Primary central nervous system (CNS) lymphoma is defined as lymphoma limited to the cranial-spinal axis without systemic disease. An increasing incidence of this disease has been seen among patients with AIDS and among other immunocompromised persons. Computed tomography (CT) scans may show ring enhancement in 50% of AIDS patients while patients without AIDS almost always show only homogeneous enhancement. Median overall survival in published trials generally ranges from 2 to 5 years.[2,3] Older age (>65 years) and HIV positivity are the most clinically relevant poor prognostic factors, but the prognosis for HIV-associated primary CNS lymphoma has improved with the use of combination antiretroviral therapy.
Poor prognostic factors include the following:
When tumor progression occurs, it is usually confined to the CNS and/or the eye. Occult systemic disease can be excluded by positron emission tomography-CT scans of the chest, abdomen, and pelvis, and sometimes with bone marrow biopsy.[7,8]
In one prospective case series of 282 patients, 17% were found to have meningeal dissemination by cytomorphology, polymerase chain reaction of rearranged immunoglobulin heavy-chain genes, or meningeal enhancement on magnetic resonance imaging.
Although more than 95% of patients with primary CNS lymphoma have lymphoma of B-cell origin, 45 patients with CNS lymphoma of T-cell origin showed no difference in presentation or outcome in a retrospective series with data collected from 12 cancer centers. Almost all primary CNS lymphomas are aggressive neoplasms of the diffuse large B-cell type.
Primary CNS lymphoma closely resembles the activated B-cell subtype of large B-cell lymphoma, with additional mutations in the B-cell receptor signaling pathway. A retrospective case series of 40 patients with low-grade primary CNS lymphoma derived from 18 cancer centers in five countries reported a better long-term outcome (median survival, 7 years) than is associated with the usually aggressive CNS lymphoma.[Level of evidence: 3iiiDiv] Anecdotal cases of primary CNS Hodgkin lymphoma have also been reported.
Other PDQ summaries containing information related to primary CNS lymphoma include:
Because of the diffuse nature of central nervous system (CNS) lymphomas, aggressive surgical decompression with partial or gross total removal of the tumor is of no benefit to the patient. Median survival with surgery alone is in the range of only 1 to 5 months. Until the mid-1990s, radiation therapy had been the standard treatment, with doses of up to 45 Gy using standard fractionation. A prospective trial by the Radiation Therapy Oncology Group (RTOG-8315) used 40 Gy whole-brain radiation therapy (WBRT) and a 20 Gy boost to the tumor and found that the results were no better than had been previously reported, with a median survival of 1 year and 28% of the patients surviving 2 years.[1,2] Disease recurs in the brain in 92% of patients despite high doses of radiation. The addition of spinal-axis radiation does not affect survival because it does not prevent cerebral relapse.
Combined Chemotherapy and Radiation Therapy
Two multicenter, prospective trials (including RTOG-8806) used preirradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by WBRT.[3,4] Median survival times were no better than for radiation therapy alone. The failure of these and other combined modality trials has been attributed to poor penetration of standard drugs through the blood-brain barrier and to increased neurologic toxic effects. Retrospective reviews suggested improved results with the use of high-dose methotrexate or cytarabine with radiation therapy rather than with other combination regimens.[5,6] While combinations of high-dose methotrexate with WBRT improved progression-free survival (PFS) and overall survival (OS) anecdotally in patients participating in phase II trials, there was unacceptable neurologic toxicity.[7,8,9]
Trials using chemotherapy alone were justified because of the unsatisfactory results using WBRT alone, and the neurologic toxic effects seen using chemotherapy combined with WBRT. Numerous phase I and phase II studies over two decades established the following active drugs for induction therapy or for treating relapsing disease. The following drugs have been used as single agents and in combinations:
Severe delayed neurologic toxic effects were rarely seen in chemotherapy-only trials in the absence of subsequent radiation therapy. However, salvage radiation can be applied for relapsed or refractory disease, sometimes at reduced dosage.[24,25]
The International Extranodal Lymphoma Study Group investigated three different induction combinations in 227 patients with newly-diagnosed HIV-negative primary CNS lymphoma who were randomly assigned to one of three groups:
With a median follow-up of 30 months, the four-drug combination had a complete remission rate of 49% (95% confidence interval [CI], 38‒60) compared with 23% (interquartile range [IQR], 14‒31) for the two-drug combination (hazard ratio [HR], 0.46; 95% CI, 0.28‒0.74) and with 30% (IQR, 21‒42) for the three-drug combination (HR, 0.61; 95% CI, 0.40‒0.94).[Level of evidence: 1iiDiv]
In a randomized nonblinded multicenter trial, 79 patients were randomly assigned to receive either high-dose methotrexate or high-dose methotrexate plus cytarabine. While the 3-year PFS was better for the two-drug regimen (HR, 0.54; 95% CI, 0.31–0.92; P = .01), there was no difference in the 3-year OS rate (46% for the two-drug regimen vs. 32% for the one-drug regimen; HR, 0.65; 95% CI, 0.38–1.13; P = .07).[Level of evidence: 1iiDiii]
In a randomized prospective multicenter trial, 200 patients were randomly assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab. With a median follow-up of 32.9 months, there was no difference in the 1-year event-free survival rate: 52% (95% CI, 42%−61%) with rituximab and 49% (95% CI, 39%−58%) without rituximab (HR, 1.00; 95% CI, 0.70−1.43; P = .99).[Level of evidence: 1iiDi]
The so-called DA-TEDDI-R regimen incorporates temozolomide, etoposide, liposomal doxorubicin, dexamethasone, ibrutinib, and rituximab.[Level of evidence: 3iiiDiv] Among 18 patients (five previously untreated), the complete remission rate was 86%, but high rates (39%) of invasive aspergillosis were reported.
