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.[11,35,36] The use of systemic chemotherapy alone, with or without osmotic blood-brain barrier disruption, may avoid the cognitive loss observed with radiation therapy.[11,16,17,36] 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.[22,36,37,38,39] 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.[40,41]
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 neurotoxicity was 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]