{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:16:17Z","timestamp":1781795777032,"version":"3.54.5"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012634","name":"novocure","doi-asserted-by":"publisher","award":["1.300.644 USD"],"award-info":[{"award-number":["1.300.644 USD"]}],"id":[{"id":"10.13039\/100012634","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"danmarks frie forskningsfond","doi-asserted-by":"publisher","award":["1.392.683 DKK"],"award-info":[{"award-number":["1.392.683 DKK"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012526","name":"sundhedsvidenskabelige fakultet, aarhus universitet","doi-asserted-by":"publisher","award":["550.000 DKK"],"award-info":[{"award-number":["550.000 DKK"]}],"id":[{"id":"10.13039\/100012526","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008363","name":"kr\u00e6ftens bek\u00e6mpelse","doi-asserted-by":"publisher","award":["1.700.000 DKK"],"award-info":[{"award-number":["1.700.000 DKK"]}],"id":[{"id":"10.13039\/100008363","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy (TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15\u2009mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety\/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age\u2009\u2265\u200918\u2009years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score\u2009\u2265\u200970, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12\u2009months (OS12), assuming OS12\u2009=\u200940% in the control group and OS12\u2009=\u200960% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04223999\">NCT0422399<\/jats:ext-link>, registered 13. January 2020.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12885-021-08709-4","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T09:02:47Z","timestamp":1631178167000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Study protocol for OptimalTTF-2: enhancing Tumor Treating Fields with skull remodeling surgery for first recurrence glioblastoma: a phase 2, multi-center, randomized, prospective, interventional trial"],"prefix":"10.1186","volume":"21","author":[{"given":"N.","family":"Mikic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. R.","family":"Poulsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. B.","family":"Kristoffersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. J.","family":"Laursen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. L.","family":"Guldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Skj\u00f8th-Rasmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. T.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"M\u00f8ller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. H.","family":"Dahlrot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. C. H.","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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AE reporting procedures will comply with <i>Guidelines on medical devices. Clinical investigations: Serious adverse event reporting (MEDDEV 2.7\/3)<\/i> and <i>Reporting of adverse reactions in clinical trials<\/i>. All data will be handled in accordance with <i>The Danish Act on Processing of Personal Data<\/i>. Clinical trial approval has been gained from the Central Denmark Region Committee of Health Research Ethics, The Danish Data Protection Agency, and the Danish Health Authorities for all sites.All patients will receive oral and written information by a certified neurosurgeon with time to consider enrollment in the trial. Based upon the written and oral information, they will give signed informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"None of the authors have any competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1010"}}