Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort
Authors: Mynarek Martin , von Hoff Katja , Pietsch Torsten , Ottensmeier Holger , Warmuth-Metz Monika , Bison Brigitte , Pfister Stefan , Korshunov Andrey , Sharma Tanvi , Jaeger Natalie , Ryzhova Marina , Zheludkova Olga , Golanov Andrey , Rushing Elisabeth Jane , Hasselblatt Martin , Koch Arend , Schüller Ulrich , von Deimling Andreas , Sahm Felix , Sill Martin , Riemenschneider Markus J. , Dohmen Hildegard , Monoranu Camelia Maria , Sommer Clemens , Staszewski Ori , Mawrin Christian , Schittenhelm Jens , Brück Wolfgang , Filipski Katharina , Hartmann Christian , Meinhardt Matthias , Pietschmann Klaus , Haberler Christine , Slavc Irene , Gerber Nicolas U. , Grotzer Michael , Benesch Martin , Schlegel Paul Gerhardt , Deinlein Frank , von Bueren André O. , Friedrich Carsten , Juhnke Björn-Ole , Obrecht Denise , Fleischhack Gudrun , Kwiecien Robert , Faldum Andreas , Kortmann Rolf Dieter , Kool Marcel , Rutkowski Stefan 
Published: April 2020

PURPOSE The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.