Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup

a retrospective integrated clinical and molecular analysis

Eric M. Thompson, Thomas Hielscher, Eric Bouffet, Marc Remke, Betty Luu, Sridharan Gururangan, Roger E. McLendon, Darell D. Bigner, Eric S. Lipp, Sebastien Perreault, Yoon-Jae Cho, Gerald Grant, Seung Ki Kim, Ji Yeoun Lee, Amulya A.Nageswara Rao, Caterina Giannini, Kay Ka Wai Li, Ho Keung Ng, Yu Yao, Toshihiro Kumabe & 87 others Teiji Tominaga, Wieslawa A. Grajkowska, Marta Perek-Polnik, David C.Y. Low, Wan Tew Seow, Kenneth T.E. Chang, Jaume Mora, Ian F. Pollack, Ronald L. Hamilton, Sarah Leary, Andrew S. Moore, Wendy J. Ingram, Andrew R. Hallahan, Anne Jouvet, Michelle Fèvre-Montange, Alexandre Vasiljevic, Cecile Faure-Conter, Tomoko Shofuda, Naoki Kagawa, Naoya Hashimoto, Nada Jabado, Alexander G. Weil, Tenzin Gayden, Takafumi Wataya, Tarek Shalaby, Michael Grotzer, Karel Zitterbart, Jaroslav Sterba, Leos Kren, Tibor Hortobágyi, Almos Klekner, Bognár László, Tímea Pócza, Peter Hauser, Ulrich Schüller, Shin Jung, Woo Youl Jang, Pim J. French, Johan M. Kros, Marie Lise C. van Veelen, Luca Massimi, Jeffrey R. Leonard, Joshua B. Rubin, Rajeev Vibhakar, Lola B. Chambless, Michael K. Cooper, Reid C. Thompson, Claudia C. Faria, Alice Carvalho, Sofia Nunes, José Pimentel, Xing Fan, Karin M. Muraszko, Enrique López-Aguilar, David Lyden, Livia Garzia, David J.H. Shih, Noriyuki Kijima, Christian Schneider, Jennifer Adamski, Paul A. Northcott, Marcel Kool, David T.W. Jones, Jennifer A. Chan, Ana Nikolic, Maria Luisa Garre, Erwin G. Van Meir, Satoru Osuka, Jeffrey J. Olson, Arman Jahangiri, Brandyn A. Castro, Nalin Gupta, William A. Weiss, Iska Moxon-Emre, Donald J. Mabbott, Alvaro Lassaletta, Cynthia E. Hawkins, Uri Tabori, James Drake, Abhaya Kulkarni, Peter Dirks, James T. Rutka, Andrey Korshunov, Stefan M. Pfister, Roger J. Packer, Vijay Ramaswamy, Michael D. Taylor

Research output: Contribution to journalArticle

72 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)484-495
Number of pages12
JournalThe Lancet Oncology
Volume17
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Fingerprint

Medulloblastoma
Disease-Free Survival
Neoplasms
Survival
Second-Look Surgery
Craniospinal Irradiation
National Institutes of Health (U.S.)
Residual Neoplasm
Gene Expression Profiling
Chemoradiotherapy
Standard of Care
Genomics
Proportional Hazards Models
Brain Neoplasms
Paraffin
Formaldehyde
Pediatrics
Morbidity
Health

