Journal Article Epublish
PubMed: 42382416 DOI: 10.1016/j.eclinm.2026.103913
Therapy and biomarker dependent progression-free survival in infant sonic hedgehog medulloblastoma: a multi-national retrospective cohort study.
EClinicalMedicine 96:103913
Authors: Stacey Richardson, Debbie Hicks, Melissa Gough, Ellie R Butler, Dean Thompson, Jemma Castle, Stephen Crosier, Miguel Garcia-Ariza, Idoia Martín-Guerrero, Sabine L A Plasschaert, Franck Bourdeaut, Christelle Dufour, Julien Masliah-Planchon, Francesca Romana Buttarelli, Veronica Biassoni, Maura Massimino, Koichi Ichimura, Yonehiro Kanemura, Vijay Ramaswamy, Amar Gajjar, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Martin Mynarek, Stefan Rutkowski, Edward C Schwalbe, Simon Bailey, Steven C Clifford
Affiliations
- Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
- Biobizkaia Health Research Institute, Pediatric Hematology and Oncology Unit, Hospital Universitario Cruces, Barakaldo, Spain.
- Department of Genetics, Physical Anthropology & Animal Physiology, Biobizkaia Health Research Institute, University of the Basque Country, UPV/EHU, Leioa, Spain.
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
- Paris-Cité University & SIREDO Oncology Center (Pediatric, Adolescent and Young Adults Oncology), Institut Curie, Paris, France.
- Département de Cancérologie de l'Enfant et de l'Adolescent, Gustave Roussy, Paris, France.
- Unité de Génétique Somatique, Institut Curie, Paris, France.
- Dipartimento Scienze Oncologiche Radiologiche Anatomo-Patologiche, Sapienza Universita di Roma, Italy.
- Dipartimento di Ematologia ed Oncoematologica Pediatrica, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
- Department of Pathology, Kyorin University Faculty of Medicine, Tokyo, Japan.
- Department of Biomedical Research and Innovation, Institute for Clinical Research, NHO Osaka National Hospital, Osaka, Japan.
- Department of Neurosurgery, NHO Osaka National Hospital, Osaka, Japan.
- Programme in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
- Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.
- Division of Pediatric Neuro-Oncology (B062), Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany.
- Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
- Department of Pediatric Hematology and Oncology, Heidelberg University Hospital and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.
Abstract
BACKGROUND
Medulloblastoma in infants (iMB; aged < 5 years) presents the challenge of achieving cure while minimising deleterious cranio-spinal irradiation (CSI)-associated late-effects. Non-randomised phase 2 studies have examined upfront CSI omission and chemotherapy intensification for favourable-risk desmoplastic/nodular (DN) tumours associated with the sonic hedgehog (SHH) molecular group (iMB SHH). Comparison of these therapies in large molecularly defined iMB SHH cohorts, alongside investigations of prognostic biomarkers in therapy-specific context, is urgently required to define future therapeutic strategies.
METHODS
In this international retrospective cohort study, a multi-national cohort of molecularly and clinically annotated iMB SHH was assembled from patient datasets in nine countries. Inclusion criteria was a principal iMB SHH group classification using DNA methylation array-based classification. Patient cohorts were assigned into upfront treatment groups based on the receipt of radiotherapy (RTx) or chemotherapy (CTx)-only. Upfront RTx treatment groups were assigned as those receiving focal-RTx or CSI. Upfront CTx only regimens used were classified into three groups to reflect disease treatment conventions: standard-dose, high-dose (intensified regimens of sufficient dosage to require stem cell support) and those including intraventricular methotrexate (IVT-MTX). We investigated molecular pathology, upfront treatments, and relationships to outcome, in this real-world setting. Outcomes of interest were progression-free survival (PFS), overall survival (OS), and post-relapse survival (PRS).
FINDINGS
Between January 20, 2018 and October 6, 2021, patient data from 267 infants with SHH medulloblastoma were collected from Canada (n = 74), Germany/USA (n = 67), and the UK (n = 54), alongside national cohorts collected from France (n = 26), Italy (n = 4), Japan (n = 20), the Netherlands (n = 11), and Spain (n = 33). 226 patients with PFS and OS data comprised the iMB survival cohort and were split into upfront treatment groups based on the receipt of RTx (n = 74, 33%) or CTx-only (n = 132, 58%). Among iMB SHH patients treated upfront with CTx-only regimens, IVT-MTX therapy (5-year PFS, 72.6%; n = 72) or high-dose therapy (73.0%; n = 29) achieved PFS outcomes comparable to upfront CSI-based regimens (n = 49; 74.0%; p = 0.51); whereas lower-intensity, standard-dose, chemotherapy-only regimens (n = 31) were inferior (48.4% PFS; p = 0.006). Rescue was common post-relapse after IVT-MTX/high-dose protocols and translated into 5-year OS of 85.6% and 88.6%, respectively. However, information on pattern of relapse and treatments received at recurrence was only available for a small proportion of our cohort (n = 43). The 5-year PFS of patients receiving focal-RTx was (58.2%; n = 25). iMB SHH encompassed SHH-1 (38%), SHH-2 (47%) and SHH-3 (14%) WHO subgroups. In CSI-naïve iMB SHH, standard-dose chemotherapy was associated with worse PFS in SHH-1 (p = 0.001), but not SHH-2. Non-DN/MBEN histology (21.2% of iMB SHH) conferred worse PFS in the upfront CSI-treated and standard-dose (p < 0.001 and p = 0.003, respectively) groups. Metastatic disease only associated with prognosis with upfront IVT-MTX-only therapies (p = 0.013), while established high-risk features of non-infant MB SHH (TP53-mutation, LCA-histology, MYCN-amplification) only associated with poor prognosis in older SHH-3 (7/7 relapsed). Finally, CSI-naïve PFS findings were validated in a re-evaluation of smaller historical trials cohorts.
INTERPRETATION
Our findings show that iMB SHH outcomes and prognostic biomarkers are therapy dependent. In our retrospective patient group, non-metastatic iMB SHH treated with high-dose or IVT-MTX chemotherapy-only had equivalent favourable outcomes, independent of histology and subgroup. With outcomes established, clinical trials are now encouraged to focus on quality-of-life following different intensified approaches to identify the kindest curative strategies.
FUNDING
Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero and Blue Skye Thinking.
MeSH
Disease-Free Survival, Progression-Free Survival, Multiple Chronic Conditions, Cohort Studies, Classification, Medulloblastoma, Drug Therapy, Biomarkers, Aged, Histology, Therapeutics, Prognosis, Infant, Chemotherapy