Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort

Abstract

We have retrospectively reviewed toxicities and response of a cohort of primary central nervous system lymphoma (PCNSL) patients treated with high dose parenteral methotrexate (MTX) monotherapy without whole brain radiation. From The Massachusetts General Hospital (MGH) Cancer Registry, active since 1946, we selected all immunocompetent patients with histologic and/or radiographic PCNSL diagnosed between 1980 and 2007. We identified the recipients of MTX with leucovorin rescue as sole therapy. No patient received radiation therapy (XRT). We analyzed this cohort for toxicity, response and patterns of recurrence. The cohort of 121 patients received on average 11 cycles of intravenous MTX at a median dose of 8 g/m2. Median interval between cycles was 10 days. After 3 months of therapy, the overall response rate was 85% (58% CR, 27% PR). The overall survival (OS) for the cohort was 7 years and progression-free survival (PFS) was 3.14 years. A trend toward a higher PFS was seen in patients who continued to receive MTX (3.48 years) every three months as compared to patients who ceased MTX after one year (2.86 years). Of 68 patients who achieved initial CR, there were 40 recurrences. Twenty-six of the 40 were re-induced with MTX as above; Sixty-nine percent again achieved CR. Eighty-one treatment-related toxicities occurred in 1316 MTX cycles. These toxicities included MRI white matter changes (N = 8) and lead to MTX cessation in 16 patients. High-dose MTX monotherapy of PCNSL is well-tolerated and provides PFS of >3 years and OS >7 years.

Advantages of Dose-dense Methotrexate Protocol for Primary Central Nervous System Lymphoma: Comparison of Two Different Protocols at a Single Institution

“…Cobert et al reported clinical results of patients, including the elderly, treated with an average of 11 cycles of 8 g/m 2 MTX. 4) The median OS was 7 years, with only a small percentage of patients experiencing severe toxicity. The disadvantage of this protocol is the long treatment period, which includes maintenance therapy every 3 months.…”

“…In terms of dosage, 1–8 g/m 2 of MTX has been adopted in various clinical trials, and 3.0 g/m 2 or more of MTX is widely acce pted. 2 – 4 , 6 – 9 , 11 , 12 , 14 , 19 , 21 – 30 , 32) MTX appears to be readily distributed into the cerebrospinal fluid when 3.0 g/m 2 or more of MTX is administered. 17) Furthermore, a recent trial has investigated changing subsequent doses of MTX based on the plasma concentration of MTX.…”

“… 3 , 8 , 9 , 29) Currently, some reports have indicated improved treatment results with an increased number of cycles of MTX. 4 , 8 , 12 , 26 , 32) One of the essential roles of dose-intensity MTX treatment is to defer whole-brain radiation therapy (WBRT) during first-line treatment and thus decrease the risk for leukoencephalopathy, especially for elderly patients, and retain the option of re-treating with MTX at relapse. When MTX is administered, a 2-week interval would hypothetically be better than a 3-week interval between cycles.…”

Immunochemotherapy for primary central nervous system lymphoma with rituximab, methotrexate, cytarabine and dexamethasone: Retrospective analysis of 18 cases

“…The prognosis of untreated PCNSL patients is extremely poor and their median survival time is 1.5-3.3 months (9). It was previously demonstrated that the MTX-based protocols could be effective compared with HD-MTX alone, but the overall response rate is poor and the toxicity is serious (10,11). Pels et al (7) reported the results of a combination of HD-MTX, high-dose of Ara-C (HD-Ara-C), vinca-alkaloids and alkylating agents treated with PCNSL.…”

Efficacy of the Nordic and the MSKCC chemotherapy protocols on the overall and progression-free survival in intracranial PCNSL

“…High-dose methotrexate (HD-MTX) is the most effective chemotherapeutic agent for PCNSL and many studies support its use as first-line therapy (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and is recommended also by the guidelines of the European Association of Neuro-Oncology (5). By the addition of calciumfolinate 24 hours after a 3-4 hour MTX infusion it is possible to increase the MTX dose by a factor of 100, thus allowing the drug to penetrate the BBB by simple diffusion.…”