Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia

Abstract

Background: Refractory hypoglycemia in patients with metastatic insulinoma is an important cause of morbidity and mortality. Everolimus could be a new therapeutic option. Methods: Within the French Group, we conducted a retrospective, multicentric study of endocrine tumors to evaluate the time to the first recurrence of symptomatic hypoglycemia, after everolimus initiation, in patients with metastatic insulinoma and refractory hypoglycemia. Ongoing hyperglycemic medical options, tumor response, and safety information were recorded. Results: Twelve patients with metastatic insulinoma and refractory hypoglycemia who were treated with everolimus between May 2007 and June 2011 were reviewed. Everolimus (starting dose, 10 mg/day, except in one patient, 5 mg/day) was given after a median of four previous therapeutic lines. Medication aimed at normalizing blood glucose levels in 11 patients. After a median duration of 6.5 months (range 1-35C months), median time to the first recurrence of symptomatic hypoglycemia was 6.5 months (range 0 to 35C months). Three patients discontinued everolimus because of cardiac and/or pulmonary adverse events at 1, 1.5, and 7 months after initiation, which led to two deaths. Three patients discontinued everolimus because of tumor progression at 2, 3, and 10 months after initiation, without recurrence of hypoglycemia. Conclusion: Everolimus appears to be a new effective treatment for patients with metastatic insulinoma and refractory hypoglycemia. Tolerance should be carefully monitored.

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

“…Interestingly, Kulke et al (72) first reported in 2009 that the use of everolimus in four patients with insulinoma and refractory hypoglycemia was associated with improved glycemic control. This 'beneficial' hyperglycemic effect of mTOR inhibitors in patients with metastatic insulinoma has since been confirmed in a large size study (73). This effect of mTOR inhibitors in cases of severe insulinoma is another proof of the hyperglycemic effect of this therapeutic class.…”

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives

“…Conversely, patients with malignant unresectable insulinomas may take great advantage of this effect, as shown by some retrospective studies in this setting (Bernard et al 2013;Ferrer-Garcia et al 2013). Therefore, everolimus could be employed as first line treatment for progressive malignant insulinomas with refractory hypoglycaemia, as suggested by recent guidelines.…”

“…Overall, 8 retrospective studies were identified (Bernard et al 2013;Capdevila et al 2015;Ferrer-Garcia et al 2013;Fiebrich et al 2011;Kulke et al 2009;Liu et al 2016;Panzuto et al 2014;Tippeswamy et al 2015), which included a total of 183 patients with pancreatic and 135 patients with extra-pancreatic NETs (see Table 2a). …”

Successful EUS-guided ethanol ablation of insulinoma, four-year follow-up. Case report and literature review

“…Conservative treatment with use of diazoxide is not always effective, and the adverse effects are often observed [2]. Therefore, new methods of treatment are proposed with use of somatostatin analogues, mTOR inhibitor (everolimus), tyrosine kinase inhibitor (sunitinib), peptide receptor radionuclide therapy (PPRT), chemoembolisation, and radiofrequency or alcoholic ablation [3][4][5][6][7][8][9][10][11].…”