{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:39:06Z","timestamp":1790314746533,"version":"4.1.0"},"reference-count":37,"publisher":"Bioscientifica","issue":"6","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Malignant insulinomas are rare pancreatic neuroendocrine tumors characterized by excessive insulin secretion and a high propensity for metastasis, leading to challenging management. This study retrospectively analyzed 57 patients treated for malignant insulinoma at Mayo Clinic sites between 1992 and 2024, focusing on the efficacy of systemic therapies in improving hypoglycemic control and survival outcomes. The most commonly used therapies included somatostatin analogs (SSA), everolimus, capecitabine-temozolomide (CAPTEM), and peptide receptor radionuclide therapy (PRRT). PRRT demonstrated the highest efficacy in controlling hypoglycemia (93%), followed by CAPTEM (68%) and everolimus (62%). SSA, chemotherapy, and streptozocin were less effective, with hypoglycemic improvement seen in 37.5, 33.3, and 28.6% of patients, respectively. Overall survival (OS) was longest with SSA at 84.67 months, followed by CAPTEM at 81.67 months and everolimus at 74.07 months. PRRT demonstrated a median OS of 49.73 months. In contrast, chemotherapy and streptozocin-based therapies had significantly shorter OS times of 15.23 and 8.35 months, respectively. These findings highlight significant variability in systemic therapy efficacy for malignant insulinoma, with PRRT emerging as a promising treatment for refractory hypoglycemia and long survival. Cox regression analysis identified primary tumor resection and a history of benign insulinoma as associated with longer OS. Optimal sequencing of therapies remains unclear, and individualized treatment plans based on hypoglycemic burden and tumor characteristics are critical for improving survival and quality of life in these patients.<\/jats:p>","DOI":"10.1530\/erc-25-0091","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T11:15:31Z","timestamp":1748517331000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":5,"title":["Comparative efficacy of systemic therapies in malignant insulinoma"],"prefix":"10.1530","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6618-6862","authenticated-orcid":true,"given":"Regina","family":"Koch","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic 1 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick Walsh","family":"McGarrah","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Mayo Clinic 2 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Vella","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Mayo Clinic 3 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Mayo Clinic 3 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J","family":"Hobday","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Mayo Clinic 2 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Bassam","family":"Sonbol","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic 4 , , ,","place":["Scottsdale, Arizona, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8674-8102","authenticated-orcid":true,"given":"Jason","family":"Starr","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic 5 , , ,","place":["Jacksonville, Florida, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Eiring","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Mayo Clinic 2 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis J","family":"McKenzie","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Surgery, Mayo Clinic 6 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Sada","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mayo Clinic 7 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Starlinger","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mayo Clinic 7 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-2769","authenticated-orcid":true,"given":"Hallbera","family":"Gudmundsdottir","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mayo Clinic 7 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorvadur R","family":"Halfdanarson","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Mayo Clinic 2 , , ,","place":["Rochester, Minnesota, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"2026070905462957800_bib1","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/j.gassur.2006.09.004","article-title":"Cytoreduction results in high perioperative mortality and decreased survival in patients undergoing pancreatectomy for neuroendocrine tumors of the pancreas","volume":"10","author":"Bloomston","year":"2006","journal-title":"J Gastrointest Surg"},{"key":"2026070905462957800_bib2","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1056\/NEJMoa1316158","article-title":"Lanreotide in metastatic enteropancreatic neuroendocrine tumors","volume":"371","author":"Caplin","year":"2014","journal-title":"N Engl J Med"},{"key":"2026070905462957800_bib3","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1210\/jc.2015-2436","article-title":"Multiple and secondary hormone secretion in patients with metastatic pancreatic