Late effects of high-dose methotrexate treatment in childhood cancer survivors—a systematic review

Abstract

Background High-dose methotrexate (HD-MTX) is used in the treatment of different childhood cancers, including leukemia, the most common cancer type and is commonly defined as an intravenous dose of at least 1 g/m2 body surface area per application. A systematic review on late effects on different organs due to HD-MTX is lacking. Method We conducted a systematic literature search in PubMed, including studies published in English or German between 1985 and 2020. The population of each study had to consist of at least 75% childhood cancer survivors (CCSs) who had completed the cancer treatment at least twelve months before late effects were assessed and who had received HD-MTX. The literature search was not restricted to specific cancer diagnosis or organ systems at risk for late effects. We excluded case reports, case series, commentaries, editorial letters, poster abstracts, narrative reviews and studies only reporting prevalence of late effects. We followed PRISMA guidelines, assessed the quality of the eligible studies according to GRADE criteria and registered the protocol on PROSPERO (ID: CRD42020212262). Results We included 15 out of 1731 identified studies. Most studies included CCSs diagnosed with acute lymphoblastic leukemia (n = 12). The included studies investigated late effects of HD-MTX on central nervous system (n = 10), renal (n = 2) and bone health (n = 3). Nine studies showed adverse outcomes in neuropsychological testing in exposed compared to non-exposed CCSs, healthy controls or reference values. No study revealed lower bone density or worse renal function in exposed CCSs. As a limitation, the overall quality of the studies per organ system was low to very low, mainly due to selection bias, missing adjustment for important confounders and low precision. Conclusions CCSs treated with HD-MTX might benefit from neuropsychological testing, to intervene early in case of abnormal results. Methodological shortcomings and heterogeneity of the tests used made it impossible to determine the most appropriate test. Based on the few studies on renal function and bone health, regular screening for dysfunction seems not to be justified. Only screening for neurocognitive late effects is warranted in CCSs treated with HD-MTX.

Neurocognitive outcomes of children with osteosarcoma treated with methotrexate

“…High‐dose methotrexate (HD‐MTX) therapy impairs neurocognitive outcomes in patients with childhood cancer 1 . There have been multiple reports of cognitive dysfunction after chemotherapy in patients with acute lymphoblastic leukemia (ALL), including those who had not received cranial radiation therapy 2 .…”

“…High-dose methotrexate (HD-MTX) therapy impairs neurocognitive outcomes in patients with childhood cancer. 1 There have been multiple reports of cognitive dysfunction after chemotherapy in patients with acute lymphoblastic leukemia (ALL), including those who had not received cranial radiation therapy. 2 As the cumulative dose of MTX used for standard osteosarcoma treatment is higher than that used for the treatment of ALL, we prospectively evaluated cognitive function in pediatric patients diagnosed with osteosarcoma.…”

Approaches to Minimise the Neurodevelopmental Impact of Choroid Plexus Carcinoma and Its Treatment

“…Methotrexate and cytosine arabinoside (araC) are toxic to the central nervous system (CNS), with both acute toxicity and worsened subsequent neurocognitive performance having been well-documented, correlating with leuko-encephalopathic changes on magnetic resonance imaging (MRI) scanning [ 50 ]. Children treated with high-dose intravenous methotrexate show significantly worse performance in neurocognitive testing, especially on the subscales of processing speed, memory, and sustained attention [ 51 ]. Children receiving intrathecal methotrexate performed worse in testing of intelligence, executive function, attention, visual perception, and short-term memory in comparison with those who did not have intrathecal treatment [ 52 ].…”

Is Methotrexate Ototoxic? Investigating the Ototoxic Late Effects of Pediatric Cancer Treatment

“…Subacute MTX neurotoxicity typically occurs 2–14 days after prolonged low-dose oral, intrathecal, or high-dose MTX and manifests with transient stroke-like symptoms, encephalopathy, seizures, and/or aphasia. Late effects may include seizures, memory loss, and problems related to academic achievement and attention ( Bhojwani et al, 2014 ; Daetwyler et al, 2022 ). Although the late effects of MTX treatment have been recognized for years, the mechanism of its pediatric neurotoxicity is not well understood ( Daetwyler et al, 2022 ).…”

“…Late effects may include seizures, memory loss, and problems related to academic achievement and attention ( Bhojwani et al, 2014 ; Daetwyler et al, 2022 ). Although the late effects of MTX treatment have been recognized for years, the mechanism of its pediatric neurotoxicity is not well understood ( Daetwyler et al, 2022 ). Animal model studies using mice have revealed a decrease in myelin sheath thickness in the white matter of MTX-treated mice and depletion of oligodendrocyte lineage cells compared to controls ( Gibson et al, 2019 ; Mateos et al, 2022 ; Umugire et al, 2022 ).…”