title: Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status.
abstract: High-dose methotrexate (HD-MTX) is effective in the initial treatment of primary central nervous system lymphoma (PCNSL). Because treatment options in patients with progressive or recurrent PCNSL are limited, prognosis is poor. Temozolomide, a well-tolerated oral alkylating agent that permeates the blood brain barrier (BBB), is effective against malignant glioma and recurrent PCNSL. The gene for the deoxyribonucleic acid (DNA) repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is closely related to cellular sensitivity to alkylating agents, is inactivated by promoter hypermethylation. We evaluated the results of temozolomide treatment and the methylation status of the promoter region of the MGMT gene in 17 patients (median age 68 years) with refractory or relapsed PCNSL. They were immunocompetent and had received initial treatment with HD-MTX (3.5 g/m(2)) with or without irradiation. All were treated with temozolomide 150-200 mg/m(2), for 5 days in the course of 28 days; treatment was continued until disease progression. We observed five complete remissions, five partial responses (PRs) with stable disease (SD), and seven with disease progression. Median overall survival after the temozolomide treatment was 6.7 months. One patient manifested grade 3 neutropenia and thrombocytopenia. Eleven tumor specimens were available for MGMT analysis. MGMT promoter methylation (mMGMT) in the tumor tissue was found in 4 (36.4%), the other seven harbored a non-methylated MGMT promoter (nmMGMT). There was no statistically significant difference in median overall survival between patients with mMGMT (11.1 months) and nmMGMT (6.7 months) (P = 0.63). Although some patients were elderly and had been heavily pre-treated, temozolomide resulted in a complete response (CR) in 29% and was well tolerated without any major toxicity.
authors: Department of Neurosurgery, Faculty of Medicine, Kumamoto University, 1-1-1 Honjo Kumamoto, Kumamoto 860-8556, Japan. kmakino@fc.kuh.kumamoto-u.ac.jp
authors: Keishi
authors: K
authors: Makino
authors: Hideo
authors: H
authors: Nakamura
authors: Taku-Ichiro
authors: T
authors: Hide
authors: Jun-Ichi
authors: J
authors: Kuratsu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016879:Salvage Therapy / Q000379:methods*; D016019:Survival Analysis; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide