title: Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study.
abstract: The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.
authors.affiliation: Department of Paediatrics, University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden. magnus.sabel@vgregion.se.
authors.forename: Magnus
authors.identifier: 0000-0002-3072-657X
authors.initials: M
authors.lastname: Sabel
authors.affiliation: Paediatrics III, Division of Paediatric Haematology and Oncology, University Hospital of Essen, Essen, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Fleischhack
authors.affiliation: Paediatrics III, Division of Paediatric Haematology and Oncology, University Hospital of Essen, Essen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Tippelt
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Gustafsson
authors.affiliation: Department of Paediatrics, Adolescent and Young Adults Oncology, Institut Curie and University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Doz
authors.affiliation: Department of Radiooncology, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kortmann
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Massimino
authors.affiliation: Biocruces Health Research Institute, Universidad Del País Vasco/EHU, Bilbao, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Navajas
authors.affiliation: University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: von Hoff
authors.affiliation: University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.affiliation: University of Würzburg, Würzburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Warmuth-Metz
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Alder Hey Children's Hospital, Liverpool, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Pizer
authors.affiliation: Department of Paediatrics, University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Lannering
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy / Q000379:methods*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008527:Medulloblastoma / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality / Q000532:radiotherapy*; D009154:Mutation / Q000235:genetics; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics; D009364:Neoplasm Recurrence, Local; D011879:Radiotherapy Dosage; D012008:Recurrence; D012044:Regression Analysis; D055502:Secondary Prevention; D016896:Treatment Outcome; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D051176:beta Catenin
keywords: Chemotherapy; Clinical trial; Medulloblastoma; Paediatric; Radiotherapy; Relapse; Secondary tumours; Survival; Treatment