ASJC Scopus subject areas

  • Oncology

Cite this

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup : a retrospective integrated clinical and molecular analysis. / Thompson, Eric M.; Hielscher, Thomas; Bouffet, Eric; Remke, Marc; Luu, Betty; Gururangan, Sridharan; McLendon, Roger E.; Bigner, Darell D.; Lipp, Eric S.; Perreault, Sebastien; Cho, Yoon-Jae; Grant, Gerald; Kim, Seung Ki; Lee, Ji Yeoun; Rao, Amulya A.Nageswara; Giannini, Caterina; Li, Kay Ka Wai; Ng, Ho Keung; Yao, Yu; Kumabe, Toshihiro; Tominaga, Teiji; Grajkowska, Wieslawa A.; Perek-Polnik, Marta; Low, David C.Y.; Seow, Wan Tew; Chang, Kenneth T.E.; Mora, Jaume; Pollack, Ian F.; Hamilton, Ronald L.; Leary, Sarah; Moore, Andrew S.; Ingram, Wendy J.; Hallahan, Andrew R.; Jouvet, Anne; Fèvre-Montange, Michelle; Vasiljevic, Alexandre; Faure-Conter, Cecile; Shofuda, Tomoko; Kagawa, Naoki; Hashimoto, Naoya; Jabado, Nada; Weil, Alexander G.; Gayden, Tenzin; Wataya, Takafumi; Shalaby, Tarek; Grotzer, Michael; Zitterbart, Karel; Sterba, Jaroslav; Kren, Leos; Hortobágyi, Tibor; Klekner, Almos; László, Bognár; Pócza, Tímea; Hauser, Peter; Schüller, Ulrich; Jung, Shin; Jang, Woo Youl; French, Pim J.; Kros, Johan M.; van Veelen, Marie Lise C.; Massimi, Luca; Leonard, Jeffrey R.; Rubin, Joshua B.; Vibhakar, Rajeev; Chambless, Lola B.; Cooper, Michael K.; Thompson, Reid C.; Faria, Claudia C.; Carvalho, Alice; Nunes, Sofia; Pimentel, José; Fan, Xing; Muraszko, Karin M.; López-Aguilar, Enrique; Lyden, David; Garzia, Livia; Shih, David J.H.; Kijima, Noriyuki; Schneider, Christian; Adamski, Jennifer; Northcott, Paul A.; Kool, Marcel; Jones, David T.W.; Chan, Jennifer A.; Nikolic, Ana; Garre, Maria Luisa; Van Meir, Erwin G.; Osuka, Satoru; Olson, Jeffrey J.; Jahangiri, Arman; Castro, Brandyn A.; Gupta, Nalin; Weiss, William A.; Moxon-Emre, Iska; Mabbott, Donald J.; Lassaletta, Alvaro; Hawkins, Cynthia E.; Tabori, Uri; Drake, James; Kulkarni, Abhaya; Dirks, Peter; Rutka, James T.; Korshunov, Andrey; Pfister, Stefan M.; Packer, Roger J.; Ramaswamy, Vijay; Taylor, Michael D.

In: The Lancet Oncology, Vol. 17, No. 4, 01.04.2016, p. 484-495.

