Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
P50 CA190991
NCI NIH HHS - United States
R01 CA159859
NCI NIH HHS - United States
CIHR - Canada
R01 NS096236
NINDS NIH HHS - United States
R01 CA163737
NCI NIH HHS - United States
R01 CA148621
NCI NIH HHS - United States
R01 CA148699
NCI NIH HHS - United States
F31 CA203372
NCI NIH HHS - United States
R01 CA163722
NCI NIH HHS - United States
PubMed
26976201
PubMed Central
PMC4907853
DOI
10.1016/s1470-2045(15)00581-1
PII: S1470-2045(15)00581-1
Knihovny.cz E-resources
- MeSH
- Child MeSH
- Adult MeSH
- Infant MeSH
- Combined Modality Therapy MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Medulloblastoma classification genetics pathology surgery MeSH
- Brain Neoplasms classification genetics pathology surgery MeSH
- Child, Preschool MeSH
- Disease-Free Survival MeSH
- Prognosis * MeSH
- Disease Progression MeSH
- Retrospective Studies MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Geographicals
- Canada MeSH
BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.
2nd Department of Pediatrics Semmelweis University Budapest Hungary
Cancer and Blood Disorders Center Seattle Children's Hospital Seattle WA USA
Center for Neuropathology Ludwig Maximilians Universität Munich Germany
Centre de Pathologie EST Groupement Hospitalier EST Université de Lyon Lyon France
Clinical Cooperation Unit Neuropathology German Cancer Research Center Heidelberg Germany
Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA
Department of Neurological Surgery University of California San Francisco San Francisco CA USA
Department of Neurological Surgery University of Pittsburgh School of Medicine Pittsburgh PA USA
Department of Neurological Surgery Vanderbilt Medical Center Nashville TN USA
Department of Neurology Children's National Medical Center Washington DC USA
Department of Neurology Vanderbilt Medical Center Nashville TN USA
Department of Neurosurgery Erasmus University Medical Center Rotterdam Netherlands
Department of Neurosurgery Hua Shan Hospital Fudan University Shanghai China
Department of Neurosurgery Kitasato University School of Medicine Sagamihara Kanagawa Japan
Department of Neurosurgery Osaka University Graduate School of Medicine Osaka Japan
Department of Neurosurgery Tohoku University Graduate School of Medicine Sendai Japan
Department of Neurosurgery University of Michigan Medical School Ann Arbor MI USA
Department of Oncology The Children's Memorial Health Institute Warsaw Poland
Department of Pathology and Laboratory Medicine University of Calgary Calgary AB Canada
Department of Pathology Duke University Durham NC USA
Department of Pathology Erasmus University Medical Center Rotterdam Netherlands
Department of Pathology The Children's Memorial Health Institute Warsaw Poland
Department of Pathology University Hospital Brno Brno Czech Republic
Department of Pathology University of Pittsburgh School of Medicine Pittsburgh PA USA
Department of Pediatric Neurosurgery Shizuoka Children's Hospital Shizuoka Japan
Department of Pediatric Oncology School of Medicine Masaryk University Brno Czech Republic
Department of Pediatrics University of Colorado Denver Aurora CO USA
Departments of Pediatrics and Human Genetics McGill University Montreal QC Canada
Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON Canada
Division of Biostatistics German Cancer Research Center Heidelberg Germany
Division of Child Neurology CHU Sainte Justine Montreal QC Canada
Division of Haematology Oncology The Hospital for Sick Children Toronto ON Canada
Division of Hematology Oncology McGill University Montreal QC Canada
Division of Neuropathology University of Debrecen Medical and Health Science Centre Debrecen Hungary
Division of Neurosurgery Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon Portugal
Division of Neurosurgery The Hospital for Sick Children Toronto ON Canada
Division of Pathology The Hospital for Sick Children Toronto ON Canada
Division of Pediatric Hematology Oncology Mayo Clinic Rochester MN USA
Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany
Division of Stem Cell Research Institute for Clinical Research Osaka National Hospital Osaka Japan
Divison of Pathology Centro Hospitalar Lisboa Norte Hospital de Santa Maria Lisbon Portugal
INSERM U1028 CNRS UMR5292 Centre de Recherche en Neurosciences Université de Lyon Lyon France
Institute of Pediatric Hematology and Oncology Lyon France
Neurosurgical Service KK Women's and Children's Hospital Singapore Singapore
Pediatric Neurosurgery Catholic University Medical School Rome Italy
The Preston Robert Tisch Brain Tumor Center Duke University Durham NC USA
UO Neurochirurgia Istituto Giannina Gaslini Genova Italy
UQ Child Health Research Centre University of Queensland Brisbane QLD Australia
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Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
Intertumoral Heterogeneity within Medulloblastoma Subgroups
