Long-term outcome of the Milano-hyperfractionated accelerated radiotherapy strategy for high-risk medulloblastoma, including the impact of molecular subtype
Authors: Massimino Maura , Barretta Francesco , Dossena Chiara , Minasi Simone , Buttarelli Francesca Romana , Biassoni Veronica , Oriani Matilde , Schiavello Elisabetta , Ficorilli Marica , Nigro Olga , Pollo Bianca , Antonelli Manila , Donofrio Vittoria , Maggioni Marco , Kool Marcel , Pecori Emilia , Vennarini Sabina , Giangaspero Felice , Gianno Francesca , Erbetta Alessandra , Chiapparini Luisa , Luksch Roberto , Barzanò Elena , Meazza Cristina , Podda Marta , Spreafico Filippo , Terenziani Monica , Bergamaschi Luca , Ferrari Andrea , Casanova Michela , Chiaravalli Stefano , Gattuso Giovanna , Modena Piergiorgio , Bailey Simon , De Cecco Loris 
Published: September 2024

Abstract

Background
We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, and MYC/MYCN amplification.

Methods
Patients over 3 years old received, after surgery, staging and histo-biological analysis, sequential high-dose-methotrexate(HD-MTX), high-dose-etoposide(HD-VP16), high-dose-cyclophosphamide(HD-Cyclo), and high-dose-carboplatin(HD-Carbo). Hyperfractionated-accelerated-radiotherapy–craniospinal(HART-CSI), administered twice daily 1.3 Gy-fractions reached a total dose tailored to the patients’ age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease, 39 Gy in other/older patients. Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy, respectively, but avoided if metastatic nodules were very big or patients were very young. Two courses of high-dose-thiotepa were delivered in case of not CR/PR after the pre-radiotherapy (RT) phase and in all M0 patients either—pre/post-HART. Subgrouping was performed where the tissue was available.

Results
Eighty-nine patients were enrolled, with a median age of 8.8 years, and a median follow-up of 136 months. Overall survival (OS) and event-free survival (EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively; 5/28 fatal events were not related to relapse(3 developed secondary malignancies). Sex, age less than 10 years, histological subtype, presence of MYC/MYCN amplification, reduction in CSI dose, omission of RT-boosts, implementation of myeloablative therapy, presence–absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P &lt; .001).Subgrouping in 66/89 patients’ samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) versus groups 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response.

Conclusions
This strategy, partly adopted in the ongoing SIOPE protocol, confirmed improved EFS and OS over previously reported outcomes in all high-risk categories; SHH tumors appeared the most aggressive.