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.
ReviewTherapeutic challenges in primary CNS lymphoma
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
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2023, Seminars in Ultrasound, CT and MRIHow I treat patients with aggressive lymphoma at high risk of CNS relapse
2017, BloodCitation Excerpt :Systemic therapy with CNS penetration is therefore paramount and an essential component for all prophylactic regimens. Systemic HD-MTX achieves tumoricidal levels in brain parenchyma at doses ≥1 g/m2 and leptomeningeal penetration at doses ≥3 g/m2.71-74 A French randomized study (prerituximab) compared doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone with a consolidation phase containing etoposide, ifosfamide, cytarabine, 4 doses of IT MTX, and 2 cycles of systemic MTX 3 g/m2 (ACVBP) with CHOP (which contained no CNS prophylaxis).75
First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)-a systematic review and individual patient data meta-analysis
2015, Annals of OncologyCitation Excerpt :However, to investigate this in further detail, more clinical information at time of relapse would have been needed. Beside HD-MTX, there is yet no defined standard treatment of newly diagnosed PCNSL as is for instance rituximab–CHOP for systemic NHL [40]. The only phase II randomized trial specifically designed for elderly PCNSL patients suggests that MPV-A may be more effective compared with HD-MTX plus temozolomide [25]; however, the differences regarding response, PFS, or OS were not statistically significance.
Resection versus biopsy for management of primary central nervous system lymphoma: a meta-analysis
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