Exclusive Hyper-fractionated Radiotherapy and reduced boost volume for standard-risk medulloblastoma: pooled analysis of the two French multicentric studies MSFOP98 and MSFOP 2007 and correlation with molecular subgroups

Abstract Purpose Medulloblastoma has recently been characterized as a heterogeneous disease with four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), group 3 and group 4, with new definition of risk stratification. We report progression-free survival, overall survival, and long-term cognitive effects in children with standard–risk medulloblastoma exclusively treated with hyper-fractionated radiotherapy (HFRT), reduced boost volume, online quality control, and we explore the prognostic value of biological characteristics in this chemotherapy-naive population. Patients and Methods Patients with standard–risk medulloblastoma enrolled in two successive prospective multicentric studies MSFOP 98 and MSFOP 2007 received exclusive HFRT (36Gy, 1Gy/fraction BID) to the cranio-spinal axis followed by a boost at 68Gy restricted to the tumor bed (1.5 cm margin), with online quality assurance prior to treatment. Patients with MYC or MYCN amplification were not excluded at the time of the study. We report PFS and OS in the global population, and according to molecular subgroups as per WHO 2016 molecular classification, and present cognitive evaluations based on Wechsler scale. Results Data from 114 patients included in the MSFOP 98 trial from Dec 1998 to Oct 2001 (N= 48), and in the MSFOP 2007 from Oct 2008 to July 2013 (N= 66) were analyzed. With a median follow-up of 16.2 (range 6.4–19.6) years for the MSFOP 98 cohort and of 6.5 (1.6–9.6) years for the MSFOP2007 cohort, 5-year overall survival (OS) and progression-free survival (PFS) in the global population were 84% (74-89) and 74% (65-81) respectively. Molecular classification was determined for 91 (WNT [N=19], SHH [N=12], and Non-WNT/non-SHH [N=60] –including Group 3 [N=9], Group 4 [N=29], not specified [N=22]). Our results showed more favorable outcome for WNT-activated subgroup and a worse prognosis for SHH-activated patients. Three patients had isolated extra-CNS relapse. The slope of neurocognitive decline in the global population was shallower than that observed in patients with normo-fractionated regimen combined with chemotherapy. Conclusion HFRT led to 5 year-survival rate similar to other treatments combined with chemotherapy, with a reduced treatment duration of only six weeks. We confirm MSFOP 98 results, and the prognostic value of molecular status in patients with medulloblastoma, even in the absence of chemotherapy. IQ is more preserved in children with medulloblastoma who received exclusive HFRT and reduced local boost, IQ decline is delayed compared with patients receiving standard regimen. HFRT may be appropriate for patients who do not consent or are not eligible to prospective clinical trials or for patients from developing countries for whom aplasia or ileus may be difficult to manage, in a context of high cost/effectiveness constraints and for whom shortened duration of RT may be easier to implement.