Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of primary CNS lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Treatment options.

This summary 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.

Some of the reference citations in the 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. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: Separate PDQ summaries on Adult Hodgkin Lymphoma Treatment and Adult Non-Hodgkin Lymphoma Treatment are also available.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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 acquired immunodeficiency syndrome (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. [1] Both groups do equally poorly without therapy (1–3 month mean survival), 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). [1] [2]

Poor prognostic factors include the following: [3] [4] [5]

• Age older than 50 years. [5]
• Performance status greater than 1 or Karnofsky performance status less than 70. [5]
• Elevated serum level of lactate dehydrogenase.
• Elevated cerebrospinal fluid protein concentration.
• Involvement of nonhemispheric areas of the brain (periventricular, basal ganglia, brainstem, and cerebellum).

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. [6] [7] 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. [8] 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. [9] 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 five countries of 40 patients with low-grade primary CNS lymphoma, a better long-term outcome was shown (7-year median survival) than is associated with the usual aggressive CNS lymphoma. [10][Level of evidence: 3iiiDiv] Anecdotal cases of primary CNS Hodgkin lymphoma have also been reported. [11]

References:

1. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993.
2. Nasir S, DeAngelis LM: Update on the management of primary CNS lymphoma. Oncology (Huntingt) 14 (2): 228-34; discussion 237-42, 244, 2000.
3. Ferreri AJ, Blay JY, Reni M, et al.: Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 21 (2): 266-72, 2003.
4. Pollack IF, Lunsford LD, Flickinger JC, et al.: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63 (5): 939-47, 1989.
5. Abrey LE, Ben-Porat L, Panageas KS, et al.: Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24 (36): 5711-5, 2006.
6. O'Neill BP, Dinapoli RP, Kurtin PJ, et al.: Occult systemic non-Hodgkin's lymphoma (NHL) in patients initially diagnosed as primary central nervous system lymphoma (PCNSL): how much staging is enough? J Neurooncol 25 (1): 67-71, 1995.
7. Abrey LE, Batchelor TT, Ferreri AJ, et al.: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23 (22): 5034-43, 2005.
8. Fischer L, Martus P, Weller M, et al.: Meningeal dissemination in primary CNS lymphoma: prospective evaluation of 282 patients. Neurology 71 (14): 1102-8, 2008.
9. Shenkier TN, Blay JY, O'Neill BP, et al.: Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol 23 (10): 2233-9, 2005.
10. Jahnke K, Korfel A, O'Neill BP, et al.: International study on low-grade primary central nervous system lymphoma. Ann Neurol 59 (5): 755-62, 2006.
11. Gerstner ER, Abrey LE, Schiff D, et al.: CNS Hodgkin lymphoma. Blood 112 (5): 1658-61, 2008.

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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 recently, radiation therapy has been the standard treatment, with doses of up to 45 Gy using standard fractionation. When the Radiation Therapy Oncology Group (RTOG-8315) used 40 Gy whole-brain radiation therapy (WBRT) and a 20 Gy boost to the tumor, 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.

Two multicenter prospective trials, one of which is 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 [5] has been attributed to poor penetration of standard drugs through the blood-brain barrier and to increased neurologic toxic effects. [3] [5] [6] [7] [8] [9] [10] 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. [11] 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. [12] Median progression-free survival (PFS) was 24 months, and median overall survival (OS) was 37 months. [13][Level of evidence: 3iiiA] Severe delayed neurologic toxic effects were seen in 15% of patients. Another multicenter trial (EORTC-20962) of 52 patients younger than 66 years 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. [14][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. [15] 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. [8] [10] [16] [17] [18] [19] [20] [21] A multicenter trial (NABTT-9607) evaluated high-dose methotrexate alone (8 g/m²) for newly diagnosed patients, with whole-brain radiation therapy 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. [22][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. [23][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. [24][Level of evidence: 3iiiA] 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. [25][Level of evidence: 3iiiDiii] Intensive chemotherapy with autologous peripheral stem cell transplantation is also under evaluation; neurologic toxic effects were not reported in the absence of radiation therapy. [26] [27] [28] [29] [30] These phase II results have never been tested in a randomized setting because of an insufficient number of patients.

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. [11] [31] [32] The use of systemic chemotherapy alone, with or without osmotic blood-brain barrier disruption, may avoid the cognitive loss observed with radiation therapy. [11] [16] [17] [32] 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. [22] [32] [33] [34] [35] 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. [36] [37]

Patients with acquired immunodeficiency syndrome (AIDS) associated primary CNS lymphoma usually have very advanced human immunodeficiency virus (HIV) infections, with CD4 counts less than 50 cells/mm³. [38] 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 prior 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. [31] [39] 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. [40] 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 as compared to systemic chemotherapy and/or WBRT. [40][Level of evidence: 3iiiDiv]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with primary central nervous system 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 Web site.

