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To evaluate high-dose intravenous methotrexate in primary central nervous system (CNS) lymphoma in HIV-infected patients.An uncontrolled pilot trial.An infectious diseases department in Paris, France.All consecutive AIDS patients with primary CNS lymphoma attending the same unit from August 1994 to March 1996.Methotrexate was intravenously administered at a dose of 3 g/m2 every 14 days with leucovorin rescue. A maximum of six cycles was planned. Steroids were given to all patients and haematological growth factors were administered as required.Rate of response, time to response and survival.Fifteen patients (10 with histological documentation) were recruited. The median time since clinical onset was 27 days (range, 7–69 days), median Karnofsky score was 51 (range, 30–70), and mean CD4+ cell count was 30 ± 19 × 106/l (range, 7–69 × 106/l). Complete responses, defined as clinical improvement and disappearance of contrast-enhancing brain abnormalities on computed tomography or magnetic resonance imaging, were obtained in seven out of 15 patients (three out of 10 patients with histological diagnosis and four out of five patients without histological confirmation). The Karnofsky score of these seven patients improved to 80 ± 10 (range, 70–100). The mean time taken to respond was 62 ± 20 days (range, 45–90 days). One patient relapsed at 6 months. Six patients failed to respond, and two died of severe sepsis on days 15 and 45. The median survival time was 290 days (range, 11–570 days): 73 days (range, 11–570 days) in the 10 patients with histological diagnosis, and 347 days (range, 286–409 days) in the five patients without histological confirmation. Side-effects occurred in 10 patients, with gastrointestinal disorders in five, mucositis and skin rash in two, and fever in three patients; however, these events were mild and did not require cycle postponement or dose changes. No cognitive dysfunction occurred.Methotrexate appears to be an attractive alternative to radiation therapy for primary CNS lymphoma and is associated with a far greater improvement in quality of life relative to historical series of radiation therapy.