Multidisciplinary management of refractory insulinomas

Abstract

Insulinomas are predominantly benign (~90%), pancreatic neuroendocrine tumours characterized by hyperinsulinaemic hypoglycaemia. They usually present as a small (<2 cm), well-demarcated, solitary nodule that can arise in any part of the organ. Treatment for sporadic insulinomas is generally aimed at curative surgical resection with special consideration in genetic syndromes. Patients with significant hypoglycaemia can pose a difficult management challenge. In isolated cases where the patient is not medically fit for surgery or with metastatic spread, other treatment options are employed. Medical therapy with diazoxide or somatostatin analogues is commonly used first line for symptom control, albeit with variable efficacy. Other medical options are emerging, including newer targeted biological therapies, including everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor) and pasireotide, a multisomatostatin receptor ligand. Pasireotide and everolimus both cause hyperglycaemia by physiological mechanisms synergistic with its antitumour/antiproliferative effects. Minimally invasive treatment modalities such as ethanol ablation are available in selected cases (particularly in patients unfit for surgery), peptide receptor radionuclide therapy (PRRT) can effectively control tumour growth or provide symptomatic benefit in metastatic disease, while cytotoxic chemotherapy can be used in patients with higher-grade tumours. This review considers the developments in the medical and other nonsurgical management options for cases refractory to standard medical management. Early referral to a dedicated neuroendocrine multidisciplinary team is critical considering the array of medical, oncological, interventional radiological and nuclear medical options. We discuss the evolving armamentarium for insulinomas when standard medical therapy fails.

WITHDRAWN: Management of canine insulinomas with toceranib phosphate: 30 cases (2009-2019)

“…Sunitinib malate (Sutent ®; P zer, Inc., New York, NY, USA) is an oral small molecule inhibitor initially approved by the Food and Drug Administration (FDA) for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumour in people, but additional applications have been subsequently identi ed [13,14]. Based on the results of a multinational, randomized, double-blind, placebo-controlled phase 3 clinical trial, sunitinib was recently approved by the FDA for treatment of locally advanced or metastatic pancreatic neuroendocrine tumours (pNETs) in people, a classi cation encompassing all tumours arising from the multipotent stem cells of pancreatic ductal epithelium, including insulinoma [5,[13][14][15][16][17][18][19][20][21][22].…”

Successful Long-Term Medical Management of Unresectable Insulinomas

“…Diazoxide is considered first-line medical therapy for symptom control, inhibiting release of insulin from β-cells by activating potassium channels [1][2][3][4]. With Patient 1, long-acting octreotide was used first-line with great efficacy.…”

“…Their efficacy may depend on SSTR subtype expression on the specific insulinoma [4]. They are considered second-line medical therapy for benign insulinomas; however, due to antiproliferative and antitumoral activity, they can be used first-line for malignant insulinomas [1,4,6]. Use of everolimus was considered during her recurrence, but was deferred, since her symptoms were controlled on octreotide and follow-up imaging was stable.…”

“…For Patient 2, the use of diazoxide caused side effects. Roughly half of patients experience side effects, including fluid retention, hirsutism, gastrointestinal symptoms, rash, and palpitations [1,4]. Her fluid retention necessitated use of HCTZ.…”

“…GI, gastrointestinal; SA, somatostatin analog; SSTR, somatostatin receptors; IM, intramuscular; SC, subcutaneous; mTOR, mammalian target of rapamycin; pNET, pancreatic neuroendocrine tumor. See [1,4]. mTOR inhibition induces peripheral insulin resistance and reduces proinsulin secretion by insulinomas [4].…”