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Author Notes:

Corresponding Author: Dr. Michael D. Taylor, MD, PhD, FRCSC, Division of Neurosurgery, 555 niversity Avenue, Toronto, ON M5G 1X8, Phone: 416-813-6427, Fax: 416-813-4975, mdtaylor@sickkids.ca

For a full list of authors and their contributions see full article

We thank Narra S Devi for administrative assistance and Susan Archer for technical writing and The Brain Tumour Tissue Bank funded by the Brain Tumour Foundation of Canada.

XF reports grants from the National Institute of Health. WJI reports grans from Children s Hospital Foundation Queensland and The BrainChild Foundation.

JO reports personal fees from American Cancer Society, non-financial support from Merck, grants from Genetech, grants from Millenium/Takeda, and grants from the National Institute of Health.

Subjects:

Research Funding:

MDT is supported by the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the National Institutes of Health (R01CA159859 and R01CA148699), The Terry Fox Research Institute, The Canadian Institutes of Health Research, and the Pediatric Brain Tumor Foundation. VR is supported by a CIHR fellowship, an Alberta Innovates-Health Solutions Clinical Fellowship and a Young Investigator Award from Alex s Lemonade Stand. SG, RM, and DB are supported by the Pediatric Brain Tumor Foundation.

MR is supported by a fellowship from the Mildred Scheel Cancer Foundation.

SMP is supported by a grant from the Deutsche Kinderkrebsstiftung. AK was supported by the Hungarian Brain Research Program - Grant No. KTIA_13_NAP-AV/3, the TÁMOP-4.2.2.A-11/1/KONV-2012-0025 project and János Bolyai Scholarship of the Hungarian Academy of Sciences. WJI and ARH are funded by Children's Hospital Foundation Queensland (Australia) and The BrainChild Foundation (Australia).

SP was funded by grants from Justine Lacoste Fundation and Fonds de Recherche en Santé du Québec (Bourses de formation en recherche post-diplôme professionnel/Fellowship).

JC is supported by a St. Baldrick's Scholar Award. KZ acknowledges research support from the project OPVK CZ.1.07/2.3.00/20.0183.

EVM is funded by Cure Childhood Cancer, St. Baldrick's Foundation, and NIH R01 NS084063, RO1 NS096236.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • POSTERIOR-FOSSA TUMORS
  • CHILDRENS CANCER GROUP
  • RISK MEDULLOBLASTOMA
  • RADIATION-THERAPY
  • ADJUVANT CHEMOTHERAPY
  • RANDOMIZED-TRIAL
  • PHASE-III
  • ONCOLOGY
  • CHILDHOOD
  • PATTERNS

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Tools:

Journal Title:

Lancet Oncology

Volume:

Volume 17, Number 4

Publisher:

, Pages 484-495

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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 cm2 tumour remaining), or sub-total resection (≥1·5 cm2 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.

Copyright information:

© 2016 Elsevier Ltd

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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