Introduction
Ependymoma, the third most common pediatric central
nervous system tumor following medulloblastoma and astrocytoma, originates from the walls of the ventricular
system or the central canal of the spinal cord.
[,] Almost 90% of pediatric ependymomas are intracranial
in origin and two-thirds are diagnosed in the posterior fossa.[] Ependymomas represent approximately
10% of all childhood brain tumors and have a
male-to-female ratio of 1.77:1.[]
Based on the current WHO classification (2016),
ependymal tumors can be classified as subependymoma
(Grade I), myxopapillary ependymoma (Grade
I), classic ependymoma (Grade II), anaplastic ependymoma
(Grade III), and RELA-fusion-positive ependymoma
(Grade II/III).[] This classification scheme has
limited clinical utility in predicting patients" results,
therefore a modern molecular system has been suggested
that separated intracranial ependymomas into
six distinct subgroups. Supratentorial ependymomas
were divided into three groups, such as YAP1, RELAfusion
anaplastic ependymoma, and subependymoma.
The three posterior fossa ependymoma (PF-EPN)
subgroups were PF-EPN-A, PF-EPN-B, and PF-SE
(subependymoma).[]
A multidisciplinary approach is required in the
management of pediatric intracranial ependymomas.
Although surgery and post-operative radiotherapy
(RT) are accepted standard of care for patients with
non-disseminated ependymoma to reduce the risk of
local recurrence, the role of chemotherapy in ependymoma
remains unproven despite large clinical trials.[]
A post-operative magnetic resonance imaging (MRI)
at no more than 3 days after surgery is indicated to detect
extent of resection. A lumbar puncture performed
at least 14 days postoperatively to exclude false-positive
results, will determine spinal metastasis and guide
management.[] Craniospinal RT is required in the
presence of spinal metastasis.[]
The purpose of this study was to assess the effect of
prognostic factors and treatment on progression-free
survival (PFS) and overall survival (OS) in childhood
intracranial ependymoma.
Methods
This retrospective study was undertaken after approval
from our institutional ethics committee. A total of 28
patients, 15 males and 13 females, who received postoperative
RT due to pediatric intracranial ependymoma
between 2000 and 2020, were analyzed in this
study. Inclusion criteria were patient age younger than
18 at the time of diagnosis, patients with confirmed
histopathological diagnosis of Grade II/III intracranial
ependymoma, and patients with no previous history
of brain irradiation. Grade I ependymomas, spinal
ependymomas, patients with severe comorbid disease, and patients with incomplete medical charts were not
included in the study.
We evaluated patients" medical records, such as patient
demographics, clinical procedures, localization of
the tumor identified by neuroimaging, operation type,
histopathologic results, and treatment modalities (i.e.,
RT and chemotherapy) applied postoperatively. The
extent of surgical resection was determined based on
the surgeon"s operative report and/or post-operative
MRI as gross total resection (GTR) or subtotal resection
(STR). Spinal MRI and lumbar puncture were
done in the post-operative period to reveal the presence
of spinal seeding metastasis.
Radiation therapy was applied to all patients. Craniospinal
RT was administered to patients with spinal
seeding metastasis. Patients received conformal RT or
intensity-modulated RT with a linear accelerator device.
During RT planning, gross tumor volume was
created by cross-section drawing in contouring tomography
through pre-operative and post-operative MRI.
Clinical target volume (CTV) was created by giving
0.5-1 cm margin to tumor bed, and planning target
volume (PTV) was created by giving 0.3-0.5 cm margin
to CTV. During the planning, when critical levels
of organs at risk volumes were exceeded, manual corrections
of PTV volume up to 0.3 cm were made.
All patients were evaluated clinically and radiographically
at routine follow-up intervals. Patients who
did not visit hospital for follow-up were called through
telephone at the data cutoff point to determine their
final status. Progression was diagnosed by clinical assessment,
neuroimaging, and pathology reports. PFS
was defined as the duration between diagnosis and
the first event of recurrence or tumor progression, and
OS was defined as the duration between diagnosis and
death or last known date of the patients" survival.
All statistical analyses were performed using IBM
SPSS v23.0. Descriptive analyzes were used to classify
patients. PFS and OS were determined using the Kaplan-
Meier method. Possible prognostic factors, such as gender,
histopathological grade, extent of resection, tumor
location, spinal metastasis, and chemotherapy, were also
analyzed. Log-rank test was used to identify predictors of
survival. P<0.05 was considered statistically significant.
Results
Patient characteristics are summarized in Table 1. Median
age at diagnosis was 4 years (range, 1-17 years).
Most of the patients (92.9%, n=26) were 3 years of age or older, and 2 patients (7.1%) were younger than
3 years of age at the time of diagnosis. Ten of the patients
included in the study had supratentorial, and 18
patients had posterior fossa located ependymoma. In
our series 32.1% of patients had Grade II histology, and
67.9% of patients had Grade III histology.
Table 1 Patient characteristics
Treatment parameters for patients are summarized
in Table 2. All children with intracranial ependymoma
underwent surgical resection of the primary tumor.
