. 2025 Sep 17;27(8):2158-2169.

doi: 10.1093/neuonc/noaf092.

Salvage therapies for first relapse of SHH medulloblastoma in early childhood

Craig Erker¹, Martin Mynarek^{2

3}, Marie Simbozel⁴, Brandon T Craig⁵, Virginia L Harrod⁶, Andrea M Cappellano⁷, Kenneth J Cohen⁸, Vicente Santa-Maria Lopez⁹, Andres Morales La Madrid⁹, Chantel Cacciotti¹⁰, Lorena Baroni¹¹, Ralph Salloum¹², Ashley S Margol¹³, George Michaiel¹⁴, Dolly Aguilera¹⁵, Claire M Mazewski¹⁵, Cassie N Kline¹⁶, Jonathan L Finlay¹⁷, Mohamed S Abdelbaki¹⁸, Jeffrey C Murray¹⁹, Kathleen Dorris²⁰, Bruce Crooks¹, Kevin F Ginn²¹, Nisreen Amayiri²², Stephan Tippelt²³, Gudrun Fleischhack²³, Svenja Tonn³, Nicolas U Gerber²⁴, Alvaro Lassaletta²⁵, Jordan R Hansford^{26

27}, Sara Khan¹², Stephen W Gilheeney²⁸, Lindsey M Hoffman²⁹, Michal Zapotocky³⁰, Valérie Larouche³¹, Shafqat Shah³², Vijay Ramaswamy³³, Amar Gajjar³⁴, Sébastien Perreault³⁵, Sabine Mueller^{36

37}, Juliette Hukin³⁸, Sylvia Cheng¹⁴, Zhihong J Wang³⁹, Kara Matheson⁴⁰, Simon Bailey⁴¹, Eric Bouffet³³, Steven C Clifford⁴¹, Giles Robinson³⁴, Christelle Dufour⁴, Stefan Rutkowski³, Lucie Lafay-Cousin⁴²

Affiliations

¹ Division of Hematology/Oncology, Department of Paediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
² Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ Department of Child and Adolescent Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, France.
⁵ Department of Pediatrics, University of Calgary and Alberta Children's Hospital Research Institute (ACHRI), Calgary, Alberta, Canada.
⁶ Departments of Pediatric Hematology and Oncology, Dell Children's Medical Center of Central Texas and University of Texas, Austin, Texas, USA.
⁷ Division of Pediatric Oncology/BMT, Instituto de Oncologia Pediátrica-GRAACC-UNIFESP, São Paulo, Brazil.
⁸ Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
⁹ Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, Barcelona, Spain.
¹⁰ Children's Hospital London Health Sciences, Division of Pediatric Hematology/Oncology, Western University, London, Ontario, Canada.
¹¹ Service of Hematology/Oncology, Hospital JP Garrahan, Buenos Aires, Argentina.
¹² Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio, USA.
¹³ Departments of Pediatrics and Radiation Oncology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
¹⁴ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
¹⁵ Division of Hematology, Oncology/Bone Marrow Transplant, Department of Pediatrics, British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
¹⁶ Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta & Emory University, Atlanta, Georgia, USA.
¹⁷ Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁸ Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
¹⁹ Division of Pediatric Hematology/Oncology, Cook Children's Medical Center, Fort Worth, Texas, USA.
²⁰ Children's Hospital of Colorado and University of Colorado School of Medicine, Denver, Colorado, USA.
²¹ Division of Pediatric Hematology and Oncology, Children's Mercy Hospital, Kansas City, Missouri, USA.
²² Department of Pediatric Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.
²³ Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany.
²⁴ Department of Oncology, University Children's Hospital, Zurich, Switzerland.
²⁵ Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
²⁶ Michael Rice Centre for Hematology and Oncology, The Women's and Children's Hospital; South Australia Health and Medical Research Institute, South Australian immunoGENomics Cancer Institute; University of Adelaide, Adelaide, Australia.
²⁷ Children's Cancer Centre, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Department of Pediatrics and Division of Hematology and Oncology, Mount Sinai, New York, USA.
²⁹ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.
³⁰ Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
³¹ Department of Pediatrics, Centre Mère-enfant Soleil du CHU de Quèbec-Université Laval, Quebec City, Quebec, Canada.
³² The University of Texas Health Science Center, Department of Pediatric Hematology-Oncology, San Antonio, Texas, USA.
³³ Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
³⁴ Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
³⁵ Centre Hospitalier Universitaire Sainte Justine, Université de Montreal, Montreal, Quebec, Canada.
³⁶ Department of Pediatrics, University of Zurich, Switzerland.
³⁷ Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, San Francisco, California, USA.
³⁸ Divisions of Neurology and Hematology, Oncology/Bone Marrow Transplant, Department of Pediatrics, British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
³⁹ Division of Hematology and Oncology, Children's Hospital of Richmond and Virginia Commonwealth University, Richmond, Virginia, USA.
⁴⁰ Research Methods Unit, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
⁴¹ Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle-upon-Tyne, UK.
⁴² Section of Pediatric Hematology and Bone Marrow Transplantation, Alberta Children's Hospital, Calgary, Alberta, Canada.

