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)