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well as endocrine and neurologic function , strategies to
delay or avoid RT have been reported The present
study focused on strategies combining surgery and HFRT
that were investigated prospectively in children >5 years at
diagnosis.
PATIENTS AND METHODS
Patient eligibility
Postoperative local HFRT was offered to all children with local-
ized intracranial EP seen between November 1996 and December
2002 in centers affiliated with the French Society of Pediatric Oncol-
ogy. The criteria for enrollment included age of 5–17 years at diag-
nosis, EP of any pathologic grade, and written informed consent.
The criteria for exclusion were spinal primary EP, disseminated
EP, previous chemotherapy or RT, relapse, associated disease, re-
fusal, or impossible follow-up. Patients with ependymoblastoma
were not included in this study. The findings were prospectively re-
corded. The primary objective was to determine the 5-year overall
survival (OS) of the patients after surgery and HFRT. Secondary ob-
jectives were to determine the response rate to HFRT when applica-
ble, identify the prognostic factors (especially the value of grading)
and patterns of relapse, and define the rate of sequelae in a homoge-
neous group of patients.
Histologic slides of all patients were reviewed by a qualified pe-
diatric neuropathologist panel (M.M. Ruchoux, A. Lellouch-Tubi-
ana, and A. Jouvet) and classified as Grade 2 (classic) or Grade
3 (anaplastic) according to the absence or presence of signs of ma-
lignancy (i.e., mitoses, necrosis, and neovascularization) according
to the World Health Organization criteria
Treatment characteristics
The extent of resection was rated by the surgeon as incomplete (bi-
opsy or remaining tumor of >1.5 cm3), subtotal (remaining tumor <1.5
cm3), or total (no recognizable residue), as recommended by the Inter-
national Society of Pediatric Oncology Brain Tumor Subcommittee
for the reporting of trials The extent of resection was rated by
the radiologist as complete (CR), partial, or doubtful as determined
from the findings on postoperative craniospinal magnetic resonance
imaging (MRI) or computed tomography (CT) performed as soon as
possible (24–48 h) after surgery. The ratings were reviewed retrospec-
tively by a panel of experts (A. Geoffray and P. Thiesse).
In the case of a CR, 60 Gy HFRT in two daily fractions of 1 Gy (sep-
arated by $6 h) was performed. The target volume was the preopera-
tive tumor volume plus a 1-cm safety margin. RT could be
conformational or not, at the discretion of the group. The photon energy
was $8MeV. No more than 44 Gy was delivered to areas in the occip-
ital region and no more than 60 Gy if more than one-third of the brain
was involved. A customized immobilization device was used for each
patient. The clinical target volumewas defined onCT, withMRI fusion
for the last patients treated, when this procedure was available.
In the case of partial removal, second-look surgery was discussed
before RT. If the second surgical resection was complete, the pa-
tients were treated as described for those with a CR. Otherwise,
an extra boost of 6 Gy was delivered to the residual volume, in ad-
dition to the 60-Gy dose already described. No patient received che-
motherapy in this first line of treatment, because the place of
chemotherapy for this disease is still debated
For patients in relapse, repeat surgery was performed whenever
feasible, unirradiated areas were irradiated, and inclusion in a protocol
of oral etoposide was encouraged.
The rules to stop the study at 2 years were defined as follows:
>30% of relapses among patients with CR and >50% of relapses
or progressive disease in patients with incomplete resection.
Evaluation procedures
The initial screening included brain MRI with and without con-
trast, and three-dimensional measurements of the tumor. Spinal
MRI was performed if the tumor was located in the posterior fossa.
Examination of the cerebrospinal fluid was mandatory only if le-
sions were found on spinal MRI. The quality of the resection was
evaluated using early postoperative imaging by the local physician
during treatment and was centrally reviewed retrospectively.
The clinical examination and MRI were repeated 6 weeks after
treatment to assess the response rate. The response to RT corre-
sponded to a reduction in the size of the residual tumor surface by
>50% on imaging . MRI was repeated every 4 months for 2
years, every 6 months during the third year, and every year for 5
years. Long-term effects ( e.g., audiometric, endocrinal, or psycho-
metric impairment and school or professional difficulties) were
recorded each year.
Statistical analysis
The OS rates, estimated using the Kaplan-Meier method, were
calculated from the date of surgery to death or the date of the last
follow-up visit for patients who were still alive. The progression-
free survival (PFS) rates were estimated from the date of surgery
to the time of documented failure (date of progression for patients
whose disease progressed before achieving complete remission,
date of relapse or date of death for others) or to the date of the last
follow-up visit for those remaining in their first complete remission.
The median follow-up was estimated using the method of Schemper
and Smith . Statistically significant differences in OS and PFS
were tested using the two-tailed log–rank test. Statistical analyses
were performed using Statistical Package for Social Sciences,
version 11.5 (SPSS, Chicago, IL).
RESULTS
Study population
A total of 24 patients from nine Society of Pediatric Oncol-
ogy centers were included. Ten patients were registered but
not included for the following reasons: previous chemother-
apy in 1, relapse in 5, nonbifractionated RT in 1, age <5 years
in 2, and wrong histologic type in 1 (medulloepithelioma).
Because of the low rate of inclusion, the study was stopped
before it reached the expected number for inclusion (n = 40).
The median age was 8.6 years (range, 5–17). Of the 24 pa-
tients, 16 were boys and 8 were girls. The tumor location was
the posterior fossa in 20 patients and supratentorial in 4.
Among the 20 patients with infratentorial EP, 19 underwent
spinal MRI; all findings were considered normal. The histo-
logic grade could be assessed in 23 of the 24 patients; 13 tu-
mors were classified as Grade 2 (classic) and 10 as Grade 3
(anaplastic).
Surgery
Surgical resection, as reported by the neurosurgeon, was
total in 15 patients, subtotal in 8, and partial in 1. One patient
underwent second-look surgery for resection of a postopera-
tive residual mass, after which the surgery was considered
Bifractionated RT in childhood ependymoma d C. CONTER et al. 1537