PMID: 40186336
PMCID: PMC12448823
DOI: 10.1093/neuonc/noaf092

Salvage therapies for first relapse of SHH medulloblastoma in early childhood

Craig Erker et al. Neuro Oncol. 2025.

. 2025 Sep 17;27(8):2158-2169.

doi: 10.1093/neuonc/noaf092.

Authors

Affiliations

¹ Division of Hematology/Oncology, Department of Paediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.
² Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ Department of Child and Adolescent Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, France.
⁵ Department of Pediatrics, University of Calgary and Alberta Children's Hospital Research Institute (ACHRI), Calgary, Alberta, Canada.
⁶ Departments of Pediatric Hematology and Oncology, Dell Children's Medical Center of Central Texas and University of Texas, Austin, Texas, USA.
⁷ Division of Pediatric Oncology/BMT, Instituto de Oncologia Pediátrica-GRAACC-UNIFESP, São Paulo, Brazil.
⁸ Pediatric Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
⁹ Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, Barcelona, Spain.
¹⁰ Children's Hospital London Health Sciences, Division of Pediatric Hematology/Oncology, Western University, London, Ontario, Canada.
¹¹ Service of Hematology/Oncology, Hospital JP Garrahan, Buenos Aires, Argentina.
¹² Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio, USA.
¹³ Departments of Pediatrics and Radiation Oncology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
¹⁴ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
¹⁵ Division of Hematology, Oncology/Bone Marrow Transplant, Department of Pediatrics, British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
¹⁶ Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta & Emory University, Atlanta, Georgia, USA.
¹⁷ Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁸ Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
¹⁹ Division of Pediatric Hematology/Oncology, Cook Children's Medical Center, Fort Worth, Texas, USA.
²⁰ Children's Hospital of Colorado and University of Colorado School of Medicine, Denver, Colorado, USA.
²¹ Division of Pediatric Hematology and Oncology, Children's Mercy Hospital, Kansas City, Missouri, USA.
²² Department of Pediatric Hematology/Oncology, King Hussein Cancer Center, Amman, Jordan.
²³ Pediatrics III, Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany.
²⁴ Department of Oncology, University Children's Hospital, Zurich, Switzerland.
²⁵ Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
²⁶ Michael Rice Centre for Hematology and Oncology, The Women's and Children's Hospital; South Australia Health and Medical Research Institute, South Australian immunoGENomics Cancer Institute; University of Adelaide, Adelaide, Australia.
²⁷ Children's Cancer Centre, The Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia.
²⁸ Department of Pediatrics and Division of Hematology and Oncology, Mount Sinai, New York, USA.
²⁹ Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA.
³⁰ Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
³¹ Department of Pediatrics, Centre Mère-enfant Soleil du CHU de Quèbec-Université Laval, Quebec City, Quebec, Canada.
³² The University of Texas Health Science Center, Department of Pediatric Hematology-Oncology, San Antonio, Texas, USA.
³³ Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
³⁴ Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
³⁵ Centre Hospitalier Universitaire Sainte Justine, Université de Montreal, Montreal, Quebec, Canada.
³⁶ Department of Pediatrics, University of Zurich, Switzerland.
³⁷ Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, San Francisco, California, USA.
³⁸ Divisions of Neurology and Hematology, Oncology/Bone Marrow Transplant, Department of Pediatrics, British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
³⁹ Division of Hematology and Oncology, Children's Hospital of Richmond and Virginia Commonwealth University, Richmond, Virginia, USA.
⁴⁰ Research Methods Unit, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
⁴¹ Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle-upon-Tyne, UK.
⁴² Section of Pediatric Hematology and Bone Marrow Transplantation, Alberta Children's Hospital, Calgary, Alberta, Canada.

PMID: 40186336
PMCID: PMC12448823
DOI: 10.1093/neuonc/noaf092

Abstract

Background: Sonic hedgehog (SHH) medulloblastoma is the most common molecular group of infant and early childhood medulloblastoma (iMB) and has no standard of care at relapse. This work aimed to evaluate the post-relapse survival (PRS) and explore prognostic factors of patients with nodular desmoplastic (ND) and/or SHH iMB.

Methods: This international retrospective study included 147 subjects diagnosed with relapsed ND/SHH iMB between 1995 and 2017, <6 years old at original diagnosis, and treated without initial craniospinal irradiation (CSI). Univariable and multivariable Cox models with propensity score analyses were used to assess PRS for those in the curative intent cohort.

Results: The 3-year PRS was 61.6% (95% confidence interval [CI], 52.2-69.6). The median age at relapse was 3.4 years (interquartile range [IQR], 2.6-4.1). Those with local relapse (40.8%) more often received salvage treatment with surgery (P < .001), low-dose CSI (≤24 Gy; P < .001), or focal radiotherapy (P = .008). Patients not receiving CSI (40.5%) more often received salvage marrow-ablative chemotherapy (HDC + AuHCR [P < .001]). On multivariable analysis, CSI was associated with improved survival (hazard ratio [HR] 0.33 [95% CI, 0.13-0.86], P = .04). Salvage HDC + AuHCR, while clinically important, did not reach statistical significance (HR 0.24 [95% CI, 0.0054-1.025], P = .065).