Research output: Contribution to journalArticle

Thompson, EM, Hielscher, T, Bouffet, E, Remke, M, Luu, B, Gururangan, S, McLendon, RE, Bigner, DD, Lipp, ES, Perreault, S, Cho, Y-J, Grant, G, Kim, SK, Lee, JY, Rao, AAN, Giannini, C, Li, KKW, Ng, HK, Yao, Y, Kumabe, T, Tominaga, T, Grajkowska, WA, Perek-Polnik, M, Low, DCY, Seow, WT, Chang, KTE, Mora, J, Pollack, IF, Hamilton, RL, Leary, S, Moore, AS, Ingram, WJ, Hallahan, AR, Jouvet, A, Fèvre-Montange, M, Vasiljevic, A, Faure-Conter, C, Shofuda, T, Kagawa, N, Hashimoto, N, Jabado, N, Weil, AG, Gayden, T, Wataya, T, Shalaby, T, Grotzer, M, Zitterbart, K, Sterba, J, Kren, L, Hortobágyi, T, Klekner, A, László, B, Pócza, T, Hauser, P, Schüller, U, Jung, S, Jang, WY, French, PJ, Kros, JM, van Veelen, MLC, Massimi, L, Leonard, JR, Rubin, JB, Vibhakar, R, Chambless, LB, Cooper, MK, Thompson, RC, Faria, CC, Carvalho, A, Nunes, S, Pimentel, J, Fan, X, Muraszko, KM, López-Aguilar, E, Lyden, D, Garzia, L, Shih, DJH, Kijima, N, Schneider, C, Adamski, J, Northcott, PA, Kool, M, Jones, DTW, Chan, JA, Nikolic, A, Garre, ML, Van Meir, EG, Osuka, S, Olson, JJ, Jahangiri, A, Castro, BA, Gupta, N, Weiss, WA, Moxon-Emre, I, Mabbott, DJ, Lassaletta, A, Hawkins, CE, Tabori, U, Drake, J, Kulkarni, A, Dirks, P, Rutka, JT, Korshunov, A, Pfister, SM, Packer, RJ, Ramaswamy, V & Taylor, MD 2016, 'Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis', The Lancet Oncology, vol. 17, no. 4, pp. 484-495. https://doi.org/10.1016/S1470-2045(15)00581-1
Thompson, Eric M. ; Hielscher, Thomas ; Bouffet, Eric ; Remke, Marc ; Luu, Betty ; Gururangan, Sridharan ; McLendon, Roger E. ; Bigner, Darell D. ; Lipp, Eric S. ; Perreault, Sebastien ; Cho, Yoon-Jae ; Grant, Gerald ; Kim, Seung Ki ; Lee, Ji Yeoun ; Rao, Amulya A.Nageswara ; Giannini, Caterina ; Li, Kay Ka Wai ; Ng, Ho Keung ; Yao, Yu ; Kumabe, Toshihiro ; Tominaga, Teiji ; Grajkowska, Wieslawa A. ; Perek-Polnik, Marta ; Low, David C.Y. ; Seow, Wan Tew ; Chang, Kenneth T.E. ; Mora, Jaume ; Pollack, Ian F. ; Hamilton, Ronald L. ; Leary, Sarah ; Moore, Andrew S. ; Ingram, Wendy J. ; Hallahan, Andrew R. ; Jouvet, Anne ; Fèvre-Montange, Michelle ; Vasiljevic, Alexandre ; Faure-Conter, Cecile ; Shofuda, Tomoko ; Kagawa, Naoki ; Hashimoto, Naoya ; Jabado, Nada ; Weil, Alexander G. ; Gayden, Tenzin ; Wataya, Takafumi ; Shalaby, Tarek ; Grotzer, Michael ; Zitterbart, Karel ; Sterba, Jaroslav ; Kren, Leos ; Hortobágyi, Tibor ; Klekner, Almos ; László, Bognár ; Pócza, Tímea ; Hauser, Peter ; Schüller, Ulrich ; Jung, Shin ; Jang, Woo Youl ; French, Pim J. ; Kros, Johan M. ; van Veelen, Marie Lise C. ; Massimi, Luca ; Leonard, Jeffrey R. ; Rubin, Joshua B. ; Vibhakar, Rajeev ; Chambless, Lola B. ; Cooper, Michael K. ; Thompson, Reid C. ; Faria, Claudia C. ; Carvalho, Alice ; Nunes, Sofia ; Pimentel, José ; Fan, Xing ; Muraszko, Karin M. ; López-Aguilar, Enrique ; Lyden, David ; Garzia, Livia ; Shih, David J.H. ; Kijima, Noriyuki ; Schneider, Christian ; Adamski, Jennifer ; Northcott, Paul A. ; Kool, Marcel ; Jones, David T.W. ; Chan, Jennifer A. ; Nikolic, Ana ; Garre, Maria Luisa ; Van Meir, Erwin G. ; Osuka, Satoru ; Olson, Jeffrey J. ; Jahangiri, Arman ; Castro, Brandyn A. ; Gupta, Nalin ; Weiss, William A. ; Moxon-Emre, Iska ; Mabbott, Donald J. ; Lassaletta, Alvaro ; Hawkins, Cynthia E. ; Tabori, Uri ; Drake, James ; Kulkarni, Abhaya ; Dirks, Peter ; Rutka, James T. ; Korshunov, Andrey ; Pfister, Stefan M. ; Packer, Roger J. ; Ramaswamy, Vijay ; Taylor, Michael D. / Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup : a retrospective integrated clinical and molecular analysis. In: The Lancet Oncology. 2016 ; Vol. 17, No. 4. pp. 484-495.
