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METHODS AND MATERIALS
In 1988, the German Pediatric Society for Hematology
and Oncology (GPOH) initiated a cooperative multicenter
trial in Germany and Austria to evaluate the treatment of
malignant brain tumors in childhood. The goals of the
studies were to determine the efficacy of adjuvant chemo-
therapy before irradiation, and to identify prognostic factors
for survival. The study plan was tested in 147 patients in a
pilot trial from March 1989 to February 1990. Since August
1991, 515 children were enrolled in the randomized trial,
which was closed in December 1997.
Eligibility
Children between 3 and 18 years of age with newly
diagnosed intracranial medulloblastomas and anaplastic
ependymomas were included in the study; 73 centers par-
ticipated. Diagnosis was made by the institutional patholo-
gist according to the World Health Organization (WHO)
classification of brain tumors (11), but a central review was
also required. Informed consents for all children were
signed by their parents or legal guardians.
Evaluation of disease
Prior to surgery, the children had computed tomography
(CT) or magnetic resonance imaging (MRI) scans of the
brain and entire spine as well as neurologic examinations.
Postoperatively, CT or MRI scans were performed within
72 hours of resection, and the cerebrospinal fluid (CSF) was
evaluated before the start of the adjuvant regimen. MRI or
CT scans were obtained again after radiotherapy and che-
motherapy and 4 months after the completion of treatment.
Thereafter, imaging was performed every 6 months. Neu-
roradiologic imaging findings were also submitted to a
central review committee.
Treatment protocol
Surgery.
The resection was performed as totally as pos-
sible without risking major impairment. Verification of his-
tologic diagnosis was mandatory.
Chemotherapy.
In HIT 88/89, the children were treated
postoperatively with preirradiation (“sandwich”) chemo-
therapy. In HIT 91, children were randomized to receive
either immediate radiotherapy followed by maintenance
chemotherapy or preirradiation chemotherapy followed by
radiotherapy (Fig. 1).
Maintenance chemotherapy.
During irradiation, vincris-
tine (VCR) was administered intravenously once a week
(1.5 mg/m
2
). Chemotherapy was started 6 weeks after the
end of irradiation and consisted of eight cycles given every
6 weeks. The chemotherapy comprised cisplatin (70 mg/m
2
iv on day 1), CCNU (75 mg/m
2
orally on day 1), and VCR
(1.5 mg/m
2
iv on days 1, 8, and 15).
Preirradiation (“sandwich”) chemotherapy.
Chemother-
apy was administered starting 14 days after surgery. It was
given in two cycles and consisted of the following agents:
ifosfamide (3 g/m
2
iv on days 1–3) and etoposide (150
mg/m
2
iv on days 1–3) during weeks 3 and 10, methotrexate
(MTX) (5 g/m
2
iv continuously), and citrovorum-factor
(CF-rescue) during weeks 5, 6, 12, and 13 and cisplatin (40
mg/m
2
iv days 1 to 3) and cytarabine (400 mg/m
2
iv days 1
to 3) during weeks 7 and 14. In the event of disease
progression during chemotherapy, radiotherapy was started
immediately. Otherwise, radiotherapy was started 3 weeks
after the last day of chemotherapy.
Radiotherapy.
All infratentorial and metastatic tumors
were to be treated by irradiation of the neuraxis followed by
an additional boost to the posterior fossa. For supratentorial
ependymomas, the treatment volume was to encompass the
tumor site only, unless the tumor was in contact with the
ventricular system. Radiotherapy was started 4 weeks after
“sandwich” chemotherapy or 3 weeks after surgery.
The prescribed total dose for the neuraxis was 35.2 Gy
(1.6 Gy per fraction, five times per week). The posterior
fossa was to receive a boost dose of 20.0 Gy given in 2.0-Gy
fractions. Lesions in patients with spinal metastases were to
be irradiated with a total dose of 50.0 Gy. No increase in
dose was recommended for patients with positive CSF
cytologic findings. In the event of a limited-volume irradi-
ation, the tumor site was to receive a total dose of 54.0 Gy
at 2.0 Gy per fraction.
Statistical considerations
The data for patients with anaplastic ependymomas, as
confirmed by the treating center and in part validated by the
reference pathology, included in the HIT 88/89 and HIT 91
trials, served as the basis for the statistical evaluation of the
prognostic factors for survival. These patients were treated
by 33 centers between 1989 and 1997. The documentation
of disease in patients was performed by the treating centers;
the center monitoring the clinical data was the Children’s
Fig. 1. Treatment schedules of chemotherapy and radiotherapy in
trials HIT 88/98 and HIT 91. OP, resection; chx, chemotherapy;
Ifo, ifosfamide; VP-16, etoposide; Mtx, Methotrexate; Cisp, Cis-
platin; CSI, craniospinal irradiation; VCR, vincristine.
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I. J. Radiation Oncology
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Biology
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Physics
Volume 46, Number 2, 2000