A prognostic classification system for extent of resection in IDH-mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group

Philipp Karschnia¹, Jacob S Young², Maarten M J Wijnenga³, Tommaso Sciortino⁴, Nico Teske⁵, Alba Corell⁶, Arthur Wagner⁷, Gilbert Youssef⁸, Yae Won Park⁹, Levin Häni¹⁰, Stephanie T Jünger¹¹, Antonio Dono¹², Felix Ehret¹³, Eduardo E Mendoza Mireles¹⁴, Nicolas Neidert¹⁵, Francesco Bruno¹⁶, Chad A Tuchek¹⁷, Thijs van der Vaart¹⁸, Marco Rossi⁴, Marco Conti Nibali⁴, Lorenzo Gay⁴, Alfred Gramelt¹⁹, Nitin Tandon¹², Sung Soo Ahn⁹, Jong Hee Chang²⁰, Michael Weller²¹, Arnaud J P E Vincent²², Roland Goldbrunner¹¹, Daniel P Cahill²³, Raymond Y Huang²⁴, Andreas Raabe¹⁰, Bernhard Meyer⁷, Juergen Beck¹⁵, Annette M Molinaro², Susan M Chang², Michael A Vogelbaum¹⁷, Roberta Rudà¹⁶, Einar O Vik-Mo¹⁴, Jorg Dietrich²⁵, Yoshua Esquenazi¹², Stefan J Grau²⁶, Patrick Y Wen⁸, Asgeir S Jakola⁶, Oliver Schnell¹⁹, Lorenzo Bello⁴, Martin J van den Bent³, Shawn Hervey-Jumper², Mitchel S Berger², Joerg-Christian Tonn²⁷

Affiliations

¹ Department of Neurosurgery, Universitaetsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany; Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany. Electronic address: philipp.karschnia@uk-erlangen.de.
² Department of Neurosurgery & Division of Neuro-Oncology, University of San Francisco, San Francisco, CA, USA.
³ Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
⁴ Division for Neuro-Oncology, Department of Oncology and Hemato-Oncology, IRCCS Galeazzi Sant'Ambrogio, University of Milan, Milan, Italy.
⁵ Department of Neurosurgery, Universitaetsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany; Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany.
⁶ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁷ Department of Neurosurgery, Technical University of Munich, Munich, Germany.
⁸ Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁹ Department of Radiology and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea.
¹⁰ Department of Neurosurgery, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland.
¹¹ Department of Neurosurgery, University of Cologne, Cologne, Germany.
¹² Department of Neurosurgery, McGovern Medical School at UT Health Houston, Houston, TX, USA.
¹³ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Berlin, Germany & German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité - Universitätsmedizin Berlin, Germany.
¹⁴ Department of Neurosurgery, Oslo University Hospital & Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
¹⁵ Department of Neurosurgery, University of Freiburg, Freiburg, Germany.
¹⁶ Division of Neuro-Oncology, Department of Neuroscience, University of Turin, Turin, Italy.
¹⁷ Department of Neurosurgery, Moffitt Cancer Center, Tampa, FL, USA.
¹⁸ Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, Netherlands; Department of Neurology, Haaglanden Medical Center, The Hague, Netherlands.
¹⁹ Department of Neurosurgery, Universitaetsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
²⁰ Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.
²¹ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
²² Department of Neurosurgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
²³ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁴ Department of Radiology, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA.
²⁵ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁶ Department of Neurosurgery, University of Cologne, Cologne, Germany; Klinikum Fulda, Academic Hospital of Marburg University, Fulda, Germany.
²⁷ Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany.

PMID: 41308678
DOI: 10.1016/S1470-2045(25)00534-0

Free article

Multicenter Study

A prognostic classification system for extent of resection in IDH-mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group

Philipp Karschnia et al. Lancet Oncol. 2025 Dec.

Free article

. 2025 Dec;26(12):1638-1650.

doi: 10.1016/S1470-2045(25)00534-0.

Authors

Affiliations

¹ Department of Neurosurgery, Universitaetsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany; Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany. Electronic address: philipp.karschnia@uk-erlangen.de.
² Department of Neurosurgery & Division of Neuro-Oncology, University of San Francisco, San Francisco, CA, USA.
³ Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
⁴ Division for Neuro-Oncology, Department of Oncology and Hemato-Oncology, IRCCS Galeazzi Sant'Ambrogio, University of Milan, Milan, Italy.
⁵ Department of Neurosurgery, Universitaetsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany; Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany.
⁶ Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁷ Department of Neurosurgery, Technical University of Munich, Munich, Germany.
⁸ Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁹ Department of Radiology and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea.
¹⁰ Department of Neurosurgery, Inselspital Bern, Bern University Hospital, University of Bern, Bern, Switzerland.
¹¹ Department of Neurosurgery, University of Cologne, Cologne, Germany.
¹² Department of Neurosurgery, McGovern Medical School at UT Health Houston, Houston, TX, USA.
¹³ Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Radiation Oncology, Berlin, Germany & German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité - Universitätsmedizin Berlin, Germany.
¹⁴ Department of Neurosurgery, Oslo University Hospital & Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
¹⁵ Department of Neurosurgery, University of Freiburg, Freiburg, Germany.
¹⁶ Division of Neuro-Oncology, Department of Neuroscience, University of Turin, Turin, Italy.
¹⁷ Department of Neurosurgery, Moffitt Cancer Center, Tampa, FL, USA.
¹⁸ Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, Netherlands; Department of Neurology, Haaglanden Medical Center, The Hague, Netherlands.
¹⁹ Department of Neurosurgery, Universitaetsklinikum Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
²⁰ Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.
²¹ Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
²² Department of Neurosurgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
²³ Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁴ Department of Radiology, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA.
²⁵ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁶ Department of Neurosurgery, University of Cologne, Cologne, Germany; Klinikum Fulda, Academic Hospital of Marburg University, Fulda, Germany.
²⁷ Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany.