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title = "Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis",
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.",
author = "Thompson, {Eric M.} and Thomas Hielscher and Eric Bouffet and Marc Remke and Betty Luu and Sridharan Gururangan and McLendon, {Roger E.} and Bigner, {Darell D.} and Lipp, {Eric S.} and Sebastien Perreault and Yoon-Jae Cho and Gerald Grant and Kim, {Seung Ki} and Lee, {Ji Yeoun} and Rao, {Amulya A.Nageswara} and Caterina Giannini and Li, {Kay Ka Wai} and Ng, {Ho Keung} and Yu Yao and Toshihiro Kumabe and Teiji Tominaga and Grajkowska, {Wieslawa A.} and Marta Perek-Polnik and Low, {David C.Y.} and Seow, {Wan Tew} and Chang, {Kenneth T.E.} and Jaume Mora and Pollack, {Ian F.} and Hamilton, {Ronald L.} and Sarah Leary and Moore, {Andrew S.} and Ingram, {Wendy J.} and Hallahan, {Andrew R.} and Anne Jouvet and Michelle F{\`e}vre-Montange and Alexandre Vasiljevic and Cecile Faure-Conter and Tomoko Shofuda and Naoki Kagawa and Naoya Hashimoto and Nada Jabado and Weil, {Alexander G.} and Tenzin Gayden and Takafumi Wataya and Tarek Shalaby and Michael Grotzer and Karel Zitterbart and Jaroslav Sterba and Leos Kren and Tibor Hortob{\'a}gyi and Almos Klekner and Bogn{\'a}r L{\'a}szl{\'o} and T{\'i}mea P{\'o}cza and Peter Hauser and Ulrich Sch{\"u}ller and Shin Jung and Jang, {Woo Youl} and French, {Pim J.} and Kros, {Johan M.} and {van Veelen}, {Marie Lise C.} and Luca Massimi and Leonard, {Jeffrey R.} and Rubin, {Joshua B.} and Rajeev Vibhakar and Chambless, {Lola B.} and Cooper, {Michael K.} and Thompson, {Reid C.} and Faria, {Claudia C.} and Alice Carvalho and Sofia Nunes and Jos{\'e} Pimentel and Xing Fan and Muraszko, {Karin M.} and Enrique L{\'o}pez-Aguilar and David Lyden and Livia Garzia and Shih, {David J.H.} and Noriyuki Kijima and Christian Schneider and Jennifer Adamski and Northcott, {Paul A.} and Marcel Kool and Jones, {David T.W.} and Chan, {Jennifer A.} and Ana Nikolic and Garre, {Maria Luisa} and {Van Meir}, {Erwin G.} and Satoru Osuka and Olson, {Jeffrey J.} and Arman Jahangiri and Castro, {Brandyn A.} and Nalin Gupta and Weiss, {William A.} and Iska Moxon-Emre and Mabbott, {Donald J.} and Alvaro Lassaletta and Hawkins, {Cynthia E.} and Uri Tabori and James Drake and Abhaya Kulkarni and Peter Dirks and Rutka, {James T.} and Andrey Korshunov and Pfister, {Stefan M.} and Packer, {Roger J.} and Vijay Ramaswamy and Taylor, {Michael D.}",
year = "2016",
month = "4",
day = "1",
doi = "10.1016/S1470-2045(15)00581-1",
language = "English (US)",
volume = "17",
pages = "484--495",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
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}