Additional randomized trials are needed to establish the optimal chemotherapy combination for induction therapy. The optimal length of induction therapy, the use of maintenance therapy, and the use of consolidation therapy are all areas of controversy that await further trial results.
Consolidation After Induction Chemotherapy
Several phase II studies have investigated consolidation with intensive chemotherapy supported by autologous stem cell transplantation (ASCT).[17,30,31,32,33,34,35,36] This approach is most applicable for younger patients with few comorbidities and good performance status, who also respond well to induction therapy.
Several prospective randomized trials are comparing or have compared the value of WBRT and the value of ASCT as consolidation after high-dose methotrexate induction therapy: International Extranodal Lymphoma Study Group 32 (IELSC32 [NCT01011920]), Pragmatic–Explanatory Continuum Indicator Summary (PRECIS [NCT00863460]), Cancer and Lymphoma Group B/Alliance (CALGB 51101 [NCT01511562]), and International Extranodal Lymphoma Study Group 43 (IELSG43 [NCT02531841]).
In a prospective, randomized trial of 551 immunocompetent patients with newly diagnosed primary CNS lymphoma, all patients received induction chemotherapy with six cycles of high-dose methotrexate (4 g/m2) with or without ifosfamide. After the completion of chemotherapy, responders were randomly assigned to receive either WBRT (45 Gy) or no treatment for complete-response patients and cytarabine for partial-response patients. There was no statistical difference in median OS, with 32.4 months for patients who received radiation therapy versus 37.1 months for those who did not receive radiation (HR, 1.06; 95% CI, 0.80–1.40; P = .71).[Level of evidence: 1iiA] Treatment-related neurotoxic effects were significantly worse on the radiation therapy arm, and such toxicity must be weighed against the possibility that the survival from chemotherapy alone may be marginally inferior to the survival when radiation is added.
In a prospective randomized trial of 410 immunocompetent patients with newly diagnosed primary CNS lymphoma, all patients were scheduled to receive high-dose methotrexate and randomly assigned to receive either WBRT or no radiation. In the intent-to-treat population, WBRT was associated with a prolongation of PFS, at 15.4 months versus 9.9 months (HR, 0.79; 95% CI, 0.64–0.98; P = .034), but no difference in OS, at 32.4 months versus 36.1 months (HR, 0.98; 95% CI, 0.79–1.26; P = .98). However, the study lacked the power to exclude a benefit or harm from the WBRT.[Level of evidence: 1iiDiii] In this study, 19 patients were diagnosed with intraocular involvement at diagnosis; intraocular lymphoma was an independent negative prognostic indicator.
An international consortium performed a retrospective review of 83 HIV-negative patients with primary intraocular lymphoma. In selected patients with no evidence of disseminated CNS disease, localized therapy with intraocular methotrexate or ocular radiation therapy is associated with equivalent outcomes seen with systemic chemotherapy and/or WBRT. Localized therapy with intraocular methotrexate or ocular radiation therapy did not affect relapse rate, median PFS, or median OS compared with systemic chemotherapy and WBRT.[Level of evidence: 3iiiDiv] Patients with intraocular disease and concomitant brain involvement had a worse prognosis than did those with brain involvement alone (19 patients with both, 391 patients with brain involvement only).
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of primary CNS lymphoma treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for primary CNS lymphoma. Listed after each reference are the sections within this summary where the reference is cited.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Primary CNS Lymphoma
Revised text to state that median overall survival in published trials generally ranges from 2 to 5 years (cited Fox et al. as reference 3).
Added Lukas et al. as reference 5.
Revised text to state that occult systemic disease can be excluded by positron emission tomography-computed tomography scans of the chest, abdomen, and pelvis, and sometimes with bone marrow biopsy.
Treatment Option Overview for Primary CNS Lymphoma
Added van der Meulen et al. as reference 9.
Added lenalidomide plus rituximab as a combination chemotherapy regimen used to treat primary CNS lymphoma (cited Ghesquieres et al. as reference 21).
Added text to state that in a randomized prospective multicenter trial, 200 patients were randomly assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab. With a median follow-up of 32.9 months, there was no difference in the 1-year event-free survival (cited Bromberg et al as reference 27 and level of evidence 1iiDi).
Added Fox et al. as reference 29.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of primary CNS lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Primary CNS Lymphoma Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Primary CNS Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389331]
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Last Revised: 2020-10-13
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