PMID: 41308678
DOI: 10.1016/S1470-2045(25)00534-0

Abstract

Background: The efficacy of resection in IDH-mutant grade 2 gliomas remain controversial since terminology for the extent of resection has been inconsistently applied across studies. We aimed to establish a standardised classification for the extent of resection and assess the association between supramaximal resection and survival across molecular subtypes.

Methods: In this international, multicentre, retrospective study, patients aged 18 years and older with newly diagnosed grade 2 IDH-mutant glioma were identified from institutional databases across 16 centres in the USA, Europe, and Asia between between Sept 1, 1993, and May 10, 2024. We used Cox proportional hazard regressions to analyse the associations between residual tumour and progression-free survival and overall survival. Patients were stratified according to a previously postulated classification system based on residual tumour volume. A cohort of patients from UCSF diagnosed between Feb 16, 1998, and Nov 14, 2017, was used for geographically and institutionally independent external validation.

Findings: We identified 1391 patients with newly diagnosed IDH-mutant grade 2 gliomas, with a median follow-up of 81 months (95% CI 78-85). 728 patients (379 with astrocytoma and 349 with oligodendroglioma) received no first-line treatment beyond surgery, allowing us to study the isolated effects of resection. Patients with maximal T2-fluid attenuated inversion recovery (T2-FLAIR) resection (class 2; 0-5 cm³ remnant) had superior progression-free and overall survival compared with submaximal T2-FLAIR resection (class 3; 5-25 cm³ remnant) or minimal T2-FLAIR resection (class 4; >25 cm³ remnant), with 10-year survival rates of 82% (95% CI 76-87) versus 75% (62-84) versus 48% (29-65; p<0·0001) and 5-year progression-free survival rates of 44% (38-50) versus 25% (16-34) versus 12% (4-24; p<0·0001), respectively. Resection beyond T2-FLAIR borders (class 1) provided survival benefits, with a 10-year survival rate of 98% (95% CI 92-99) and a 5-year progression-free survival rate of 83% (76-88) for supramaximal T2-FLAIR resection (class 1). Associations between survival and extensive resection were evident after 3 years in astrocytomas, whereas survival curves separated after 6-8 years in oligodendrogliomas. The prognostic relevance of the four-tier classification was conserved in multivariable analyses, in 625 patients receiving first-line chemotherapy or radiotherapy (with or without chemotherapy), and in the external UCSF cohort of 381 patients with IDH-mutant grade 2 gliomas.

Interpretation: The proposed RANO classification for extent of resection could serve as a tool for prognostic stratification. Although associations between survival and extensive surgery are evident sooner in patients with astrocytoma, supramaximal resection also translates into survival benefits for patients with oligodendrogliomas.

Funding: None.

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Conflict of interest statement

Declaration of interests PK reports consulting for the American Society for Clinical Oncology. MMJW reports consulting for Servier. FE reports research funding from German Cancer Aid and Accuray and honoraria and travel support from Accuray and ZAP Surgical Systems. NN reports advisory board participation and consulting for Servier and B Braun New Ventures. MW reports research grants from Novartis, Quercis, and Versameb and honoraria or advisory board participation and consulting for Anheart, Bayer, CureVac, Medac, Neurosense, Novartis, Novocure, Orbus, Philogen, Pfizer, Roche, and Servier. DPC reports advisory board participation for Lilly, GlaxoSmithKline, Incephalo, Boston Pharmaceuticals, Servier, Boston Scientific, and Pyramid Biosciences (equity interest), speaker Honoria from Merck, and clinical trial and grant review for the US National Institutes of Health and Department of Defense. RYH reports advisory board participation for Vysioneer and consulting for Nuvation Bio. MAV reports indirect equity and patent royalty interests from Infuseon Therapeutics, honoraria from Chimerix and Midatech, and research grants from DeNovo Pharma, Oncosynergy, Infuseon, and Chimerix. RR reports honoraria, advisory board participation, and consulting for UCB, Bayer, Novocure, Genenta, and Servier. JD reports consulting and advisory board participation for Amgen, Novartis and Janssen, research support from Ono Therapeutics and Novartis, and royalties from Wolters Kluwer. PYW reports research support from AstraZeneca, Black Diamond, Bristol Meyers Squibb, Chimerix, Eli Lily, Erasca, Global Coalition for Adaptive Research, Kazia, MediciNova, Merck, Novartis, Quadriga, Servier, and VBI Vaccines and advisory board participation or consulting for Anheart, AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GlaxoSmithKline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, and VBI Vaccines. MJvdB reports consulting for Celgene, Boehringer, Carthera, Nerviano, Genenta, Servier, Anheart Therapeutics, Boehringer Ingelheim, Fore Biotherapeutics, Incyte, and Symbiopharma. J-CT reports honoraria or advisory board participation and consulting for CarThera, Servier, ERCM, and Impatients. All other authors declare no competing interests.

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A prognostic classification system for extent of resection in IDH-mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group

Affiliations

A prognostic classification system for extent of resection in IDH-mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group

Authors

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Abstract

Conflict of interest statement

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