References:

1. Pollack IF, Lunsford LD, Flickinger JC, et al.: Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 63 (5): 939-47, 1989.
2. Nelson DF, Martz KL, Bonner H, et al.: Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23 (1): 9-17, 1992.
3. O'Neill BP, O'Fallon JR, Earle JD, et al.: Primary central nervous system non-Hodgkin's lymphoma: survival advantages with combined initial therapy? Int J Radiat Oncol Biol Phys 33 (3): 663-73, 1995.
4. Schultz C, Scott C, Sherman W, et al.: Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 14 (2): 556-64, 1996.
5. Bessell EM, Graus F, López-Guillermo A, et al.: CHOD/BVAM regimen plus radiotherapy in patients with primary CNS non-Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 50 (2): 457-64, 2001 Jun 1.
6. Chamberlain MC, Levin VA: Primary central nervous system lymphoma: a role for adjuvant chemotherapy. J Neurooncol 14 (3): 271-5, 1992.
7. Fine HA: Treatment of primary central nervous system lymphoma: still more questions than answers. Blood 86 (8): 2873-5, 1995.
8. Blay JY, Bouhour D, Carrie C, et al.: The C5R protocol: a regimen of high-dose chemotherapy and radiotherapy in primary cerebral non-Hodgkin's lymphoma of patients with no known cause of immunosuppression. Blood 86 (8): 2922-9, 1995.
9. O'Brien P, Roos D, Pratt G, et al.: Phase II multicenter study of brief single-agent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol 18 (3): 519-26, 2000.
10. Gavrilovic IT, Hormigo A, Yahalom J, et al.: Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 24 (28): 4570-4, 2006.
11. Blay JY, Conroy T, Chevreau C, et al.: High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 16 (3): 864-71, 1998.
12. Fisher B, Seiferheld W, Schultz C, et al.: Secondary analysis of Radiation Therapy Oncology Group study (RTOG) 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma. J Neurooncol 74 (2): 201-5, 2005.
13. DeAngelis LM, Seiferheld W, Schold SC, et al.: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20 (24): 4643-8, 2002.
14. Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al.: High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol 21 (24): 4483-8, 2003.
15. Ekenel M, Iwamoto FM, Ben-Porat LS, et al.: Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer 113 (5): 1025-31, 2008.
16. Dahlborg SA, Henner WD, Crossen JR, et al.: Non-AIDS Primary CNS Lymphoma: First Example of a Durable Response in a Primary Brain Tumor using Enhanced Chemotherapy Delivery without Cognitive Loss and without Radiotherapy Cancer J Sci Am 2 (3): 166-74, 1996.
17. Gabbai AA, Hochberg FH, Linggood RM, et al.: High-dose methotrexate for non-AIDS primary central nervous system lymphoma. Report of 13 cases. J Neurosurg 70 (2): 190-4, 1989.
18. Sandor V, Stark-Vancs V, Pearson D, et al.: Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 16 (9): 3000-6, 1998.
19. DeAngelis LM: Primary central nervous system lymphomas. Curr Treat Options Oncol 2 (4): 309-18, 2001.
20. Kiewe P, Fischer L, Martus P, et al.: Primary central nervous system lymphoma: monocenter, long-term, intent-to-treat analysis. Cancer 112 (8): 1812-20, 2008.
21. Angelov L, Doolittle ND, Kraemer DF, et al.: Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J Clin Oncol 27 (21): 3503-9, 2009.
22. Batchelor T, Carson K, O'Neill A, et al.: Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol 21 (6): 1044-9, 2003.
23. Hoang-Xuan K, Taillandier L, Chinot O, et al.: Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 21 (14): 2726-31, 2003.
24. Pels H, Schmidt-Wolf IG, Glasmacher A, et al.: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 21 (24): 4489-95, 2003.
25. Shah GD, Yahalom J, Correa DD, et al.: Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25 (30): 4730-5, 2007.
26. Soussain C, Suzan F, Hoang-Xuan K, et al.: Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol 19 (3): 742-9, 2001.
27. Abrey LE, Moskowitz CH, Mason WP, et al.: Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol 21 (22): 4151-6, 2003.
28. Illerhaus G, Marks R, Ihorst G, et al.: High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 24 (24): 3865-70, 2006.
29. Colombat P, Lemevel A, Bertrand P, et al.: High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant 38 (6): 417-20, 2006.
30. Soussain C, Hoang-Xuan K, Taillandier L, et al.: Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol 26 (15): 2512-8, 2008.
31. Fine HA, Mayer RJ: Primary central nervous system lymphoma. Ann Intern Med 119 (11): 1093-104, 1993.
32. Nasir S, DeAngelis LM: Update on the management of primary CNS lymphoma. Oncology (Huntingt) 14 (2): 228-34; discussion 237-42, 244, 2000.
33. DeAngelis LM: Primary Central Nervous System Lymphoma: Curable Without Toxicity? Cancer J Sci Am 2 (3): 137-9, 1996.
34. Bessell EM, López-Guillermo A, Villá S, et al.: Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol 20 (1): 231-6, 2002.
35. Abrey LE, Batchelor TT, Ferreri AJ, et al.: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23 (22): 5034-43, 2005.
36. Reni M, Ferreri AJ, Landoni C, et al.: Salvage therapy with temozolomide in an immunocompetent patient with primary brain lymphoma. J Natl Cancer Inst 92 (7): 575-6, 2000.
37. Wong ET, Tishler R, Barron L, et al.: Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer 101 (1): 139-45, 2004.
38. Levine AM: Acquired immunodeficiency syndrome-related lymphoma. Blood 80 (1): 8-20, 1992.
39. Corn BW, Donahue BR, Rosenstock JG, et al.: Performance status and age as independent predictors of survival among AIDS patients with primary CNS lymphoma: a multivariate analysis of a multi-institutional experience. Cancer J Sci Am 3 (1): 52-6, 1997 Jan-Feb.
40. Grimm SA, Pulido JS, Jahnke K, et al.: Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report. Ann Oncol 18 (11): 1851-5, 2007.

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Changes to This Summary (02/10/2010)

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

Added text to state that anecdotal cases of primary CNS have been reported (cited Gerstner et al. as reference 11).

Treatment Option Overview

Added Angelov et al. as reference 21.

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