Abstract
BackgroundSerious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. The objective was to assess the incidence of NAE related to high-dose thiotepa and to identify potential contributing factors that could exacerbate the occurrence of this neurotoxicity.MethodsFrom May 1987 to March 2011, children with solid tumours treated with high-dose thiotepa were retrospectively identified. Each NAE detected led to an independent case analysis. Potential contributing factors were pre-specified and univariate/multivariable analyses were performed.ResultsThree hundred seven courses of thiotepa (251 patients) were identified. The total dose per treatment ranged from 600 to 900 mg/m2. 81 NAE (26%) were identified. 46 NAE were related to high-dose thiotepa during the first course (18.3%) and 11 during the second course (19.6%). The symptoms appeared in a median time of 2 days after the introduction of thiotepa. Central and peripheral symptoms were headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. High-dose thiotepa was reintroduced in 18 cases and symptoms reappeared in 5 children. For 3 patients who had seizures during the first course, premedication with clonazepam for the second course has prevented recurrence of NAE. As contributing factors, brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively.ConclusionsThe incidence of neurotoxicity was 18.3%. Brain tumours and tramadol treatment are risk factors to consider when using high-dose thiotepa. The outcome of patients was favourable without sequelae in all cases and rechallenge with thiotepa was possible.
Highlights
Serious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours
Brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively
Little is known about the possible relationship between exposure to high-dose thiotepa and the occurrence of neurological disorders
Summary
Serious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has improved the survival of Maritaz et al BMC Cancer (2018) 18:177 children with high-risk solid tumours. Its major metabolite tepa, has similar alkylating activity [10, 11]. This hepatic biotransformation is mediated by CYP3A4 and CYP2B6, and conjugation is catalyzed by glutathione Stransferase (GST) [12, 13]. Due to its metabolic profile, concomitant administration of thiotepa with CYP3A4 or CYP2B6 inhibitors may increase plasma thiotepa concentrations and potentially decrease the concentrations of the active metabolite tepa. Concomitant administration of thiotepa with CYP3A4 or CYP2B6 inducers may reduce plasma thiotepa concentrations and increase those of tepa. Toxicity to the gastrointestinal and central nervous system is dose-limiting and the maximum tolerated dose (MTD) of thiotepa is between 1005 and 1125 mg/m2 [7, 21, 22]
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