Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis - 31/03/16

Doi : 10.1016/S1470-2045(15)00581-1

Eric M Thompson, MD ^a,^h,^{*
Co-first authors}, Thomas Hielscher, MSc ^k,^{*
Co-first authors}, Eric Bouffet, ProfMD ^b,^c, Marc Remke, MD ^o, Betty Luu, BSc ^d, Sridharan Gururangan, ProfMBBCh ^j, Roger E McLendon, ProfMD ⁱ, Darell D Bigner, ProfMD ^i,^j, Eric S Lipp, MD ⁱ, Sebastien Perreault, MD ^p, Yoon-Jae Cho, MD ^q,^r, Gerald Grant, MD ^r,^s, Seung-Ki Kim, ProfMD ^t, Ji Yeoun Lee, MD ^t, Amulya A Nageswara Rao, MD ^u, Caterina Giannini, ProfMD ^v, Kay Ka Wai Li, MD ^w, Ho-Keung Ng, ProfMD ^w, Yu Yao, MD ^x, Toshihiro Kumabe, MD ^y, Teiji Tominaga, ProfMD ^z, Wieslawa A Grajkowska, ProfMD ^aa, Marta Perek-Polnik, ProfMD ^ab, David C Y Low, MBBCh ^ac, Wan Tew Seow, MBBS ^ac, Kenneth T E Chang, MBBCh ^ad, Jaume Mora, ProfMD ^ae, Ian F Pollack, ProfMD ^af, Ronald L Hamilton, MD ^ag, Sarah Leary, MD ^ah, Andrew S Moore, PhD ^ai,^aj, Wendy J Ingram, PhD ^ai, Andrew R Hallahan, MBBS ^ai,^aj, Anne Jouvet, MD ^ak, Michelle Fèvre-Montange, PhD ^al, Alexandre Vasiljevic, MD ^am,^an, Cecile Faure-Conter, MD ^ao, Tomoko Shofuda, PhD ^ap, Naoki Kagawa, MD ^aq, Naoya Hashimoto, MD ^aq, Nada Jabado, MD ^ar, Alexander G Weil, MD ^as, Tenzin Gayden, PhD ^as, Takafumi Wataya, MD ^at, Tarek Shalaby, MD ^au, Michael Grotzer, ProfMD ^au, Karel Zitterbart, PhD ^av, Jaroslav Sterba, ProfMD ^av, Leos Kren, MD ^aw, Tibor Hortobágyi, ProfPhD ^ax, Almos Klekner, PhD ^ax, Bognár László, ProfPhD ^ax, Tímea Pócza, MSc ^ay, Peter Hauser, MD ^ay, Ulrich Schüller, MD ^az, Shin Jung, ProfMD ^ba, Woo-Youl Jang, MD ^ba, Pim J French, ProfPhD ^bb, Johan M Kros, ProfMD ^bc, Marie-Lise C van Veelen, MD ^bb, Luca Massimi, MD ^bd, Jeffrey R Leonard, ProfMD ^be, Joshua B Rubin, MD ^bf, Rajeev Vibhakar, MD ^bg, Lola B Chambless, MD ^bh, Michael K Cooper, MD ^bi, Reid C Thompson, ProfMD ^bh, Claudia C Faria, MD ^bj, Alice Carvalho, MD ^bl, Sofia Nunes, MD ^bm, José Pimentel, MD ^bk, Xing Fan, MD ^bn, Karin M Muraszko, ProfMD ^bo, Enrique López-Aguilar, MD ^bp, David Lyden, ProfMD ^bq, Livia Garzia, PhD ^d, David J H Shih, PhD ^d,^g, Noriyuki Kijima, MD ^d, Christian Schneider, MD ^a, Jennifer Adamski, PhD ^b, Paul A Northcott, PhD ^l, Marcel Kool, PhD ^l, David T W Jones, PhD ^l, Jennifer A Chan, MD ^br, Ana Nikolic, MD ^br, Maria Luisa Garre, MD ^bs, Erwin G Van Meir, ProfPhD ^bt, Satoru Osuka, MD ^bt, Jeffrey J Olson, ProfMD ^bu, Arman Jahangiri, BSc ^bv, Brandyn A Castro, BSc ^bv, Nalin Gupta, MD ^bv,^bw, William A Weiss, ProfMD ^bv,^bw,^bx, Iska Moxon-Emre, MSc ^e, Donald J Mabbott, PhD ^e, Alvaro Lassaletta, MD ^b, Cynthia E Hawkins, ProfMD ^f, Uri Tabori, MD ^b,^c, James Drake, ProfMD ^a, Abhaya Kulkarni, ProfMD ^a, Peter Dirks, ProfMD ^a,^c, James T Rutka, ProfMD ^a,^c,^g, Andrey Korshunov, ProfMD ^m, Stefan M Pfister, ProfMD ^l,ⁿ, Roger J Packer, ProfMD ^by, Vijay Ramaswamy, MD ^a,^b,^c,^d,^g,^{^{†
Co-senior authors}}, Michael D Taylor, Dr ProfMD ^a,^c,^d,^g,^{^{†
Co-senior authors},}⁎
^a Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada
^b Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
^c The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
^d Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
^e Program in Neuroscience and Mental Health and Department of Psychology, The Hospital for Sick Children, Toronto, ON, Canada
^f Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada
^g Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
^h Department of Neurosurgery, Duke University, Durham, NC, USA
ⁱ Department of Pathology, Duke University, Durham, NC, USA
^j The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA
^k Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
^l Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
^m Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany
ⁿ Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg, Germany
^o Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
^p Division of Child Neurology, CHU Sainte-Justine, Montreal, QC, Canada
^q Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
^r Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
^s Department of Neurosurgery, Lucille Packard Children’s Hospital, Stanford, CA, USA
^t Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
^u Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA
^v Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
^w Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, China
^x Department of Neurosurgery, Hua Shan Hospital, Fudan University, Shanghai, China
^y Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
^z Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan
