicine I; Hendrik Pels, Neurologische Klinik, Universitätsklinikum; Uwe Schlegel, Department of Neurology, University of Bonn; Ingo Schmidt-Wolf, Medizinische Universitätsklinik und Poliklinik, Bonn; Eckhard Thiel and Agnieszka Korfel, Medizinische Klinik III, Klinikum B. Franklin FU/Berlin, Berlin, Germany; Francisco Graus and Armando López-Guillermo, Serviceof Neurology and Hematology, Hospital Clinic, Universitat de Barcelona, Spain; Mary Gospodarowicz, Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, University Health Network, Toronto; Tamara Schenkier, British Colombia Cancer Agency, Vancouver, Canada; Hanny Haaxma-Reiche, Department of Neurology, University Hospital Groningen; Hanneke Kluin-Nelemans, Universitair Ziekenhuis Groningen, Groningen; Elly Lugtenburg, Department of Hematology, University Hospital Rotterdam, Rotterdam; Philip Poortmans, Dr Bernard Verbeeten Instituut, Department for Radiation Oncology, Tilburg; Gustaaf van Imhoff, Universitair Ziekenhuis Groningen, the Netherlands; Mads Hansen, Rigshospitalet, Copenhagen; Elisa Jacobsen, University Hospital Aarhus, Aarhus, Denmark; Jacob Hochman, Department of Cell and Animal Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel; Peter O’Brien, Department of Radiation Oncology, Newcastle Mater Hospital, Newcastle, New South Wales, Australia; José Thomas, Oncology Department, UZ-Gasthuisberg, Leuven; and Achiel van Hoof, AZ St Jan, Brugge, Belgium.
The Workshop on Primary CNS Lymphomas (Lugano, Switzerland, June 11, 2002) has been supported by an educational grant of the European School of Oncology and, in part, by the Swiss Cancer League.
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ABSTRACT
INTRODUCTION