Simultaneous determination of plasma methotrexate and 7-hydroxy methotrexate by UHPLC-MS/MS in patients receiving high-dose methotrexate therapy.

The plasma concentrations of methotrexate (MTX) and its major metabolite 7-hydroxy methotrexate (7-OH-MTX) are highly correlated with the toxicities in patients with high-dose MTX therapy. Routine monitoring of MTX and 7-OH-MTX plasma levels is useful for dose adjustment of rescue drugs and toxicity prevention. A UHPLC-MS/MS method for simultaneous determination of plasma MTX and 7-OH-MTX was developed, validated, and applied in 181 plasma samples. The ion transition was m/z 455.2 → 308.2 for MTX and m/z 471.2 → 324.1 for 7-OH-MTX. The flow rate was 0.4 mL/min with a run time of 2.6 min. The calibration range was 0.002-2 µM for MTX, and 0.01-10 µM for 7-OH-MTX. The intra-day and inter-day inaccuracy and imprecision were -5.50% to 10.93% and less than 9.20% for both analytes. The internal standard (MTX-D3) normalized recovery and matrix factor were consistent at four quality control levels. 14 h, 38 h, and 62 h after dosing, MTX and 7-OH-MTX plasma levels were significantly higher in patients with impaired renal function compared to those with normal renal function. 7-OH-MTX plasma levels were significantly higher in patients with impaired liver function compared to those with normal liver function.

Central nervous system prophylaxis with high-dose methotrexate does not give rise to significant electroencephalographic changes in children with acute lymphoblastic leukemia.

Acute, subacute, and chronic neurologic complications have been reported in children treated with high-dose methotrexate for various malignant diseases. It was the aim of this study to monitor central nervous system treatment with high-dose methotrexate in children with acute lymphoblastic leukemia by serial electroencephalographic (EEG) examinations. Electroencephalographic examinations with quantitative computed analysis were performed in 21 children before and on the third day after each of four high-dose methotrexate infusions with leucovorin rescue according to protocol M of trial ALL-BFM 90 of the German Society for Pediatric Haematology and Oncology. Six patients with a medium risk of relapse also received L-asparaginase. In the cohort treated with methotrexate solely, no statistically significant changes of the quantitative EEG parameters could be demonstrated. Only two children with delayed serum methotrexate clearance showed reversible diffuse EEG slowing of a slight to moderate degree. In the group with additional L-asparaginase treatment, slight transient EEG slowing also occurred. Our findings indicate that in patients with a normal methotrexate clearance during central nervous system treatment with high-dose methotrexate according to trial BFM-ALL 90, usually no subacute or cumulative EEG changes have to be expected. If neurologic or psychiatric symptoms or EEG slowing occur, delayed methotrexate clearance must be suspected.

Use of corticosteroids in neuro-oncology.

Glucocorticosteroids (GC) play an important role in the treatment of neuro-oncologic patients. GC are used for the management of malignant brain tumors, either primary of secondary, neoplastic epidural spinal cord compression (NESC), as adjuvant chemotherapy of some central nervous system tumors and perioperatively in brain surgery. GC are believed to exert their influence on brain tumors mainly by reducing the tumor-associated vasogenic edema, probably by decreasing the increased capillary permeability of the blood-brain barrier (BBB). Experimental as well as clinical studies applying computed tomography, magnetic resonance and PET have supported these theories. However, other mechanisms have been proposed and investigated, such as a reduction of cerebral blood flow and oncolytic effects, the latter being controversial. The effect of GC is best observed in patients with cerebral metastases and gliomas. Studies on the effect of non-steroidal anti-inflammatory drugs (NSAIDs) gave conflicting results. Although some prefer methylprednisolone, dexamethasone is the GC given in the majority of neuro-oncologic patients, at an empirically chosen dosage of 4 mg qid. Dose-effect studies in patients with cerebral metastases as well as in patients suffering from NESC have been performed and lower doses in a twice daily regime may be sufficient. Side-effects may be divided in three groups: those originating from the mineralocorticoid activity, the withdrawal of the drug and the chronic excess GC administration. Steroid myopathy is the most frequent occurring serious side-effect in neuro-oncologic patients. Others include gastrointestinal perforation and hemorrhage, opportunistic infections, steroid diabetes, and skin and facial changes. The most important interaction is that with phenytoin. The influence of dexamethasone on the effects of chemotherapy and radiotherapy is also discussed. New developments in GC treatment include the local administration of dexamethasone.