{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:22:14Z","timestamp":1790504534191,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T00:00:00Z","timestamp":1571356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000098","name":"NIH Clinical Center","doi-asserted-by":"publisher","award":["Translational Science Award KL2 Training Grant TR0"],"award-info":[{"award-number":["Translational Science Award KL2 Training Grant TR0"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012875","name":"Cancer Institute, University of Cincinnati","doi-asserted-by":"publisher","award":["University of Cincinnati Cancer Institute Pilot aw"],"award-info":[{"award-number":["University of Cincinnati Cancer Institute Pilot aw"]}],"id":[{"id":"10.13039\/100012875","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2020,1,15]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The 5\u2010year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000\u00a0mg, 2550\u00a0mg, and 3000\u00a0mg daily in divided doses in addition to cisplatin (at a dose of 100\u00a0mg\/m<jats:sup>2<\/jats:sup> on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56\u00a0years and the majority were male (83%), were white (88%), had p16\u2010positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5\u00a0days. The most common grade \u22653 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose\u2010limiting toxicities included diarrhea and acute kidney injury. After a median follow\u2010up of 19\u00a0months, the 2\u2010year overall survival and progression\u2010free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>To the authors\u2019 knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression\u2010free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.32539","type":"journal-article","created":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T14:54:06Z","timestamp":1571410446000},"page":"354-362","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Phase 1 dose\u2010finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer"],"prefix":"10.1002","volume":"126","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6793-9694","authenticated-orcid":false,"given":"Shuchi","family":"Gulati","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8673-1327","authenticated-orcid":false,"given":"Janki","family":"Desai","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences James L. Winkle College of Pharmacy University of Cincinnati Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Palackdharry","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8183-751X","authenticated-orcid":false,"given":"John C.","family":"Morris","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Environmental Health University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2145-045X","authenticated-orcid":false,"given":"Roman","family":"Jandarov","sequence":"additional","affiliation":[{"name":"Department of Environmental Health University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1855-7862","authenticated-orcid":false,"given":"Muhammad K.","family":"Riaz","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2499-3516","authenticated-orcid":false,"given":"Vinita","family":"Takiar","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3923-9970","authenticated-orcid":false,"given":"Michelle","family":"Mierzwa","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology University of Michigan Ann Arbor Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-4482","authenticated-orcid":false,"given":"J. Silvio","family":"Gutkind","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California at San Diego Moores Cancer Center La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Molinolo","sequence":"additional","affiliation":[{"name":"Department of Pathology University of California at San Diego Moores Cancer Center La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3001-1603","authenticated-orcid":false,"given":"Pankaj B.","family":"Desai","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences James L. Winkle College of Pharmacy University of Cincinnati Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nooshin Hashemi","family":"Sadraei","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7279-4028","authenticated-orcid":false,"given":"Trisha M.","family":"Wise\u2010Draper","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,10,18]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Surveillance Epidemiology and End Results.Common cancer sites\u2013Cancer Stat Facts. Accessed June 10 2019.https:\/\/seer.cancer.gov\/statfacts\/html\/common.html"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0000000000000595"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy102"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.5633"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2009.04.014"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2016.5526"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8194"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23743"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hed.23409"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.26489"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0894"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0103"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124989"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.187"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.45.7903"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/1753-0407.12900"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc18-1662"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.2165\/11534750-000000000-00000"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01111"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1984.86"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)32105-1"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2015.01.007"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.54"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.27224"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2016-000132"},{"key":"e_1_2_8_27_1","unstructured":"ClinicalTrials.gov.Chemotherapy and radiation therapy with or without metformin hydrochloride in treating patients with stage III non\u2013small cell lung cancer. Accessed December 19 2018.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02186847"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.32539","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.32539","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cncr.32539","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.32539","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T13:45:43Z","timestamp":1760276743000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.32539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,18]]},"references-count":26,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,1,15]]}},"alternative-id":["10.1002\/cncr.32539"],"URL":"https:\/\/doi.org\/10.1002\/cncr.32539","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,18]]},"assertion":[{"value":"2019-04-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-10-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}