Elsevier

The Lancet Neurology

Volume 8, Issue 6, June 2009, Pages 581-592
The Lancet Neurology

Review
Therapeutic challenges in primary CNS lymphoma

https://doi.org/10.1016/S1474-4422(09)70091-2Get rights and content

Summary

Optimum treatment for patients with primary CNS lymphoma remains challenging because there have not been any large randomised clinical trials of this rare tumour. Drugs used in treating systemic non-Hodgkin lymphoma have mostly proven ineffective because of difficulties crossing the blood–brain barrier. The recognition of the efficacy of high-dose methotrexate was a substantial therapeutic breakthrough and further advances, such as the development of polychemotherapy regimens, have built on this. Whole-brain radiotherapy can consolidate response to chemotherapy, but the associated toxic effects of chemoradiation can be unacceptable. Other effective approaches include disruption of the blood–brain barrier and the use of high-dose chemotherapy. Recently, there have been attempts to optimise multi-drug chemotherapy regimens by focusing on improving survival and reducing toxic effects. A promising area of research is the incorporation of novel targeted drugs into standard treatment frameworks. In the future, greater cooperation between research groups should hopefully lead to further therapeutic advances.

Introduction

Primary CNS lymphoma (PCNSL) is a rare B-cell variant of non-Hodgkin lymphoma that is confined to the brain, leptomeninges, spinal cord, and eyes. Although PCNSL accounts for less than 7% of brain tumours, its incidence is increasing, particularly in immunocompetent individuals.1 By contrast with most primary brain tumours, PCNSL is sensitive to corticosteroids, chemotherapy, and radiotherapy. Durable complete responses and long-term survival are possible with these treatments; however, outcome for patients with PCNSL is substantially worse than that for patients with a similar stage of systemic non-Hodgkin lymphoma. Advances in treatment have been limited not only because PCNSL is a rare tumour and large randomised clinical trials have not been successfully done, but also because of a lack of consensus about which questions these studies should address. Several other difficulties also exist; for example, many patients with PCNSL are older at diagnosis, have substantial comorbidities, and have worse performance status than do other groups with systemic non-Hodgkin lymphoma. Modern combination chemotherapy regimens used for the treatment of systemic non-Hodgkin lymphoma have mostly proven ineffective in PCNSL because of the drugs' poor penetration of the CNS and their inability to cross the blood–brain barrier.

Despite these obstacles, substantial progress has been made. A growing body of evidence from phase II clinical trials has shown the efficacy of several treatment strategies. Results from several studies of high-dose methotrexate have shown improved disease control and longer survival.2, 3, 4, 5, 6 Effective combination chemotherapy regimens have been developed to incorporate methotrexate and whole-brain radiotherapy.2, 3, 4, 6 Immunotherapy, which revolutionised the treatment of systemic non-Hodgkin lymphoma, also seems to offer benefits for patients with PCNSL. Substantial progress has also been made in the treatment of subpopulations with PCNSL, such as patients with intraocular lymphoma and PCNSL associated with HIV. However, the optimum treatment for patients with PCNSL remains challenging and at present there is no universally accepted therapeutic approach for patients with newly diagnosed disease. Relapse is a common problem with little consensus on appropriate second-line treatments. For patients with durable remission, substantial treatment-related neurotoxicity has emerged as a major problem—one that is particularly prominent in patients older than 60 years at diagnosis.7 In this Review, we discuss the recent progress in the management of PCNSL and identify specific challenges for the future. More general overviews of the epidemiology, staging, and diagnosis of PCNSL are provided in other comprehensive reviews.8, 9

Section snippets

High-dose methotrexate

Initial attempts to treat PCNSL with chemotherapy focused on standard drugs with proven efficacy for non-Hodgkin lymphoma. One of the most active and commonly used regimens was the four-drug combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Although regimens such as CHOP induced an initial radiographical response in PCNSL, these responses were not durable and patients relapsed rapidly. Similar problems are reported with corticosteroids when used as monotherapy

Recurrent or refractory PCNSL

Despite treatment advances, relapse from PCNSL remains a substantial problem. Salvage treatment is needed for patients who develop recurrent or refractory PCNSL after initial treatment; best estimates suggest that up to half of patients will relapse after initial remission and 10–15% of patients will have primary refractory PCNSL.73 Unfortunately, there are few available data for the optimum approach to management in this setting. Additionally, treatments for relapsed or refractory disease are

Ocular lymphoma

Ocular lymphoma can present in isolation, as primary intraocular lymphoma, or as an extension of parenchymal brain lymphoma. Primary intraocular lymphoma on its own is very rare and probably occurs in only 100–200 patients every year in the USA. This disease is diagnostically challenging as many patients present with symptoms that are identical to non-specific uveitis; however, primary intraocular lymphoma eventually becomes refractory to topical steroid application. Diagnosis is usually made

HIV-related PCNSL

Acquired immunodeficiency is the only established risk factor for PCNSL, but since the advent of highly active antiretroviral drugs, incidence in this population has been declining. Current National Comprehensive Cancer Network guidelines93 recommend the use of high-dose methotrexate, whole-brain radiotherapy, or initiation of highly active antiretroviral therapy for patients with HIV-associated PCNSL. However, recent population-based data suggest that many patients do not receive any

Conclusions and future challenges

Although PCNSL is a rare brain tumour, its sensitivity to several therapeutic strategies makes it unique in neuro-oncology. Historically, whole-brain radiotherapy and corticosteroids were the mainstay of treatment but the development of high-dose methotrexate has radically altered modern treatments. Methotrexate has successfully been incorporated into multi-drug chemotherapy regimens, which are associated with notable improvements in response and survival. Alternative strategies, including

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the search terms “PCNSL”, “primary AND CNS lymphoma”, and “CNS AND lymphoma”. No date restriction was set—all papers were searched up to February, 2009. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.

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