{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:54:49Z","timestamp":1789584889765,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,2,16]],"date-time":"2018-02-16T00:00:00Z","timestamp":1518739200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004416","name":"Novartis Foundation for Sustainable Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004416","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Neuroendocrine tumors (NETs) metastasize to the liver. Everolimus and selective internal radioembolization (SIRT) are approved treatments. Pasireotide is a somatostatin analogue with an affinity for somatostatin receptors 1, 2, 3, and 5. Everolimus and pasireotide may potentiate SIRT radiosensitization and inhibit rebound angiogenesis. This study evaluated the safety of pasireotide, everolimus, and SIRT.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>This 3 + 3 phase 1 trial evaluated 3 dose levels of everolimus (2.5, 5, and 10 mg\/day), pasireotide (600 \u03bcg twice daily), and SIRT (SIR\u2010Spheres dose on days 9 and 37). Eligibility criteria included well or moderately differentiated NETs, bilobar liver metastases, and progression on long\u2010acting octreotide. Toxicities and responses were evaluated with the Common Terminology Criteria for Adverse Events and the Response Evaluation Criteria in Solid Tumors (version 1.1). Dose\u2010limiting toxicities (DLTs) were defined in the first 28 days. Correlative markers\u2014angiopoietin 1, angiopoietin 2, basic fibroblast growth factor, collagen V, insulin\u2010like growth factor binding protein 1, insulin\u2010like growth factor binding protein 1, interleukin 8, M30, M65, placenta growth factor, and vascular endothelial growth factor receptor 2\u2014were assessed. The Norfolk Quality of Life\u2013Neuroendocrine Tumor Questionnaire was used to assess the quality of life (QOL).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Thirteen patients were enrolled; 1 was not evaluable for the primary endpoint. Eleven patients had well\u2010differentiated tumors. The primary sites included small bowel (4), pancreas (3), lung (2), colon (1), gastric (1), and unknown primary (2) were unknown. Four had liver\u2010only disease; 12 completed the planned treatment. No DLTs were observed. There was no treatment\u2010related mortality. The most common toxicity was hyperglycemia. Clinically significant liver toxicity was not observed. One patient had liver progression. QOL improved on treatment. The median progression\u2010free survival and overall survival were 18.6 and 46.3 months, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The recommended phase 2 dose of everolimus is 10 mg daily in combination with pasireotide and SIRT. The regimen is well tolerated. Preliminary activity appears promising. <jats:bold><jats:italic>Cancer<\/jats:italic> 2018;124:1992\u20102000.<\/jats:bold> \u00a9 <jats:italic>2018 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.31192","type":"journal-article","created":{"date-parts":[[2018,2,16]],"date-time":"2018-02-16T09:56:39Z","timestamp":1518774999000},"page":"1992-2000","source":"Crossref","is-referenced-by-count":37,"title":["Phase 1b study of pasireotide, everolimus, and selective internal radioembolization therapy for unresectable neuroendocrine tumors with hepatic metastases"],"prefix":"10.1002","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3077-9989","authenticated-orcid":false,"given":"Hyun S.","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Interventional Radiology, Yale Cancer Center Yale School of Medicine New Haven 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