^aa Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
^ab Department of Oncology, The Children’s Memorial Health Institute, Warsaw, Poland
^ac Neurosurgical Service, KK Women’s and Children’s Hospital, Singapore, Singapore
^ad Department of Pathology & Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
^ae Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
^af Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
^ag Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
^ah Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, USA
^ai UQ Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia
^aj Oncology Service, Lady Cilento Children’s Hospital, Children’s Health Queensland, Brisbane, QLD, Australia
^ak Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, Lyon, France
^al INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences, Université de Lyon, Lyon, France
^am Centre de Pathologie et Neuropathologie Est, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron
^an ONCOFLAM, Neuro-Oncologie et Neuro-Inflammation Centre de Recherche en Neurosciences de Lyon, Lyon, France
^ao Institute of Pediatric Hematology and Oncology, Lyon, France
^ap Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, Osaka, Japan
^aq Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
^ar Division of Hematology/Oncology, McGill University, Montreal, QC, Canada
^as Departments of Pediatrics and Human Genetics, McGill University, Montreal, QC, Canada
^at Department of Pediatric Neurosurgery, Shizuoka Children’s Hospital, Shizuoka, Japan
^au Departments of Oncology and Neuro-Oncology, University Children’s Hospital of Zurich, Zurich, Switzerland
^av Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno, Czech Republic
^aw Department of Pathology, University Hospital Brno, Brno, Czech Republic
^ax Division of Neuropathology, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary
^ay 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
^az Center for Neuropathology, Ludwig-Maximilians-Universität, Munich, Germany
^ba Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam South Korea
^bb Department of Neurosurgery, Erasmus University Medical Center, Rotterdam, Netherlands
^bc Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
^bd Pediatric Neurosurgery, Catholic University Medical School, Rome, Italy
^be Department of Neurosurgery, Division of Pediatric Neurosurgery, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, MO, USA
^bf Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, MO, USA
^bg Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
^bh Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA
^bi Department of Neurology, Vanderbilt Medical Center, Nashville, TN, USA
^bj Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
^bk Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
^bl Departamento de Oncologia Pediátrica, Hospital Pediátrico de Coimbra, Centro Hospitalar de Coimbra, Coimbra, Portugal
^bm Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
^bn Department of Neurosurgery and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
^bo Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA
^bp Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico
^bq Department of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
^br Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
^bs UO Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy
^bt Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, USA
^bu Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, USA
^bv Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
^bw Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
^bx Department of Neurology, University of California San Francisco, San Francisco, CA, USA
^by Department of Neurology, Children’s National Medical Center, Washington, DC, USA

^*Correspondence to: Dr Michael D Taylor, Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G 1X8, CanadaDivision of NeurosurgeryHospital for Sick ChildrenTorontoONM5G 1X8Canada

Summary

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=0·016) 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.

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Plan

Introduction

Methods

Specimen processing and subgroup identification

Extent of resection

Statistical analysis

Role of the funding source

Results

Discussion

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Vol 17 - N° 4

P. 484-495 - avril 2016 Retour au numéro

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Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis - 31/03/16

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