MDB-04. Long-Term Outcome of the Milano Strategy for High-Risk Medulloblastoma, Including the Impact of Molecular Subtype

Abstract BACKGROUND Since 2008 we have been using the same strategy as for M+ medulloblastoma for all other high-risk subgroups(LC/A histology,TP53 mutations,and/or MYC/MYCN amplification). METHODS After surgery,patients 3-year-old received staging/histo-biological revision and sequential HD-methotrexate,HD-VP16,HD-Cyclo,HD-Carbo.HART-CSI,in two daily 1.3 Gy-fractions/5-days-a-week, reached doses tailored to age and pre-radiation response to chemotherapy:31.2 Gy under 10 years-old if CR+PR or no metastases,39 Gy in other/older patients.Boosts to posterior fossa/residual M+ deposits were given reaching total doses of 59.7–60 Gy and 9 Gy,respectively and avoided if metastatic nodules very big or patients very young.Two courses of high-dose thiotepa were delivered in case of not-optimal response after pre-RT phase and in all M0 patients either in pre/post-RT phase.Subgrouping was obtained through IHC and methylation EPICv2.0 in rescued samples. RESULTS Patients were 89,median age 8.8 years,64 males,median fup 136 months. OS/PFS/EFS at 5/15-years were 75.9/66.5%,71.1/69.8%,68.2/65.3%,respectively; 6/28 fatal events were not correlated to medulloblastoma relapse(four 2nd tumors).Sex,age below 10/over 15 years, post-sugical residues,histological subtype(#24 LC/A,#57 classic,#7 nodular-desmoplastic),MYC amplification(#17),CSI dose reduction(#31),absence of boosts(#16),use of myeloablative courses(#45),presence/absence of metastases(#77 M+) did not impact prognosis.Patients progressing after pre-HART chemotherapy(#14) and SD+PD after HART(# 10) did significantly worse(P0.001)with 1/0 survivors, respectively.Subgrouping done in 44/89 patients so far,showed significant worse PFS/EFS for patients with SHH-tumors(#11, 2 with constitutional Tp53-mutations) vs. groups3 and 4(11 and 22 patients, respectively).Patients younger than 10 had worse response to CT and less boosts (P=0.03 in both) but could receive lower CSI-doses if stratified according to CT-response. CONCLUSIONS This strategy, partly adopted in the ongoing SIOPE protocol, confirmed satisfying results in all high-risk categories; SHH tumors appeared the most aggressive in this context.