{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:36:22Z","timestamp":1794029782212,"version":"4.8.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101103655"],"award-info":[{"award-number":["101103655"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg\/m<jats:sup>2<\/jats:sup> every 6 weeks) or lomustine (110 mg\/m<jats:sup>2<\/jats:sup> every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (<jats:italic>IDH<\/jats:italic>) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0\u20132. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union\u2019s Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-024-08213-7","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T05:01:48Z","timestamp":1717736508000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Lomustine with or without reirradiation for first progression of glioblastoma, LEGATO, EORTC-2227-BTG: study protocol for a randomized phase III study"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3541-2315","authenticated-orcid":false,"given":"Matthias","family":"Preusser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1\u0161","family":"Kazda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Le Rhun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Sahm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Smits","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Gempt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan AF","family":"Koekkoek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo F","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcell","family":"Csanadi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e1nos Gy\u00f6rgy","family":"Pitter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Bulbek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Fournier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Quoilin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Gorlia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Weller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Minniti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the European Organisation for Research, Treatment of Cancer (EORTC) Brain Tumor Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"issue":"3","key":"8213_CR1","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/s41571-020-00447-z","volume":"18","author":"M Weller","year":"2021","unstructured":"Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170\u201386.","journal-title":"Nat Rev Clin Oncol"},{"key":"8213_CR2","doi-asserted-by":"publisher","first-page":"102029","DOI":"10.1016\/j.ctrv.2020.102029","volume":"87","author":"M Weller","year":"2020","unstructured":"Weller M, Le Rhun E. How did lomustine become standard of care in recurrent glioblastoma? Cancer Treat Rev. 2020;87:102029.","journal-title":"Cancer Treat Rev"},{"issue":"6","key":"8213_CR3","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1200\/JCO.22.00164","volume":"41","author":"CI Tsien","year":"2023","unstructured":"Tsien CI, Pugh SL, Dicker AP, Raizer JJ, Matuszak MM, Lallana EC, et al. NRG Oncology\/RTOG1205: a randomized phase II trial of concurrent bevacizumab and reirradiation versus bevacizumab alone as treatment for recurrent glioblastoma. J Clin Oncol. 2023;41(6):1285\u201395.","journal-title":"J Clin Oncol"},{"key":"8213_CR4","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.radonc.2021.12.019","volume":"167","author":"P Navarria","year":"2022","unstructured":"Navarria P, Pessina F, Clerici E, Bellu L, Franzese C, Franzini A, et al. Re-irradiation for recurrent high grade glioma (HGG) patients: results of a single arm prospective phase 2 study. Radiother Oncol. 2022;167:89\u201396.","journal-title":"Radiother Oncol"},{"issue":"18","key":"8213_CR5","doi-asserted-by":"publisher","first-page":"3048","DOI":"10.1200\/JCO.2009.25.6941","volume":"28","author":"SE Fogh","year":"2010","unstructured":"Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, et al. Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol. 2010;28(18):3048\u201353.","journal-title":"J Clin Oncol"},{"issue":"4","key":"8213_CR6","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/S0360-3016(98)00457-X","volume":"43","author":"M Arcicasa","year":"1999","unstructured":"Arcicasa M, Roncadin M, Bidoli E, Dedkov A, Gigante M, Trovo MG. Reirradiation and lomustine in patients with relapsed high-grade gliomas. Int J Radiat Oncol Biol Phys. 1999;43(4):789\u201393.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"2","key":"8213_CR7","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/s11060-023-04407-2","volume":"164","author":"R De Pietro","year":"2023","unstructured":"De Pietro R, Zaccaro L, Marampon F, Tini P, De Felice F, Minniti G. The evolving role of reirradiation in the management of recurrent brain tumors. J Neurooncol. 2023;164(2):271\u201386.","journal-title":"J Neurooncol"},{"issue":"1","key":"8213_CR8","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13014-021-01767-9","volume":"16","author":"G Minniti","year":"2021","unstructured":"Minniti G, Niyazi M, Alongi F, Navarria P, Belka C. Current status and recent advances in reirradiation of glioblastoma. Radiat Oncol. 2021;16(1):36.","journal-title":"Radiat Oncol"},{"issue":"3","key":"8213_CR9","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s11060-015-1745-x","volume":"122","author":"G Minniti","year":"2015","unstructured":"Minniti G, Agolli L, Falco T, Scaringi C, Lanzetta G, Caporello P, et al. Hypofractionated stereotactic radiotherapy in combination with bevacizumab or fotemustine for patients with progressive malignant gliomas. J Neurooncol. 2015;122(3):559\u201366.","journal-title":"J Neurooncol"},{"issue":"2","key":"8213_CR10","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s00066-009-1969-9","volume":"185","author":"G Henke","year":"2009","unstructured":"Henke G, Paulsen F, Steinbach JP, Ganswindt U, Isijanov H, Kortmann RD, et al. Hypofractionated reirradiation for recurrent malignant glioma. Strahlenther Onkol. 2009;185(2):113\u20139.","journal-title":"Strahlenther Onkol"},{"issue":"1","key":"8213_CR11","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ijrobp.2017.08.038","volume":"100","author":"W Shi","year":"2018","unstructured":"Shi W, Scannell Bryan M, Gilbert MR, Mehta MP, Blumenthal DT, Brown PD, et al. Investigating the effect of reirradiation or systemic therapy in patients with glioblastoma after tumor progression: a secondary analysis of NRG Oncology\/Radiation Therapy Oncology Group Trial 0525. Int J Radiat Oncol Biol Phys. 2018;100(1):38\u201344.