Conclusions: Survival of patients with relapsed SHH iMB is not satisfactory and relies on treatments associated with toxicities including CSI and/or HDC + AuHCR. Cure at initial diagnosis to avoid relapse is crucial. For patients with localized relapse undergoing resection, alternative salvage regimens that avoid high-dose CSI (>24 Gy) can be considered.

Keywords: SHH; infant and early childhood; medulloblastoma; relapse.

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Conflict of interest statement

C.E. is a DSMC member for CONNECT. M.M. was supported for data collection by the German Childhood Cancer Foundation. He has grants supported by the German Cancer Aid (Deutsche Krebshilfe). B.C. is a DSMC member for re-irradiation of progressive or recurrent DIPG, NCT03126266, member of the Medical Advisory Committee and NS Chapter Advisory Board, and Make-A-Wish Canada. J.R.H. receives consulting fees from Alexion Pharmaceuticals and Bayer Pharmaceuticals. Receives funding for travel or meetings from Alexion Pharmaceuticals. Institution receives payment from Servier Pharmaceuticals for work on Scientific Advisory Board. He is the director of ANZHOG. V.L. receives payment for presentations on pediatric neurofibromatosis and from Alexion. DSMC member for re-irradiation of progressive or recurrent DIPG, NCT03126266. J.L.F. has received consulting fee payments from Nkore Biotherapeutics Inc. and the Department of Defense. He has received payment from Nationwide Children’s Hospital Research Institute. He has received payment for expert review from Muro & Lampe Law Firm Consultation. S.C.C. has received funding from Cancer Research UK. A.G. is a member of the Day One Therapeutics Advisory Board. A.M.C. serves as president of both the Latin American Society of Pediatric Oncology and the International Society of Pediatric Oncology Continental President for Latin America. C.M.M. is the co-chair for the Children’s Oncology Group protocol ACNS0334: a randomized phase 3 trial of intensified chemotherapy with or without methotrexate for high-risk embryonal brain tumors in young children, which is unpaid. A.L. has received payment from Alexion and Eli Lilly. He also serves on advisory boards for Alexion and Servier. L.M.H. has received payment for membership in the following DSMBs: Children’s Oncology Group, Pediatric Brain Tumour Consortium, and Georgia Cancer Center. C.N.K. holds grant funds with the Cannonball Kids’ Cancer Foundation, the Kortney Rose Foundation, and the Bristol-Myers Squibb Foundation. She has contracts related to clinical trial work with Curis Inc, Regeneron Pharmaceuticals, Day One Biotherapeutics, Midatech, Ipsen, Chimerix, Kazia, and Bristol-Myers Squibb. She also has leadership roles on scientific advisory board for the Cannonball Kids’ Cancer Foundation, the Raymond A. Wood Foundation, the Children’s Brain Tumor Network, and the Neev Kolte & Brave Ronil Foundation. K.D. was a member of the advisory board for RAF inhibitors for Day One Bio. Kathleen has CRSP stock and is currently employed by Cogent Biosciences. G.F. has a research grant from the German Children’s Cancer Foundation. G.F. is a member of the DSMB for the clinical trial, NCT04738162. S.T. has grant funding with Deutsche Kinderkrebsstiftung (DKKS). V.R. has received consulting fees from Alexion and Servier. S.R. has received funding from the German Children’s Cancer Foundation and BMBF. He has received consulting fees from FennecPharma and Norgine GmbH. The other authors have no conflicts of interest to declare.

Figures

**Figure 1.**
(A) Pie chart of pattern of relapse for curative intent cohort; (B) bar graph for salvage CSI dosing for curative intent cohort; (C) Kaplan–Meier plot showing the overall survival of curative intent cohort with the gray zone representing the 95% confidence interval.

**Figure 2.**
Kaplan–Meier plot showing post-relapse survival for curative intent cohort with the 95% confidence intervals demonstrated for (A) those treated with and without salvage radiation therapy; (B) treatment with salvage CSI compared to those treated with salvage focal radiation therapy; (C) treatment with salvage CSI at ≤24 Gy compared to >24 Gy; (D) treatment with salvage CSI alone compared to salvage CSI with systemic chemotherapy.

**Figure 3.**
Post-relapse survival forest plot of exploratory multivariable analysis of curative intent cohort. The whiskers represent the 95% confidence interval of the hazard ratio (HR), which is represented by the small square.

See this image and copyright information in PMC

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Salvage therapies for first relapse of SHH medulloblastoma in early childhood

Affiliations

Salvage therapies for first relapse of SHH medulloblastoma in early childhood

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources