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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.[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; 57% of patients age 60 or younger were still alive at a median follow-up of 8 years.[24,25][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.[26][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.[27,28,29,30,31] 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.[11,32,33] The use of systemic chemotherapy alone, with or without osmotic blood-brain barrier disruption, may avoid the cognitive loss observed with radiation therapy.[11,16,17,33] 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.[22,33,34,35,36] 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.[37,38]

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.[39] 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.[32,40] Treatment of these patients requires special consideration. (Refer to the PDQ summary on AIDS-Related Lymphoma Treatment for more information.)