neuroendocrine tumours","volume":"101","author":"Crona","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905462957800_bib4","volume-title":"Endotext. South Dartmouth","author":"de Herder","year":"2000"},{"key":"2026070905462957800_bib5","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1016\/j.ejca.2014.10.002","article-title":"Bevacizumab combined with 5-FU\/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial)--a phase II non-randomised trial","volume":"50","author":"Ducreux","year":"2014","journal-title":"Eur J Cancer"},{"key":"2026070905462957800_bib6","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00280-012-2055-z","article-title":"Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the Pancreas Center at Columbia University experience","volume":"71","author":"Fine","year":"2013","journal-title":"Cancer Chemother Pharmacol"},{"key":"2026070905462957800_bib7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.2967\/jnumed.123.265894","article-title":"Peptide receptor radionuclide therapy is effective for clinical control of symptomatic metastatic insulinoma: a long-term retrospective analysis","volume":"65","author":"Friebe","year":"2024","journal-title":"J Nucl Med"},{"key":"2026070905462957800_bib8","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1136\/pgmj.73.864.640","article-title":"Diazoxide treatment for insulinoma: a national UK survey","volume":"73","author":"Gill","year":"1997","journal-title":"Postgrad Med J"},{"key":"2026070905462957800_bib9","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1080\/13651820701504199","article-title":"Hepatic resection for metastatic gastrointestinal and pancreatic neuroendocrine tumours: outcome and prognostic predictors","volume":"9","author":"Gomez","year":"2007","journal-title":"HPB"},{"key":"2026070905462957800_bib10","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.bpg.2005.05.008","article-title":"Insulinoma","volume":"19","author":"Grant","year":"2005","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"2026070905462957800_bib11","doi-asserted-by":"crossref","first-page":"4840","DOI":"10.1245\/s10434-023-13372-z","article-title":"Survival and symptomatic relief after cytoreductive hepatectomy for neuroendocrine tumor liver metastases: long-term follow-up evaluation of more than 500 patients","volume":"30","author":"Gudmundsdottir","year":"2023","journal-title":"Ann Surg Oncol"},{"key":"2026070905462957800_bib12","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1586\/eem.09.83","article-title":"Insulin secretion and insulin-producing tumors","volume":"5","author":"Guettier","year":"2010","journal-title":"Expert Rev Endocrinol Metab"},{"key":"2026070905462957800_bib13","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1097\/MPA.0000000000001569","article-title":"Effectiveness of liver-directed therapy for the management of intractable hypoglycemia in metastatic insulinoma","volume":"49","author":"Habibollahi","year":"2020","journal-title":"Pancreas"},{"key":"2026070905462957800_bib14","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1210\/clinem\/dgad641","article-title":"Approach to the patient: insulinoma","volume":"109","author":"Hofland","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905462957800_bib15","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/hpb.12326","article-title":"Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference","volume":"17","author":"Kennedy","year":"2015","journal-title":"HPB"},{"key":"2026070905462957800_bib16","doi-asserted-by":"crossref","first-page":"4762","DOI":"10.1200\/JCO.2004.04.024","article-title":"Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas","volume":"22","author":"Kouvaraki","year":"2004","journal-title":"J Clin Oncol"},{"key":"2026070905462957800_bib17","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1056\/NEJMc0806740","article-title":"Glycemic control in patients with insulinoma treated with everolimus","volume":"360","author":"Kulke","year":"2009","journal-title":"N Engl J Med"},{"key":"2026070905462957800_bib18","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvab149","article-title":"Hepatic artery embolization for palliation of symptomatic hypoglycemia in patients with hepatic insulinoma metastases","volume":"5","author":"Linch","year":"2021","journal-title":"J Endocr Soc"},{"key":"2026070905462957800_bib19","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000012784","article-title":"Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: a meta-analysis","volume":"97","author":"Lu","year":"2018","journal-title":"Medicine"},{"key":"2026070905462957800_bib20","article-title":"Metastatic insulinoma-outcomes in the current era","volume":"30","author":"Masharani","year":"2024","journal-title":"Oncologist"},{"key":"2026070905462957800_bib21","doi-asserted-by":"crossref","first-page":"489","DOI":"10.14310\/horm.2002.1706","article-title":"Glycemic control in patients with