1592 / 1708
viously reported perioperative mortality rate of 17% (24,
40) was diminished to 0% in our study.
Chemotherapy
The effectiveness of adjuvant chemotherapy is difficult to
assess in our study because all patients received either
maintenance or sandwich chemotherapy. However, former
trials have failed to show a survival advantage for chemo-
therapy, including the SIOP (Societe´ Internationale Oncolo-
gie Pediatrique) and the Children’s Cancer Study Group
trials (7, 16, 24, 37, 41, 42), but many patients with low-
grade ependymomas also were enrolled in these studies,
which could influence the results. Ependymomas have been
shown to respond to chemotherapy (43–46). In particular,
Needle
et al.
(34) reported in 1997 a survival benefit for
adjuvant chemotherapy consisting of carboplatin, vincris-
tine, ifosfamide, and etoposide, though they also included
hyperfractionated radiotherapy in their treatment strategy.
Ku¨hl
et al.
(47) reported a combined partial and complete
response of 55% for patients with anaplastic ependymomas
in the HIT88/89 trial. However, the chemotherapy admin-
istered in our study population, which consisted of different
agents given in different schedules, did not alter the prog-
nosis in our patients.
Irradiation
Since postoperative irradiation started to be used, the
survival rate has improved from 20% to 60% (5, 6, 9, 16, 48,
49). There is now uniform agreement that craniospinal
radiotherapy is indicated for anaplastic ependymomas (21,
50) and useful in preventing spinal seeding (51). However,
because some authors have reported that spinal seeding
occurs only in infratentorial ependymomas (36, 52), others
have prescribed craniospinal irradiation only for dissemi-
nated and infratentorial tumors. This was the strategy in our
trial and was based on these experiences. According to our
findings, irradiation of the tumor region was sufficient for
localized supratentorial tumors, and the distribution of risk
factors was equivalent in both groups. At present, many
oncologic centers treat localized infratentorial tumors with
limited-volume irradiation to reduce toxicity. The impact of
this approach on the risk of spinal failure is unclear. How-
ever, the low spinal relapse rate observed in our study does
not support this strategy since irradiation of the neuraxis
was an essential part of treatment. An additional consider-
ation in interpreting the findings from previous studies is
that many low-grade ependymomas and also many adults
have been included in some of these series and only a few
children with infratentorial anaplastic ependymomas treated
with local fields were observed for more than 5 years.
In our series, radiotherapy of the craniospinal region in
disseminated disease could not prevent progression despite
irradiation of the neuraxis, thereby suggesting a need to
intensify treatment.
Another irradiation parameter is the dose level. Retro-
spective series indicate that doses greater than 45 Gy have
to be delivered to the primary site (48, 49, 52, 53). Merchant
et al.
(15), who studied exclusively anaplastic ependymo-
mas, found that by increasing the dose to the primary site,
the outcome was positively influenced. We were unable to
analyze the dose–response relationship for survival, how-
ever, because the majority of the children were treated with
a very small dose range (42–55.8 Gy) to the primary site,
similar to the treatment approach used in the study of
Rousseau
et al.
(6), who also could not demonstrate a
difference. Recent advances in radiotherapy techniques
have as their aim improvements in the therapeutic ratio in
childhood brain tumors by adding potentially more effective
strategies that increase tumor control and limit radiation
toxicity. For example, hyperfractionated radiotherapy has
the potential of safely increasing the dose to the tumor while
sparing late effects (54). Pilot studies of hyperfractionated
radiotherapy in medulloblastomas have revealed excellent
tumor control of up to 95% in such patients with acceptable
acute toxicity (55, 56). A Children’s Cancer Group Phase
I/II trial investigated the effectiveness of hyperfractionated
radiotherapy in brainstem gliomas with total doses of 78 Gy
(57); although the survival rate remained poor, the treatment
modality was tolerated relatively well with a prolonged
need for steroid treatment and intralesional necrosis the only
drawbacks. Another advance in radiotherapy is fractionated
stereotactic irradiation, which focuses the dose on the tumor
while sparing surrounding normal tissue, thus allowing bet-
ter local dose escalation. Local dose intensification by ra-
diosurgery might be a valuable approach, although data for
children with CNS malignancies are scant . Grabb
et al.
(58)
evaluated the role of stereotactic radiosurgery in 25 children
with inoperable brain tumors, of whom 7 had ependymo-
mas. The results in these patients with ependymomas were
discouraging, but the authors (58) proposed that the therapy
might be more effective if administered as part of primary
treatment. Loeffler
et al.
(59) performed radiosurgery in 2
patients with ependymomas, both of whom were in com-
plete remission 13 and 5 months after therapy.
CONCLUSIONS
The multimodal regimen used in the present study, con-
sisting of adjuvant combined irradiation and chemotherapy,
is effective in the treatment of anaplastic ependymomas in
childhood. The predominant site of failure is the region of
the primary tumor. The only significant predictive factors
for overall and progression-free survival are the extent of
resection and the dissemination of tumor at presentation.
Therefore, exact staging techniques, including MRI of the
brain and spine and cytologic studies of the CSF, are indis-
pensable. Irradiation of the tumor site is sufficient for the
treatment of localized supratentorial tumors. Whether this
procedure is also sufficient for infratentorial ependymomas
requires further studies to reduce toxicity. The prognosis
remains very poor for patients with residual disease. In
addition, because of the high frequency of local recurrence,
it might be appropriate to intensify local treatment by using,
for example, hyperfractionated schedules or a stereotactic
293
Anaplastic ependymomas in childhood
●
B. T
IMMERMANN
et al.