paediatrics Brussels 17

I. J. Radiation Oncology ● Biology ● Physics

288

Volume 46, Number 2, 2000

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

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.

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