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. The natural history of this disorder differs between patients with AIDS and those without AIDS. Computed tomographic (CT) scans may show ring enhancement in 50% of AIDS patients while patients without AIDS almost always show only homogeneous enhancement.  Both groups do equally poorly without therapy (mean survival, 1–3 months), but the overall survival for treated patients is much better for patients without AIDS (18.9 months) than for those with AIDS (2.6 months).  
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 staging with bone marrow biopsy and CT scans of the chest, abdomen, and pelvis.  
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.  The clinical impact of meningeal involvement on prognosis and therapy remains to be evaluated.
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. In a retrospective case series derived from 18 cancer centers in 5 countries of 40 patients with low-grade primary CNS lymphoma, a better long-term outcome was shown (median survival, 7 years) than is associated with the usual 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.   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.
Two multicenter, prospective trials (including RTOG-8806) used preirradiation cyclophosphamide, doxorubicin, vincristine, and dexamethasone followed by WBRT.   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.        A retrospective review of 226 patients suggested improved results with the use of high-dose methotrexate or cytarabine with radiation therapy rather than with other combination regimens. 
A multicenter trial (RTOG-9310) of 102 patients used high-dose methotrexate (2.5 g/m2) for five cycles, intravenous vincristine, oral procarbazine, intraventricular methotrexate, and either 45 Gy of WBRT or 36 Gy in a hyperfractionated schedule.  Median progression-free survival (PFS) was 24 months, and median overall survival (OS) was 37 months. [Level of evidence: 3iiiA] Severe delayed neurologic toxic effects were seen in 15% of patients.
Another multicenter trial (EORTC-20962 [NCT00003061]) was comprised of 52 patients younger than 66 years who used high-dose methotrexate, teniposide, carmustine, methylprednisolone, intrathecal methotrexate, cytarabine, and hydrocortisone followed by 40 Gy of radiation therapy; the median survival was 46 months, but a 10% toxic death rate occurred even in this younger patient population. [Level of evidence: 3iiiA] Follow-up was too short (median, 27 months) to fully assess severe delayed neurologic toxic effects.
Because of unsatisfactory results of WBRT alone and the neurologic toxic effects of chemotherapy and radiation therapy, a major focus is now on trials with chemotherapy alone.  Multiple reports have described systemic chemotherapy, which has been employed alone or with osmotic blood-brain barrier disruption, usually including high-dose methotrexate with frequent hospitalizations.        
A multicenter trial (NABTT-9607) evaluated high-dose methotrexate alone (8 g/m2) for newly diagnosed patients, with WBRT administered only at disease recurrence. With a median follow-up of 2 years, median PFS was 13 months and median OS had not been reached at 23 plus months. [Level of evidence: 3iiiA] Another multicenter trial (EORTC-26952) of 50 patients older than 60 years used high-dose methotrexate (3 g/m2/cycle), lomustine, procarbazine, methylprednisolone, and intrathecal methotrexate and cytarabine. The 1-year PFS was 40%, and the median OS was 14.3 months in this older patient group with a median age of 72 years. [Level of evidence: 3iiiA] Another multicenter trial of 65 patients used both high-dose methotrexate and high-dose cytarabine, including ifosfamide, cyclophosphamide, vinca alkaloids, dexamethasone, and intrathecal methotrexate, cytarabine, and prednisolone. The median time-to-treatment failure was 15 months with a median survival of 34 months; 57% of patients age 60 or younger were still alive at a median follow-up of 8 years.  [Level of evidence: 3iiiA] Patients with recurrent or refractory CNS lymphoma after methotrexate-based chemotherapy are candidates for salvage chemotherapy. 
Severe delayed neurologic toxic effects were rarely seen in these chemotherapy-only trials (in the absence of subsequent radiation therapy). Reduction of dosage for subsequent radiation to 23.4 Gy has been applied for patients who achieve clinical complete response after induction chemotherapy. [Level of evidence: 3iiiDiii]
Many of the aforementioned phase II results have never been tested in a randomized setting because of an insufficient number of patients.
