Discussion
Although multiple drugs have been applied inanition to MTX, the acute neurotoxicity reported in cancer patients who are undergoing therapy is usually attributed to MTX. MTX is associated with clinical or neuroradiological evidence of leukoencephalopathy in survivors with childhood acute lymphoblastic leukemia (ALL) and CNS or head and neck tumors. It is reported that, the impaired low intelligence quotient (IQ) is strongly related to the reduced white matter volume in MB patients treated with chemotherapy and radiotherapy after surgery [7]. A study describes the long-term neurocognitive outcomes of young children with ALL receiving CNS-directed therapy consisting of chemoradiotherapy, high-dose intravenous MTX and very high-dose intravenous MTX in addition to intrathecal therapy. The results show that for young children with ALL, the avoidance of CRT is associated with good long-term neurocognitive outcomes, while the dose of intravenous MTX did not affect these outcomes[8]. As such, it has been recommended to reconsider the use of intrathecal MTX in the treatment of MB since then on.
However, dose these mean MTX intrathecal injection be totally avoided for the treatment of MB patients? Indeed, intrathecal MTX was an independent prognostic factor for good prognosis in our study, even though there was no statistical significance. R0 resection, none diffuse anaplasia histology and M0 status were all the independent predicting factors for good prognosis, as revealed by multivariate Cox proportional hazard analysis. But the p -values of all these three well-known factors showed no statistical significance, which might be correlated with the small sample size of the two groups.
Moreover, to our knowledge, till now, the best 5-year PFS of metastatic MB is 71%, with the addition of carboplatin at 35 mg/m2 for 30 doses before daily radiotherapy[4]. For children with high-risk disease, the 5-year PFS of 62% to 70% has been reported after radiotherapy combined with a variety of chemotherapeutic agents used during and after radiotherapy[7, 9-11]. Typically, a 70% 5-year PFS was reported in the St. Jude prospective study that adopted post-radiotherapy high-dose chemotherapy and stem cell rescue[10]. In our study, the 5-year PFS was 70.99% and 5-year OS was 72.99% for MTX group. To be mentioned, there were 32 patients in MTX group, 28 of whom were included in molecular analyses. Except for the unknown molecular subtype of these 4 patients, none of the remaining cases belonged to WNT subtype, suggesting that about 10% of all MB patients had excellent prognosis[12]. The 5-year PFS for MTX group was 70.99%, which improved upon the previously reported PFS, suggesting a benefit for patients who received intrathecal MTX combined with chemotherapy and radiotherapy. Moreover, our study also reported a good 5-year OS rate, and there were statistically significant differences in the 5-year PFS and 5-year OS between MTX and control groups.
Interestingly, all patients who developed acute leukoencephalopathy were uniformly group 4 MB females. Although the mechanism of MTX-related leukoencephalopathy remains unclear, several mechanisms have been proposed, for instance, certain gene polymorphisms such as single nucleotide polymorphisms in the methylenetetrahydrofolate reductase[13], glutathione S-transferase Pi 1genes[14] and ATP binding cassette subfamily B member 1[15]. Furthermore, a recent study implicates that adenosine receptors and high cumulative dose of systemic MTX administration are significantly associated with MTX-related leukoencephalopathy in patients with hematological malignancies[16]. However, no existing study has focused on the mechanisms of MTA in inducing leukoencephalopathy in MB patients. Leukoencephalopathy during active treatment was referred to as “acute leukoencephalopathy” in our study[17]. The biologic foundation of group 4 tumors is poorly understood, and the key alternation is KDM6A, a histone demethylase. In a study on triple negative breast cancer, recruitment of KDM6A leads to tumor recurrence. Inhibition of adenosine receptors A2BR delays tumor recurrence in vivo[18]. These results show that there may be some interaction between the two genes. It is necessary to delineate the molecular mechanism by which KDM6A is associated with adenosine receptors that leads to a susceptibility to acute leukoencephalopathy in group 4 MB. As such, taking into account the excellent 5-year PFS, it is recommended to add intrathecal MTX to high risk MB patients of both SHH and group 3 subgroups.
Nevertheless, several limitations should be noted in our study. This was a retrospective study, and the sample size (especially for control group) was quite small. Besides, compared with MTX group, patients in control group were diagnosed earlier when surgical techniques were worse in those days. R+ was quite common in control group, and it was impossible to make confident conclusions about the effect of incomplete resection on survival in this small cohort. Besides, long-term neurocognitive outcome data were limited to a small subset of patients.
Conflict of Interest statement: The authors indicated no potential conflicts of interest.
Acknowledgements: We thank for the Project supported by the Natural Science Foundation of Jilin Province, China. (Grant No. YDZJ202201ZYTS128)
Availability of data and materials: Patient’s data were available in medical records room of the first hospital of Jilin university. The datasets generated and/or analysed during the current study are not publicly available due to they are files in medical records room in our hospital, but are available from the corresponding author on reasonable request.
Code availability : Not applicable
Ethics approval: Approved by the Ethical Institution of the first hospital of Jilin university.
Consent to participate: Because of its retrospective manner, informed consent was waived by the Ethical Institution of the first hospital of Jilin university
Consent for publication: Not applicable
Funding: Project supported by the Natural Science Foundation of Jilin Province, China. (Grant No. YDZJ202201ZYTS128 to YT-Z)