ID #514 Treatment de-intensification for WNT medulloblastoma: Results from the favourable-risk arm of the SIOP-PNET5-MB study.
François Doz, Martin Mynarek, Véronique Mosseri, Gail Horan, Shivaram Avula, Stefan Pfister, Julien Masliah-Planchon, Laetitia Padovani, Hervé Brisse, Torsten Pietsch, Kim Bull, Rosie Yarrow, Denise Obrecht-Sturm, Regine Riechers, Martin Benesch, Sandra Jacobs, Jaroslav Sterba, Astrid Sehested, Virve Pentikäinen, Anne Vestli, Miguel Alejandro, García Ariza, Magnus Sabel, Nicolas Gerber, Sabine Plasschaert, Mette Jorgensen, Maura Massimino, Steven Clifford, Stefan RutkowskiAbstract
The favourable risk stratum of SIOP-PNET5-MB aimed to confirm good prognosis for children <16 years old with WNT activated R0M0, classic histology medulloblastoma, when treated with reduced dose neuraxis irradiation (CSI) and chemotherapy.
Methods
RT had to start within 40 days post-resection. 18 Gy CSI was delivered, followed by a 36 Gy boost to the tumour region. Six chemotherapy cycles were then administered: 3 A (Cisplatin CCNU Vincristine) and 3 B (Cyclophosphamide Vincristine). Staging, histology, and biological analysis were centrally reviewed. Amended criteria for defining WNT group were beta-catenin mutation combined to isolated monosomy 6 and/or WNT methylation profile. Per-protocol (PP) criteria were: confirmed WNT, RT starting within 40 days after surgery, CSI dose 18 Gy, and no more than six chemotherapy cycles. Both intent to treat (ITT) and PP analysis were performed using a modified Fleming procedure. Quality of survival was assessed by BRIEF, HUI3, PedsQL, and SDQ.
Results
Between 2014 and 2022, 82 patients were included in the ITT, 68 in the PP analysis. Reasons not to include into PP were lack of molecular confirmation of WNT-status (n = 5), start of RT later than d40 (n = 3), CSI-dose >18Gy (n = 5) and >6 chemotherapy cycles (n = 1). With 67 months median follow-up, 3-year EFS was 88.7% [81.8-95.7] (ITT) and 91% [84.2-97.9] (PP). GH treatment was necessary in 7/59 patients; grade 3-4 hearing toxicity was observed in 3/45. TP53 mutation was not associated with prognosis; OTX2 gains were not observed. QoS outcomes at two years post diagnosis suggested poor QoL, health status and fatigue, which was to be expected with this follow-up, whereas executive function and behavioural functioning appeared to be within normal ranges.
Conclusions
Decreased CSI dose to 18 Gy combined with reduced maintenance chemotherapy can be safely used in this population, with some preliminary encouraging data regarding late effects.