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Disseminating Necrotizing Leukoencephalopathy Associated With Intra-CSF Methotrexate Chemotherapy: A Retrospective
Ki Hoon Kim1, Moowan Park1, Eun Young Park1
1From the Department of Neurology (K.H.K., S.-H.K., J.-W.H., H.J.K.), Department of Neurosurgery/Neuro-oncology Clinic (M.P., H.-S.G., Y.-S.D., S.-H.S., H.Y., K.C.W.), Biostatistics Collaboration Team (E.Y.P.), Department of Cancer Control (H.-S.G.), Graduate School of Cancer Science and Policy, and Department of Radiology (J.W.S.), Research Institute and Hospital of National Cancer Center, Goyang, South Korea.
Background And Objectives:
Leptomeningeal metastases (LMs) are neoplasms that proliferate to membranes lining the brain and spinal cord. Intra-CSF methotrexate (MTX) chemotherapy is a prevalent treatment option. However, resultant long-term neurotoxicity can lead to irreversible disseminated necrotizing leukoencephalopathy (DNL). This study aims to determine the incidence, characteristics, risk factors, and outcomes of DNL following intra-CSF MTX chemotherapy for LM.
Methods:
We retrospectively reviewed patients with LM who received intra-CSF MTX between 2001 and 2021 at the National Cancer Center of Korea. Patients with a follow-up duration of <3 months and those without follow-up MRI after MTX administration were excluded. The primary outcome was the development of DNL, evaluated based on the clinical and radiologic definitions of DNL. Logistic and Cox proportional regression models were used to assess the risk of DNL in patients with LM receiving intra-CSF MTX chemotherapy.
Results:
Of the 577 patients included in the DNL investigation, 13 (2.3%) were identified to have irreversible DNL. The MRI features of DNL typically include necrotic changes in the bilateral anterior temporal region, extensive white matter, and/or brainstem lesions. All patients with DNL experienced fatal clinical course despite MTX cessation. Logistic regression analysis revealed that a cumulative dose of MTX significantly affected DNL occurrence. Multivariable analysis showed that the factor of ≥10 MTX rounds was significant for DNL development after adjusting for route of MTX administration and prior brain radiotherapy (odds ratio 7.32, 95% CI 1.42-37.77 at MTX rounds ≥10 vs < 10). In the Cox proportional hazards model considering time to occurrence of DNL, ≥10 rounds of MTX were identified as an independent predictor of DNL (hazard ratio 12.57, 95% CI 1.62-97.28, p = 0.015), even after adjusting for the synergistic effect of brain radiotherapy.
Discussion:
DNL is a rare but fatal complication of intra-CSF MTX chemotherapy, and its progression cannot be prevented despite early recognition. The cumulative dose of intra-CSF MTX was an independent risk factor for DNL occurrence. Thus, intra-CSF MTX treatment for patients with LM should be administered with caution considering the possibility of the cumulative irreversible neurotoxicity.
Insights
Disseminated necrotizing leukoencephalopathy (DNL) is a rare, fatal complication of intra-CSF methotrexate (MTX) chemotherapy for leptomeningeal metastases (LM). A cumulative dose of MTX, particularly ≥10 rounds, significantly increases DNL risk.
Area of Science:
- Neuro-oncology
- Chemotherapy
- Neurotoxicity
Background:
- Leptomeningeal metastases (LM) are cancers spreading to the brain and spinal cord linings.
- Intra-CSF methotrexate (MTX) is a common treatment, but can cause severe neurotoxicity.
- Disseminated necrotizing leukoencephalopathy (DNL) is a potentially irreversible complication of this treatment.
Purpose of the Study:
- To determine the incidence and characteristics of DNL after intra-CSF MTX for LM.
- To identify risk factors and outcomes associated with DNL development.
- To inform cautious administration of intra-CSF MTX chemotherapy.
Main Methods:
- Retrospective review of 577 patients with LM treated with intra-CSF MTX (2001-2021).
- Exclusion of patients with <3 months follow-up or no post-MTX MRI.
- Logistic and Cox regression models used to assess DNL risk factors.
Main Results:
- 13 patients (2.3%) developed irreversible DNL.
- DNL MRI features include bilateral anterior temporal necrotic changes and white matter lesions.
- Cumulative MTX dose, especially ≥10 rounds, was a significant independent predictor of DNL (HR 12.57).
Conclusions:
- DNL is a rare but fatal complication of intra-CSF MTX chemotherapy.
- Progression of DNL cannot be prevented even with early recognition.
- Cumulative intra-CSF MTX dose is an independent risk factor, necessitating cautious treatment administration.