Intensive chemotherapy with autologous peripheral stem cell transplantation is also under evaluation; neurologic toxic effects were not reported in the absence of radiation therapy.        A phase II feasibility study used chemotherapy induction with methotrexate, temozolomide, and rituximab (given once every 2 weeks for 10 doses) plus consolidation with etoposide and high-dose cytarabine; with a median follow-up of 4.9 years, this phase II Cancer and Leukemia Group B (CALGB) trial of 44 patients reported a complete radiographic response in 66% of the patients, a 2-year PFS of 57%, and an estimated OS of 65% at 4 years. [Level of evidence: 3iiiDiv]
In a phase II study of 32 patients, induction chemotherapy with rituximab plus methotrexate (3.5 g/m2) plus procarbazine plus vincristine was consolidated with high-dose chemotherapy with thiotepa, cyclophosphamide, and busulfan, followed by autologous stem cell transplant (ASCT) and no WBRT. With a median follow-up of 45 months and a median age of 57 years, the 2-year PFS was 79% (95% CI, 58–90) and 2-year OS was 81% (95% CI, 63–91), along with stable neurocognitive function posttransplant. [Level of evidence: 3iiiDiv]
Several prospective randomized trials are comparing 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 [NCT01511562]), and International Extranodal Lymphoma Study Group 43 (IELSG43 [NCT02531841]). 
Severe cognitive deficits are reported with all intensive therapies due to iatrogenic leukoencephalopathy. Retrospective data suggest a decreased risk of dementia when chemotherapy is employed prior to radiation therapy and even less when radiation therapy is avoided.    The use of systemic chemotherapy alone, with or without osmotic blood-brain barrier disruption, may avoid the cognitive loss observed with radiation therapy.     Comparative trials with validated measures of cognitive function will be necessary to determine the value of delaying radiation therapy until relapse after high-dose chemotherapy.      Glucocorticoids can also produce substantial but short-lived remissions. Steroid efficacy may complicate the diagnostic evaluation by obscuring the histologic findings. Other drugs that cross the blood-brain barrier are under clinical evaluation.  
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.  Upon completion of chemotherapy, responders were randomly assigned to WBRT (45 Gy) or to 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 receiving radiation therapy versus 37.1 months for those not receiving radiation (hazard ratio [HR] = 1.06; 95% confidence interval [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 randomized, nonblinded, multicenter trial, 79 patients were randomly assigned to high-dose methotrexate versus high-dose methotrexate plus cytarabine.  While 3-year PFS was better for the 2-drug regimen (HR, 0.54; 95% CI, 0.31–0.92; P = .01), there was no difference in 3-year OS (46% for the 2-drug regimen vs. 32% for the 1-drug regimen, HR, 0.65; 95% CI, 0.38–1.13; P = .07). [Level of evidence: 1iiDiii]
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 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 = .34), 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. 
Patients with HIV-associated primary CNS lymphoma usually have very advanced infections with CD4 counts less than 50 cells/mm3.  Consequently, most patients die of opportunistic infections regardless of therapy for the lymphoma. Groups that benefit most from radiation therapy, with or without antecedent chemotherapy, include those HIV-seropositive patients with no previous opportunistic infections or tumors for whom the CNS lymphoma is the AIDS-defining illness, and those patients with a good performance status, high CD4 lymphocyte count (>100mm3), and symptoms referable only to the CNS lymphoma.   Treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)
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 those with brain involvement alone (19 patients with both, 391 patients with brain involvement only). 
Check the list of NCI-supported cancer clinical trials that are now accepting patients with primary central nervous system non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
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.
Treatment Option Overview for Primary CNS Lymphoma
Added Ferreri et al. as reference 34.
Added text to state that in a phase II study of 32 patients, induction chemotherapy with rituximab plus methotrexate plus procarbazine plus vincristine was consolidated with high-dose chemotherapy with thiotepa, cyclophosphamide, and busulfan, followed by autologous stem cell transplant (ASCT) and no whole-brain radiation therapy (WBRT). Also added statistics for median follow-up (cited Omuro et al. as reference 36 and level of evidence 3iiiDiv).
Added text to state that several prospective randomized trials are comparing the value of WBRT and the value of ASCT as consolidation after high-dose methotrexate induction therapy; named the studies involved.
Added text to state that in a prospective randomized trial of 410 immunocompetent patients with newly diagnosed primary central nervous system lymphoma, all patients were scheduled to receive high-dose methotrexate and randomly assigned to receive WBRT or no radiation. Also added statistics about the intent-to-treat population, including data that showed the association of WBRT with a prolongation of progression-free survival but no difference in overall survival; the study lacked the power to exclude a benefit or harm from the WBRT (cited Korfel et al. as reference 46 and level of evidence 1iiDiii). In this study, 19 patients were diagnosed with intraocular involvement at diagnosis; intraocular lymphoma was an independent negative prognostic indicator (cited Kreher et al. as reference 47).
Added text to state that patients with intraocular disease and concomitant brain involvement had a worse prognosis than those with brain-involvement alone.
Added Key References for Primary CNS Lymphoma Treatment as a new section.
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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.
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).
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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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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: http://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389331]
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Date last modified: 2016-10-28
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