We limited our search to the adult population and excluded AIDS-related lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, and primary CNS lymphoma trials. We searched PubMed, the Cochrane Library, and the Web of Science databases between April, 1975, and April, 2011, for the terms “non-Hodgkin lymphoma”, “diffuse large B-cell lymphoma”, “central nervous system”, “leptomeningeal”, “recurrence”, “relapse”, and “event”, alone and in combination. The term “rituximab” was then added to the
Personal ViewPrevention of CNS relapse in diffuse large B-cell lymphoma
Introduction
Diffuse large B-cell lymphoma (DLBCL) represents 25–58% of adult non-Hodgkin lymphomas, with a crude incidence of three to four cases per 100 000 every year.1 It is a potentially curable disease, with 3-year overall survival rates ranging from about 70% in young patients with poor-prognosis and elderly patients2, 3 to more than 90% in young patients with favourable outlooks.2 CNS involvement is an uncommon finding at diagnosis when assessed by standard cytology of cerebrospinal fluid (CSF), but is a serious complication in 1·6–8·3% of patients during the course of the disease.4 Many CNS events occur soon after diagnosis (4·7–9 months) and a substantial proportion present during therapy or shortly after completion of treatment,5, 6, 7, 8, 9, 10 which suggests that initial CNS involvement could have gone undetected in some cases.11, 12, 13 The outcome of patients with CNS relapse is poor, with median survival times of 2–5 months.5, 6, 7, 8, 9, 10
Thus, the prevention of CNS recurrence in DLBCL seems desirable. Theoretical strategies include prophylactic cranial irradiation, intrathecal therapy with methotrexate, standard or slow-release cytarabine or corticosteroids, and intravenous administration of drugs with sufficient CNS penetration to achieve therapeutic concentrations in either the CSF or brain parenchyma, or both.14, 15 When administered alone or in combination, these procedures form an integral part of treatment protocols for acute lymphoblastic leukaemia, and lymphoblastic and Burkitt's lymphomas. Without a preventive approach, CNS relapse rates are 30–50% in these three diseases, and prophylaxis has unequivocally been shown to reduce the occurrence of CNS relapse and improve survival rates.16, 17 In DLBCL, the situation is controversial because no clear evidence exists. Guidelines from the National Comprehensive Cancer Network (NCCN) in the USA18 and the European Society of Medical Oncology (ESMO)19 recommend a diagnostic lumbar puncture and CNS prophylaxis for high-risk patients. The NCCN guidelines suggest four to eight doses of intrathecal methotrexate or cytarabine, or both, for selected patients, whereas the ESMO guidelines do not recommend intrathecal methotrexate as the best possible preventive strategy.
Unsurprisingly, treatment practices vary widely as shown by various surveys20, 21 and an analysis of the NCCN lymphoma database,22 showing that administration of CNS prophylaxis is a result of personal preferences rather than available evidence. In this Personal View we critically review studies that are often regarded as the basis for current practice to assess whether the use of CNS prophylaxis should be challenged.
Section snippets
Clinical risk factors
Many investigators have analysed potential risk factors for CNS recurrence in non-Hodgkin lymphoma (table 1). The factors that are most consistently associated with an increased risk of CNS recurrence are raised serum lactate dehydrogenase and the involvement of more than one extranodal site or the testes. A large retrospective series28 of primary lymphoma of the testis (373 patients) by the International Extranodal Lymphoma Study Group, reported a 15% CNS relapse rate. Similarly, a 2011
Chemotherapies
Several retrospective studies have reported outcomes after CNS prophylaxis, but they were limited by potential selection biases.24, 27, 43, 44, 45 No prospective study has been designed to specifically address the issue of prophylaxis, but some information can be obtained from landmark randomised trials in which some treatment groups received CNS prophylaxis (table 2).
Does systemic rituximab prevent CNS recurrences?
The addition of rituximab to CHOP has substantially improved outcomes in patients with DLBCL, with few additional toxic effects.32, 58, 59, 60, 61 Table 3 shows relevant studies comparing CNS outcomes in patients treated with and without rituximab. In the GELA trial,6 rituximab did not seem to affect the risk of CNS recurrence in 399 elderly patients (aged 60–80 years) with DLBCL randomly assigned to eight cycles of CHOP-21 (CHOP every 3 weeks) or R-CHOP-21 (R-CHOP every 3 weeks) without CNS
Why is intrathecal chemotherapy unlikely to prevent CNS relapses?