TY - JOUR

T1 - Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup

T2 - a retrospective integrated clinical and molecular analysis

AU - Thompson, Eric M.

AU - Hielscher, Thomas

AU - Bouffet, Eric

AU - Remke, Marc

AU - Luu, Betty

AU - Gururangan, Sridharan

AU - McLendon, Roger E.

AU - Bigner, Darell D.

AU - Lipp, Eric S.

AU - Perreault, Sebastien

AU - Cho, Yoon-Jae

AU - Grant, Gerald

AU - Kim, Seung Ki

AU - Lee, Ji Yeoun

AU - Rao, Amulya A.Nageswara

AU - Giannini, Caterina

AU - Li, Kay Ka Wai

AU - Ng, Ho Keung

AU - Yao, Yu

AU - Kumabe, Toshihiro

AU - Tominaga, Teiji

AU - Grajkowska, Wieslawa A.

AU - Perek-Polnik, Marta

AU - Low, David C.Y.

AU - Seow, Wan Tew

AU - Chang, Kenneth T.E.

AU - Mora, Jaume

AU - Pollack, Ian F.

AU - Hamilton, Ronald L.

AU - Leary, Sarah

AU - Moore, Andrew S.

AU - Ingram, Wendy J.

AU - Hallahan, Andrew R.

AU - Jouvet, Anne

AU - Fèvre-Montange, Michelle

AU - Vasiljevic, Alexandre

AU - Faure-Conter, Cecile

AU - Shofuda, Tomoko

AU - Kagawa, Naoki

AU - Hashimoto, Naoya

AU - Jabado, Nada

AU - Weil, Alexander G.

AU - Gayden, Tenzin

AU - Wataya, Takafumi

AU - Shalaby, Tarek

AU - Grotzer, Michael

AU - Zitterbart, Karel

AU - Sterba, Jaroslav

AU - Kren, Leos

AU - Hortobágyi, Tibor

AU - Klekner, Almos

AU - László, Bognár

AU - Pócza, Tímea

AU - Hauser, Peter

AU - Schüller, Ulrich

AU - Jung, Shin

AU - Jang, Woo Youl

AU - French, Pim J.

AU - Kros, Johan M.

AU - van Veelen, Marie Lise C.

AU - Massimi, Luca

AU - Leonard, Jeffrey R.

AU - Rubin, Joshua B.

AU - Vibhakar, Rajeev

AU - Chambless, Lola B.

AU - Cooper, Michael K.

AU - Thompson, Reid C.

AU - Faria, Claudia C.

AU - Carvalho, Alice

AU - Nunes, Sofia

AU - Pimentel, José

AU - Fan, Xing

AU - Muraszko, Karin M.

AU - López-Aguilar, Enrique

AU - Lyden, David

AU - Garzia, Livia

AU - Shih, David J.H.

AU - Kijima, Noriyuki

AU - Schneider, Christian

AU - Adamski, Jennifer

AU - Northcott, Paul A.

AU - Kool, Marcel

AU - Jones, David T.W.

AU - Chan, Jennifer A.

AU - Nikolic, Ana

AU - Garre, Maria Luisa

AU - Van Meir, Erwin G.

AU - Osuka, Satoru

AU - Olson, Jeffrey J.

AU - Jahangiri, Arman

AU - Castro, Brandyn A.

AU - Gupta, Nalin

AU - Weiss, William A.

AU - Moxon-Emre, Iska

AU - Mabbott, Donald J.

AU - Lassaletta, Alvaro

AU - Hawkins, Cynthia E.

AU - Tabori, Uri

AU - Drake, James

AU - Kulkarni, Abhaya

AU - Dirks, Peter

AU - Rutka, James T.

AU - Korshunov, Andrey

AU - Pfister, Stefan M.

AU - Packer, Roger J.

AU - Ramaswamy, Vijay

AU - Taylor, Michael D.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

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U2 - 10.1016/S1470-2045(15)00581-1

DO - 10.1016/S1470-2045(15)00581-1

M3 - Article

VL - 17

SP - 484

EP - 495

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 4

ER -