- Thirteen patients with primary and metastatic CNS tumors have been treated with methotrexate (MTX) using three different approaches: (a) high-dose MTX with leucovorin (LV) rescue; (b) high-dose MTX with carboxypeptidase (CPDG) rescue; and (c) intraventricular administration of low doses of MTX for extended periods (concentration X time [CXT]). Eleven patients had central nervous system (CNS) lymphoma (one primary, one patient had recurrent medulloblastoma, and another patient had metastatic breast carcinoma. All 13 patients received high-dose MTX-LV rescue, while 3 patients were subsequently given MTX-CPDG. One patient received MTX by all three modalities. In patients with CNS lymphomas, complete responses (45%) and partial responses (36%) produced CNS disease-free intervals ranging from 1 to 23+ months. Survival for the complete responders has thus far ranged from 2.5 to 35 months, while the partial responders survived from 3 to 5 months. Two patients failed to respond and survived 2.5 and 3 months. Responses were obtainable with high-dose MTX-CPDG in patients resistant to MTX-LV. One patient who became sensitized to CPDG subsequently responded to MTX by intraventricular CXT administration. Thus, MTX can be effectively administered to patients with CNS tumors by several different approaches.