Comparison of serum and cerebrospinal fluid levels of methotrexate in man during high-dose chemotherapy for aggressive non-Hodgkin's lymphoma

Abstract

The relationship between plasma and cerebrospinal fluid levels of methotrexate was studied in five patients, four with aggressive non-Hodgkin's lymphoma and one with mixed epithelial mesothelial tumour, who were treated with high-dose methotrexate (1.5 g/m2) as part of combination chemotherapy. Cerebrospinal fluid was sampled for 24 h via a permanent indwelling lumbar catheter. No complications were observed with this technique. In two patients with central nervous system involvement adequate "cytotoxic" levels (greater than 10(-6) M) were obtained for greater than 12 h. The remaining three patients, with no direct evidence of central nervous system involvement, never attained adequate cytotoxic methotrexate levels in the cerebrospinal fluid. Serum levels were therapeutic in all patients. These results suggest that patients with central nervous system tumour involvement may receive adequate doses of methotrexate in the cerebrospinal fluid. Patients with occult central nervous system tumour involvement may not attain adequate cerebrospinal fluid levels. A 24-h serum methotrexate level of greater than 10(-5) M may indicate that patients have achieved therapeutic cerebrospinal fluid levels of methotrexate. Cranial irradiation following chemotherapy is still recommended in this tumour group until adequate cytotoxic levels of methotrexate can be obtained in all patients for prolonged periods.

Phase II Multicenter Study of Brief Single-Agent Methotrexate Followed by Irradiation in Primary CNS Lymphoma

“…42 The BBB is disrupted in the presence of PCNSL and it is likely that cytotoxic levels of methotrexate will occur in the CSF after doses as low as 1 g/m 2 are given intravenously. 43,44 Only two patients in our series suffered CSF relapse, so intrathecal therapy can probably be avoided in most patients, reserving it for those with CSF involvement at the time of diagnosis, provided adequate doses of IV methotrexate are used. Similarly, it is unlikely that spinal irradiation has a role other than in the rare patient with spinal cord involvement at the time of diagnosis.…”

Diffuse large B‐cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era

“…For limited stage patients, a similar approach could be considered as a consolidative therapy to avoid the toxicity of integrating high dose methotrexate with R-CHOP (Abramson et al, 2010). The optimal dose of high dose methotrexate is also unknown but studies suggest that doses above 3Á0 g/m 2 may be preferable due to limited penetration of lower doses (Canellos et al, 1981;Gilchrist et al, 1985). The IELSG is currently evaluating the role of intermediate dose methotrexate (1Á5 g/m 2 ) in a phase 2 study (IELSG-30) following completion of R-CHOP chemotherapy, the lower dose chosen due to the advanced age of most patients in an attempt to limit toxicity.…”

“…A reliably effective CNS prophylaxis strategy has yet to be defined and the value of IT chemotherapy remains controversial as there is no definitive evidence that it is protective and as intrathecally administered therapy is unlikely to impact the risk of relapse in the brain parenchyma (Kridel & Dietrich, 2011). The optimal dose of high dose methotrexate is also unknown but studies suggest that doses above 3Á0 g/m 2 may be preferable due to limited penetration of lower doses (Canellos et al, 1981;Gilchrist et al, 1985). There is some evidence suggesting a reduction in risk of CNS relapse in high risk DLBCL patients treated with high dose methotrexate (Tilly et al, 2003;Abramson et al, 2010;Holte et al, 2013;Cheah et al, 2014b).…”

Long‐term survival of a patient with leptomeningeal involvement by nasopharyngeal carcinoma after treatment with high‐dose intravenous methotrexate

“…When administered intravenously, methotrexate enters cells by passive diffusion. Plasma concentration of methotrexate appears to correlate well with CNS concentration, such that higher infusion dose results in similarly elevated CNS concentrations 29…”