Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology

Abstract

This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.

Fig. 1.

Participant flow. AMB, anaplastic medulloblastoma (MB); CCR, continuous complete remission; CMB, classic MB; CR, complete response; CSI, craniospinal radiotherapy; DMB, desmoplastic MB; IMP, improvement; local RT, local radiotherapy; MBEN, MB with extensive nodularity; PD, progressive disease; PR, partial response; R0, complete resection; R+, incomplete resection; SD, stable disease.

Fig. 2.

CONSORT flow chart showing primary treatment of patients. Numbers in parentheses indicate the number of patients with relapse or progressive disease. AMB, anaplastic medulloblastoma (MB); CMB, classic MB; CR, complete response; CSF, cerebrospinal fluid; CSI, craniospinal radiotherapy; DMB, desmoplastic MB; MBEN, MB with extensive nodularity; PD, progressive disease. *Protocol noncompliance was observed in 5 patients.

Fig. 3.

Survival of patients with nonmetastatic medulloblastoma (MB). Kaplan-Meier estimates for event-free survival (EFS; panel A), overall survival (OS; panel B), and radiation (RT)–free survival (panel C).

Fig. 4.

Survival according to histology. Nineteen patients (13 patients with desmoplastic medulloblastoma [DMB)] and 6 patients with medulloblastoma with extensive nodularity [MBEN]) had better event-free survival (EFS; panel A) and overall survival (OS; panel B) rates (5-year rates, 95% ± 5% and 100% ± 0%, respectively) than did 23 patients with classic medulloblastoma (CMB; 30% ± 11% [P < .001] and 68% ± 10% [P = .008], respectively).

Fig. 5.

Survival according to postoperative residual tumor. Thirty-nine patients without residual tumor or with small residual tumor (≤1.5 cm²) had slightly better rates of event-free survival (EFS; 5-year rates, 60% ± 9% vs 33% ± 19%; P = .110) (panel A) and overall survival (OS; 5-year rates, 84% ± 6% vs 50% ± 20%; P = .044) (panel B), compared with 6 patients with residual tumor >1.5 cm².