Elsevier

The Lancet Oncology

Volume 12, Issue 13, December 2011, Pages 1258-1266
The Lancet Oncology

Personal View
Prevention of CNS relapse in diffuse large B-cell lymphoma

https://doi.org/10.1016/S1470-2045(11)70140-1Get rights and content

Summary

CNS relapse occurs in about 5% of patients during the course of diffuse large B-cell lymphoma and entails a dismal prognosis. This consideration has led to the adoption of CNS prophylaxis, although known risk factors do not allow for an accurate prediction of CNS recurrences because they have insufficient sensitivity and specificity. Here, we review the reports of CNS events in major studies of diffuse large B-cell lymphoma before and after the introduction of rituximab, and probe the evidence that underlies prophylactic strategies such as intrathecal or high-dose intravenous chemotherapy. Now that rituximab is available, CNS prophylaxis relies on little—if any—evidence and should not be routinely administered. Nonetheless, several patient subgroups probably have a high risk of systemic and CNS relapses, and how to manage their treatment is a challenge. These subgroups include patients with testicular lymphoma or those who have more than one extranodal site involved plus at least one additional risk factor. For such patients, we recommend against prophylactic intrathecal chemotherapy because of the rare occurrence of isolated leptomeningeal relapses, the absence of evidence-based efficacy, and the potential harmful side-effects that are associated with this procedure. Because many CNS events are a result of primary resistance to treatment or accompany systemic relapses, high-dose intravenous methotrexate has been suggested as an alternative approach that needs to be validated in prospective controlled trials.

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

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

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