Treatment of young children with CNS-primitive neuroectodermal tumors/pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy

Abstract

Background: Especially in young children, primitive neuroectodermal tumors of the central nervous system (CNS-PNET) and pineoblastomas are associated with an unfavorable outcome, and only a few prospective trials have been conducted thus far.

Methods: From January 2001 through January 2005, 17 eligible children aged <4 years with CNS-PNET not otherwise specified (n = 8), ependymoblastoma (n = 1), or pineoblastoma (n = 8) confirmed by central review were prospectively treated in the trial HIT 2000. In nonmetastatic disease (n = 11), up to 5 postoperative cycles of HIT-SKK systemic multiagent chemotherapy (8 months duration), followed by craniospinal radiotherapy (CSI), were given. In metastatic disease (M1-M3, n = 6), treatment consisted of a shorter induction chemotherapy (2-3 months) with carboplatin and etoposide, followed by tandem high-dose chemotherapy (HDCT) in case of good response to induction. During induction and HDCT, patients received intraventricular methotrexate. CSI was applied to all patients with poor response to induction or residual disease after HDCT and was optional for patients with residual disease before HDCT.

Results: Five-year event-free survival and overall survival rates ± standard error for all eligible patients were 24% ± 10% and 40% ± 12%, respectively (median follow-up of survivors: 8.3 years). Only one patient with nonmetastatic disease remained free of relapse/progressive disease during induction. Three of 6 patients with metastatic disease responded to induction and received tandem-HDCT, followed by preventive CSI, and remain in continuous complete remission.

Conclusions: Short intensive induction chemotherapy followed by tandem-HDCT in young children with CNS-PNET/pineoblastomas seems to be superior to the prolonged and less intensive induction regimen.

Fig. 1.

Treatment schedule for patients with CNS-PNET/PBL who were treated in the standard SKK treatment arm (nonmetastatic disease) or in the intensified therapy arm (metastatic disease). Abbreviations: HDCT, high-dose chemotherapy; MTX i. ventr., intraventricular methotrexate; PBSCT, peripheral blood stem cell transplantation.

Fig. 2.

Flow diagram of patients showing the response to primary treatment. Abbreviations: CCR, continuous complete remission; CR, complete remission; GBM, glioblastoma multiforme; HDCT, high-dose chemotherapy; LFU, lost to follow-up; MTX i. ventr., intraventricular methotrexate; PD, progressive disease; PR, partial remission; SD, stable disease.

Fig. 3.

Survival of young children aged <4 years at time of diagnosis of CNS-PNET or pineoblastoma. Kaplan–Meier estimates for event-free survival (EFS; panel A), overall survival (OS; panel B), and craniospinal radiotherapy-free survival (CSI-free survival; Panel C).

Fig. 4.

Survival according to treatment arms. Event-free survival (EFS; panel A) and overall survival (OS; panel B) tended to be higher in the group of metastatic patients who received intensified chemotherapy (n = 6) compared to patients with nonmetastatic disease treated with standard SKK (n = 11) (5-year EFS 50 ± 20 vs 9 ± 9, respectively; and 5-year OS 67 ± 19 vs 27 ± 13, respectively).

Fig. 5.

Survival in relation to craniospinal irradiation (CSI). Overall survival of patients receiving CSI after failure to primary treatment (Salvage; n = 8) was not different to that of patients not receiving CSI (None; n = 6), of whom all but one patient had failure to primary treatment (P = .436). All patients receiving preventive CSI were in complete remission after the intensified treatment and survived (Preventive; n = 3).