GTR was achieved in 16 (57.1%), and STR in 12 (42.9%) patients. The median time from initial surgery to RT
was 2.1 months (range, 1-35 months). Twenty-three patients
received only cranial RT and five patients received
craniospinal RT. All patients" median cranial dose was
54 Gy (range, 45-60 Gy), and spinal dose of five patients
who received craniospinal RT was 36 Gy. Daily fractionation
was used with a median dose of 1.8 Gy (range,
1.6-2.0 Gy). Fourteen patients (50%) received chemotherapy
either concurrently, adjuvantly, or both.
Table 2 Treatment parameters for patients
Eighteen (64.2%) patients suffered disease progression.
The median time from diagnosis to progression
was 46.7 months (range, 8-253 months). The 3 and
5-year PFS rates of patients were 66% and 38%, respectively.
Statistical analysis showed that only the extent
of resection was associated with improved PFS. The
5-year estimated PFS rates in GTR group and STR
group were 57% and 16%, respectively (p=0.04). The
PFS curves for GTR and STR patients are shown in
Figure 1. After progression was detected, only four
patients underwent re-surgery and only two patients
were re-irradiated in our study.
Fig. 1. Progression-free survival curves for all 28 patients
according to the extent of resection.
STR: Subtotal resection, GTR: Gross total resection.
After a median follow-up of 66.9 months (range,
8-253 months), 10 (35.7%) patients were alive with no
evidence of disease; 2 (7.1%) were alive with disease;
and 16 (57.2%) were dead. The 3 and 5-year OS rates
of patients were 88% and 55%, respectively. Statistical
analysis showed that only the extent of resection was
associated with improved OS. The 5-year estimated OS
rates in GTR group and STR group were 78% and 27%,
respectively (p=0.02). The OS curves for GTR and STR
patients are shown in Figure 2.
Fig. 2. Overall survival curves for all 28 patients according
to the extent of resection.
STR: Subtotal resection, GTR: Gross total resection.
Other factors, such as gender, histopathological
grade, tumor location, spinal metastasis, and chemotherapy,
showed no significant effect on PFS and OS
outcomes. The results of statistical analysis of prognostic
factors are summarized in Table 3. No serious
acute or late radiation complication was reported in
the study patients.
Table 3 Prognostic factors for PFS and OS
Discussion
Management of childhood intracranial ependymomas
requires multidisciplinary treatment approaches, and
maximum surgical resection followed by RT is accepted
as the current treatment standard. This recommendation
is based on historical studies showing better
survival results in children receiving post-operative RT
compared to surgery alone, and in GTR group compared
to STR group.[-] In our study, 28 pediatric
intracranial ependymoma cases treated in line with
these suggestions were retrospectively evaluated.
EPNAt
present, it is estimated that complete resection
is achieved in 70-90% of supratentorial ependymomas,
but complete resection is less frequently possible in
patients with infratentorial ependymomas which often are located close to brainstem structures. Several
studies confirmed the crucial role of a GTR in patients
with newly diagnosed ependymomas.[,] However,
the studies of Mansur et al. and Paulino et al.[,]
did not find such a significant difference between total
tumor removal and better survival.
Five-year PFS rates range from 50% to 70% after
GTR and from zero to 30% after STR.[,] Similar to
these reports, 5-year PFS rate was found as 57% in the
GTR group, and 16% in the STR group, in our study
(p=0.04). Five-year OS rates range from 80% to 90%
after GTR and from 50% to 60% after STR.[,] In
our study, 5-year OS rate was found as 78% in the GTR
group, and 27% in the STR group. Aggressive salvage
local treatments for patients with residual disease can
result in good OS. In the AIEOP study, 5 of the 17 patients
with residual disease underwent re-surgery for
potentially resectable tumor after chemotherapy and
none of these operations were followed by persistent
morbidity.[] Similarly, Merchant et al.[] have had
some benefit with re-surgery and the second course of
irradiation in selected patients. As local salvage therapy,
only four patients underwent re-surgery and only
two patients were re-irradiated in our study. The lack
of aggressive salvage treatments may have caused our
5-year OS rate in the STR group to remain lower than
these studies. As a result of our study, it can be suggested
that salvage treatments such as second-look surgery
and re-irradiation should be improved in our institute.
The role of standard histologic classification in
prognosis has been controversial. The second prospective
AIEOP study which was stratified patients to histopathologic
grade and extent of resection reported that
higher 5-year PFS and OS rates among Grade II tumors
(75.3% and 90.5%), compared with Grade III tumors
(57.0% and 73.3%) (p=0.018 in PFS and p=0.031 in
OS).[]. However, Agaoglu et al.[] did not show any
significant difference in OS or PFS between the two histologic
subtypes. Similarly, distinct histological grades
demonstrated no statistically significant differences in
PFS and OS rates in our study. This finding may have
occurred due to the insufficient number of patients.