In addition to the benefit provided by rituximab or intensive systemic polychemotherapy, whether a prophylactic treatment delivered directly to the leptomeninges intrathecally can further reduce the CNS relapse rate is unknown. Unfortunately, intrathecal chemotherapy has several inherent limitations. Ideally, intrathecally administered chemotherapy should homogeneously diffuse into the leptomeninges, reach the brain parenchyma, and stay in these compartments with a sufficient half-life to kill
Factors that hamper prospective, randomised trials
Several barriers preclude the appropriate design of randomised clinical trials that aim to assess the potential efficacy of prophylactic strategies. First, no consensus about the choice of an experimental group has been reached. How should we choose the best drug (methotrexate, liposomal cytarabine, or even rituximab71) and best schedule? Should we begin at treatment initiation or when complete remission is achieved? Second, the question of how to identify patients at risk of CNS relapse with
Discussion
We have reviewed CNS events in large cohorts of patients with DLBCL or related lymphomas (with the exception of Burkitt's, lymphoblastic, and HIV-associated lymphomas). Improved systemic lymphoma control seems to be associated with fewer CNS recurrences, as suggested by the low incidence of CNS events when patients are treated with an intensive chemotherapeutic regimen such as ACVBP5, 46 and by the probable reduction in CNS recurrence achieved by addition of rituximab to CHOP (the present
Search strategy and selection criteria
References (76)
Therapy of diffuse large B-cell lymphomas
Eur J Cancer
(2009)- et al.
Should intra-cerebrospinal fluid prophylaxis be part of initial therapy for patients with non-Hodgkin lymphoma: what we know, and how we can find out more
Semin Oncol
(2009) - et al.
Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin's lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients
Ann Oncol
(2000) - et al.
Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab
Ann Oncol
(2004) - et al.
Incidence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)
Ann Oncol
(2007) - et al.
Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up
Ann Oncol
(2007) - et al.
CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Blood
(2009) - et al.
High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology
Blood
(2005) - et al.
Critical role of multidimensional flow cytometry in detecting occult leptomeningeal disease in newly diagnosed aggressive B-cell lymphomas
Leuk Res
(2008) - et al.
CNS prophylaxis in lymphoma: who to target and what therapy to use
Blood Rev
(2006)
The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia
Blood
Adult Burkitt leukemia and lymphoma
Blood
Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
Central nervous system involvement following diagnosis of non-Hodgkin's lymphoma: a risk model
Ann Oncol
Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy
Ann Oncol
Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma
Blood
Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)
Lancet Oncol
A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases
Blood
Double-hit B-cell lymphomas
Blood
MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy
Blood
Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma
Blood
Expression of the chemokine receptors CXCR4, CXCR5, and CCR7 in primary central nervous system lymphoma
Blood
The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma
Ann Oncol
Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma
Blood
Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL
Blood
Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL
Blood
Dose-escalated CHOP plus etoposide (MegaCHOEP) followed by repeated stem cell transplantation for primary treatment of aggressive high-risk non-Hodgkin lymphoma
Blood
CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group
Lancet Oncol
Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment
Blood
Statistical and trial design considerations in central nervous system prophylaxis studies
Semin Oncol
Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours
Lancet Oncol
Response: intrathecal methotrexate and central nervous system events
Blood
WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues
Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte
J Clin Oncol
Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516—the Southwest Oncology Group
J Clin Oncol
Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin's lymphoma: improved sensitivity of flow cytometry
J Clin Oncol
Intrathecal chemotherapy for hematologic malignancies: drugs and toxicities
Ann Hematol
National Comprehensive Cancer Network guidelines for treatment of cancer by site: non-Hodgkin's lymphoma
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Central nervous system nocardiosis mimicking recurrence of diffuse large B cell lymphoma with cerebral involvement
2023, International Journal of Infectious DiseasesCombined chemotherapy and radiotherapy improves survival in 1897 testicular Lymphoma patients from a contemporary cohort
2020, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :The improved survival rates among CHT-RT patients with Stage 3 and 4 diseases in our study supports this recommendation. Testicular involvement increases the risk of CNS relapse among DLBCL patients, especially when it is associated with other risk factors including elevated LDH and other extranodal sites [21]. A series of 373 PTL patients reported a 15% CNS relapse rate at 10 years [1].
Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis
2020, Blood AdvancesCitation Excerpt :In the rituximab era, the rate and patterns of CNS involvement with DLBCL have evolved.12 The overall risk of CNS progression has been reduced to 5%; for high-risk patients with more than one extranodal site and elevated lactate dehydrogenase (LDH) levels, this risk is 10% to 15%,13-15 and particularly those with renal or adrenal involvement.16 In addition, localization of CNS relapse has shifted to the brain parenchyma in the majority of cases.12
Cancer complications in patients with hematologic malignancies
2020, Neuro-Oncology for the Clinical NeurologistCentral Nervous System Lymphoma
2019, Hematology/Oncology Clinics of North America