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Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate
W Boogerd1, J J vd Sande, D Moffie
1Neurological Department of the Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
Abstract:
Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mean time of 5 months and a low mean dose of 44 mg MTX. DNL was also noted in two patients without a previous febrile reaction or whole brain radiotherapy, following prolonged intraventricular MTX therapy after a mean time of 19.5 months and a mean dose of 147 mg MTX. These findings confirm the hazards of (1) high cumulative doses of intrathecal MTX and (2) combined intrathecal chemotherapy and whole brain radiotherapy. This study also suggests a possible relationship between an early and transient febrile reaction during intraventricular administration of MTX and the development of DNL.
Insights
Intraventricular methotrexate (MTX) can cause serious brain damage called disseminated necrotising leukoencephalopathy (DNL). This risk increases with higher MTX doses and combined whole brain radiotherapy.
Area of Science:
- Neuro-oncology
- Chemotherapy Toxicity
- Neuropathology
Background:
- Meningeal carcinomatosis is a serious complication of breast cancer.
- Intraventricular methotrexate (MTX) is used to treat meningeal carcinomatosis.
- Disseminated necrotising leukoencephalopathy (DNL) is a potential neurotoxic complication.
Purpose of the Study:
- To investigate the incidence and risk factors for DNL in patients receiving intraventricular MTX.
- To evaluate the role of MTX dose, duration, and combination therapy with whole brain radiotherapy (WBRT) in DNL development.
Main Methods:
- Retrospective analysis of 14 patients with breast carcinoma and meningeal carcinomatosis treated with intraventricular MTX.
- Correlation of DNL development with MTX dosage, duration, concurrent WBRT, and acute febrile reactions.
Main Results:
- Nine of 14 patients (64%) developed DNL after surviving >4 months.
- All 4 patients receiving both intraventricular MTX and WBRT developed DNL.
- DNL occurred in 5/6 patients with prior acute febrile reactions at lower MTX doses and in 2/8 patients without these factors at higher doses/longer durations.
Conclusions:
- High cumulative doses of intrathecal MTX and combined intrathecal chemotherapy with WBRT are hazardous.
- An early febrile reaction following intraventricular MTX may predict DNL development.
- Careful monitoring and consideration of treatment combinations are crucial to mitigate MTX-induced neurotoxicity.