As a result of advances in genomic, transcriptomic
and epigenomic profiling, different molecular subtypes
have been determined even for ependymomas
of similar histology. Molecular subtypes have unique
clinical characteristics and provide insights into individual
treatment.[] ST-EPN-RELA, which accounts
for more than 70% of supratentorial ependymomas,
occurs generally in children and young adults, and is
associated with a poor prognosis. Conversely, ST-EPN-YAP1 tumor is only seen in very young children and
has a better prognosis.[] The most common and aggressive
subgroup, posterior fossa ependymoma group
A (PF-EPN-A), appears in young children. In contrast,
posterior fossa ependymoma Group B (PF-EPN-B) are
seen in older children and has favorable clinical results.
[] Since the tests required for molecular subtyping
could not be done in our institute, analyzes involving
molecular subtypes were not performed in our study.
Considering that individualized treatments will come
to the fore in the future, molecular subtyping should be
made available in cancer treatment centers.
Several studies have related that patients with supratentorial
ependymomas have indicated better
prognosis compared with patients with infratentorial
location.[,] However, our results and others have
failed to demonstrate a significant difference between
location of tumor and survival.[,] Similar to our
study, Paulino et al. and Tashvighi et al.[,] did not
find such a significant difference between gender and
survival. Conversely, Merchant et al.[] found worse
PFS in male patients (p=0.04).
In our study, 28 patients with pediatric intracranial
ependymoma retrospectively evaluated and 5-year PFS
and OS rates were found 38% and 55%, respectively.
Marinoff et al.[] retrospectively evaluated 103 patients
with median follow-up time of 11 years. They
reported that 5-year PFS and OS rates were 39% and 67% and 10-year PFS and OS rates were 29% and 50%,
respectively. They concluded that current management
is not satisfactory to maintain long-term control of pediatric
intracranial ependymoma, and novel treatment
strategies are required.
The common approach is to deliver 50.4-59.4 Gy to
the tumor bed with a margin. Local control rates are
superior in patients treated with high dose RT, and current
strategies propose 59.4 Gy for the volume at highest
risk for local tumor recurrence.[] The second prospective
AIEOP study evaluated that patients with residual
tumor received chemotherapy, second-look surgery,
and 59.4 Gy RT followed by an 8 Gy boost in two fractions.
They reported that this management tended to
improve the prognosis of patients with residual tumors.
[] Correspondingly, the current SIOP-EP-II trial appraises
the effect of a hypofractionated boost, 8 Gy in
two fractions, to quantitative residual disease after tumor
bed RT in an attempt to improve local control in
this subgroup of children with a poorer prognosis.[]
The benefits of chemotherapy in patients with newly
diagnosed non-metastatic ependymoma remain debate.
In our study, no statistically significant benefit was
observed in terms of OS and PFS in the chemotherapy
group. For patients with ependymoma, chemotherapy
for two cycles is used postoperatively to improve the
ability to perform a second surgery in patients with an
STR. ACNS0121 is the first prospective trial, to suggest the use of chemotherapy and second surgery before
RT. However, the effect of chemotherapy on survival
was not demonstrated in the ACNS0121 trial.[] The
COG trial (ACNS0831, NCT01096368) and the SIOP
trial (EP-II, NCT02265770) were launched to shed light
on the usefulness of adjuvant chemotherapy.[,]
The ACNS0831 trial is primarily evaluating PFS and
OS in children between 1 and 20 years of age with nonmetastatic
newly diagnosed ependymoma treated with
local RT alone versus local RT followed by four cycles
of adjuvant combination chemotherapy with cisplatin,
cyclophosphamide, etoposide, and vincristine.[] The
SIOP-EP-II trial is primarily assessing GTR rate, PFS
and number of treatment responders. In the SIOP-EPII
trial, patients with no evidence of residual disease are
randomly distributed to receive 16 weeks of multiagent
chemotherapy or observation after RT, while patients
with residual disease receive pre-RT conventional chemotherapy
with or without methotrexate and post-RT
conventional chemotherapy.[]
Conclusion
Post-operative RT is an efficient treatment for childhood
intracranial ependymoma. GTR is essential for
longer PFS and OS among pediatric patients diagnosed
with intracranial ependymoma. Better management
will undoubtedly depend on classification according to
the molecular biology of the tumor and tailoring the
treatment to the individual. Future ependymoma trials
should consider molecular classification when determining
treatment indications and patient management.
Acknowledgments: We gratefully thank Deniz Ozel from
Akdeniz University for the statistical analysis used in this
study.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Akdeniz University Faculty of Medicine Clinical Research
Ethics Committee (No: KAEK-95, Date: 05/02/2020).
Financial Support: This study has received no financial
support.
Authorship contributions: Concept - R.A.A.; Design -
E.G., M.G.A.; Supervision - M.G.; Funding - M.G.; Materials
- S.K.; Data collection and/or processing - Y.Ş.; Data
analysis and/or interpretation - R.A.A.; Literature search -
R.A.A., M.G.A.; Writing - R.A.A.; Critical review ? M.G.
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Accessed Nov 15, 2021.