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"2","key":"8213_CR12","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/S0360-3016(98)00416-7","volume":"43","author":"RS Hudes","year":"1999","unstructured":"Hudes RS, Corn BW, Werner-Wasik M, Andrews D, Rosenstock J, Thoron L, et al. A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys. 1999;43(2):293\u20138.","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"3","key":"8213_CR13","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s11060-010-0446-8","volume":"103","author":"G Minniti","year":"2011","unstructured":"Minniti G, Armosini V, Salvati M, Lanzetta G, Caporello P, Mei M, et al. Fractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma. J Neurooncol. 2011;103(3):683\u201391.","journal-title":"J Neurooncol"},{"key":"8213_CR14","doi-asserted-by":"publisher","first-page":"h2147","DOI":"10.1136\/bmj.h2147","volume":"350","author":"K Loudon","year":"2015","unstructured":"Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ. 2015;350:h2147.","journal-title":"BMJ"},{"issue":"9","key":"8213_CR15","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1080\/13696998.2019.1624080","volume":"22","author":"AK Kawata","year":"2019","unstructured":"Kawata AK, Lenderking WR, Eseyin OR, Kerstein D, Huang J, Huang H, et al. Converting EORTC QLQ-C30 scores to utility scores in the brigatinib ALTA study. J Med Econ. 2019;22(9):924\u201335.","journal-title":"J Med Econ"},{"issue":"1","key":"8213_CR16","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/s40258-021-00682-0","volume":"20","author":"A Meunier","year":"2022","unstructured":"Meunier A, Soare A, Chevrou-Severac H, Myren KJ, Murata T, Longworth L. Indirect and direct mapping of the cancer-specific EORTC QLQ-C30 onto EQ-5D-5L utility scores. Appl Health Econ Health Policy. 2022;20(1):119\u201331.","journal-title":"Appl Health Econ Health Policy"},{"issue":"20","key":"8213_CR17","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1056\/NEJMoa1707358","volume":"377","author":"W Wick","year":"2017","unstructured":"Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377(20):1954\u201363.","journal-title":"N Engl J Med"},{"issue":"26","key":"8213_CR18","doi-asserted-by":"publisher","first-page":"3212","DOI":"10.1200\/JCO.2012.47.2464","volume":"31","author":"TT Batchelor","year":"2013","unstructured":"Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31(26):3212\u20138.","journal-title":"J Clin Oncol"},{"key":"8213_CR19","doi-asserted-by":"crossref","unstructured":"Seliger C, Nurnberg C, Wick W, Wick A. Lung toxicity of lomustine in the treatment of progressive gliomas. Neurooncol Adv. 2022;4(1):vdac068.","DOI":"10.1093\/noajnl\/vdac068"},{"issue":"7","key":"8213_CR20","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1093\/neuonc\/noad038","volume":"25","author":"M Weller","year":"2023","unstructured":"Weller M, Le Rhun E, Van den Bent M, Chang SM, Cloughesy TF, Goldbrunner R, et al. Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults. Neuro Oncol. 2023;25(7):1200\u201324.","journal-title":"Neuro Oncol"},{"issue":"10","key":"8213_CR21","doi-asserted-by":"publisher","first-page":"e469","DOI":"10.1016\/S1470-2045(22)00447-8","volume":"23","author":"N Andratschke","year":"2022","unstructured":"Andratschke N, Willmann J, Appelt AL, Alyamani N, Balermpas P, Baumert BG, et al. European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus on re-irradiation: definition, reporting, and clinical decision making. Lancet Oncol. 2022;23(10):e469\u201378.","journal-title":"Lancet Oncol"},{"issue":"28","key":"8213_CR22","doi-asserted-by":"publisher","first-page":"3199","DOI":"10.1200\/JCO.2015.62.3488","volume":"33","author":"TJ Smith","year":"2015","unstructured":"Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(28):3199\u2013212.","journal-title":"J Clin Oncol"},{"key":"8213_CR23","doi-asserted-by":"publisher","first-page":"e7586","DOI":"10.1136\/bmj.e7586","volume":"346","author":"A-W Chan","year":"2013","unstructured":"Chan A-W, Tetzlaff JM, G\u00f8tzsche PC, Altman DG, Mann H, Berlin J, et al. SPIRIT 2013 Explanation and Elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.","journal-title":"BMJ"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08213-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-024-08213-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08213-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T05:08:04Z","timestamp":1717736884000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-024-08213-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,7]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["8213"],"URL":"https:\/\/doi.org\/10.1186\/s13063-024-08213-7","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,7]]},"assertion":[{"value":"2 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval is assigned by all participating sites before patients\u2019 enrollment. All participating patients will provide written informed consent. Informed consent will be collected by the local investigators, who are board-certified physicians with current good clinical practice (GCP) certification, and confirmed delegation and completed training for clinical trial activities.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"This manuscript does not contain individual personal data from patients. No identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. The participant information materials and informed consent form are available from the authors on request and after relevant contractual arrangements.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MP has received honoraria for lectures, consultation, or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, B\u00f6hringer-Ingelheim, Telix, and Medscape.JG has received honoraria for lectures, consultation, or advisory board participation from the following for-profit companies: Zeiss and Saegen.JK: the author declares that he has no competing interests.TK: the author declares that he has no competing interests.FS: Honoraria from Illumina and co-founder and shareholder of Heidelberg Epignostix GmbHTG, BF, and CQ (EORTC): the authors declare that they have no competing interests.TGO: the author declares that he has no competing interests.ELR has received research grants from Bristol Meyers Squibb (BMS), and honoraria for lectures or advisory board participation or consulting from Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics, and Servier.MW has received research grants from Novartis, Quercis, and Versameb and honoraria for lectures or advisory board participation or consulting from Anheart, Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Pfizer, Philogen, Roche, and Servier.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"366"}}