insulinoma","volume":"15","author":"Matej","year":"2016","journal-title":"Hormones"},{"key":"2026070905462957800_bib22","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1056\/NEJM199202203260804","article-title":"Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma","volume":"326","author":"Moertel","year":"1992","journal-title":"N Engl J Med"},{"key":"2026070905462957800_bib23","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1111\/j.1365-2265.2007.03161.x","article-title":"Continuous glucose monitoring in patients with insulinoma","volume":"68","author":"Munir","year":"2008","journal-title":"Clin Endocrinol"},{"key":"2026070905462957800_bib24","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1093\/annonc\/mdh216","article-title":"Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system","volume":"15","author":"Oberg","year":"2004","journal-title":"Ann Oncol"},{"key":"2026070905462957800_bib25","first-page":"S207","article-title":"Cytoreductive surgery in advanced endocrine tumours of the pancreas","volume":"31","author":"Pederzoli","year":"1999","journal-title":"Ital J Gastroenterol Hepatol"},{"key":"2026070905462957800_bib26","doi-asserted-by":"crossref","first-page":"4656","DOI":"10.1200\/JCO.2009.22.8510","article-title":"Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group","volume":"27","author":"Rinke","year":"2009","journal-title":"J Clin Oncol"},{"key":"2026070905462957800_bib27","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1007\/s00268-020-05445-x","article-title":"Malignant insulinoma: a rare form of neuroendocrine tumor","volume":"44","author":"Sada","year":"2020","journal-title":"World J Surg"},{"key":"2026070905462957800_bib28","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.amjsurg.2020.08.003","article-title":"Comparison of benign and malignant insulinoma","volume":"221","author":"Sada","year":"2021","journal-title":"Am J Surg"},{"key":"2026070905462957800_bib29","doi-asserted-by":"crossref","first-page":"880","DOI":"10.4158\/EP.14.7.880","article-title":"Use of a continuous glucose monitor in the management of inoperable metastatic insulinoma: a case report","volume":"14","author":"Sawyer","year":"2008","journal-title":"Endocr Pract"},{"key":"2026070905462957800_bib30","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/S0025-6196(12)62083-7","article-title":"Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study","volume":"66","author":"Service","year":"1991","journal-title":"Mayo Clin Proc"},{"key":"2026070905462957800_bib31","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/cncr.25425","article-title":"First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas","volume":"117","author":"Strosberg","year":"2011","journal-title":"Cancer"},{"key":"2026070905462957800_bib32","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1477-2574.2012.00528.x","article-title":"Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection","volume":"15","author":"Taner","year":"2013","journal-title":"HPB"},{"key":"2026070905462957800_bib33","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1210\/jc.2011-1563","article-title":"Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy","volume":"96","author":"van Schaik","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905462957800_bib34","doi-asserted-by":"crossref","DOI":"10.1210\/clinem\/dgaf195","article-title":"Efficacy and safety of pasireotide in insulinoma-associated hypoglycemia: a systematic review","author":"Vega-Beyhart","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905462957800_bib35","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1530\/EJE-19-0989","article-title":"Clinico-pathological features, treatments and survival of malignant insulinomas: a multicenter study","volume":"182","author":"Veltroni","year":"2020","journal-title":"Eur J Endocrinol"},{"key":"2026070905462957800_bib36","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.jamcollsurg.2016.12.032","article-title":"Aggressive surgical approach to the management of neuroendocrine tumors: a report of 1,000 surgical cytoreductions by a single institution","volume":"224","author":"Woltering","year":"2017","journal-title":"J Am Coll Surg"},{"key":"2026070905462957800_bib37","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1210\/jc.2018-01991","article-title":"Symptomatic and radiological response to 177Lu-DOTATATE for the treatment of functioning pancreatic neuroendocrine tumors","volume":"104","author":"Zandee","year":"2019","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/32\/6\/ERC-25-0091.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/32\/6\/ERC-25-0091.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0091\/247069\/erc-25-0091.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-25-0091\/247069\/erc-25-0091.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T09:46:38Z","timestamp":1783590398000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/32\/6\/e250091\/25989\/Comparative-efficacy-of-systemic-therapies-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,29]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-25-0091","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2025,5,29]]},"article-number":"e250091"}}