eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Insulinoma: Treatment & Medication

Author: Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Coauthor(s): Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Nov 3, 2009

Treatment

Medical Care

Medical therapy is indicated in patients with malignant insulinomas and in those who will not or cannot undergo surgery. These measures are designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden. In malignant insulinomas, dietary therapy with frequent oral feedings or enteral feedings may control mild symptoms of hypoglycemia. A trial of glucagon may be attempted to control hypoglycemia.

  • Diazoxide is related to the thiazide diuretics and reduces insulin secretion. Adverse effects include sodium retention, a tendency to congestive cardiac failure, and hirsutism.
  • Prescribe hydrochlorothiazide to counteract the edema and hyperkalemia secondary to diazoxide and to potentate its hyperglycemic effect.
  • Of patients with insulinoma, 50% may benefit from the somatostatin analogue octreotide to prevent hypoglycemia.22
    • The effect of the therapy depends on the presence of somatostatin receptor subtype 2 on insulinoma tumor cells.
    • As studies have shown, an OctreoScan is not a prerequisite before starting octreotide treatment. In patients with insulinoma and a negative scan finding, somatostatin decreased insulin levels significantly and lowered the incidence of hypoglycemic events.
  • CT-guided radiofrequency ablation has been used successfully to treat insulinoma in an elderly patient whose hypoglycemia that was refractory to diazoxide, and who was not a candidate for surgery because of comorbidities and poor physical condition.23

Surgical Care

Because insulinoma resection achieves cure in 90% of patients, it is currently the therapy of choice.

  • Preoperative management
    • Administer diazoxide on the day of surgery in patients who respond to it. Diazoxide reduces the need for glucose supplements and the risk of hypoglycemia.
    • Monitor blood glucose level throughout surgery.
    • Infuse 10% dextrose in water at a rate of at least 100 mL/h.
    • A preoperative trial with diazoxide is indicated to determine whether the patient is a responder. (Five to 10% of patients do not respond.) This information helps determine the intraoperative strategy if the tumor is not localized.
    • In MEN 1, hypercalcemia must be corrected first by parathyroidectomy before insulinoma resection.24
  • Successful tumor location
    • Fully expose the pancreas, including a wide Kocher maneuver to allow complete bimanual palpation.
    • A large study from Spain showed laparoscopic surgery to be safe and effective in benign and malignant tumor resection. It led to a shorter hospital stay compared to open resection.5
    • Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described recently.25
    • Because of the small likelihood that a tumor that presents without metastatic spread is malignant, insulinomas may be removed by enucleation. Care should be taken to achieve total tumor capsule removal to prevent tumor recurrence. If enucleation is not possible, a larger pancreatic resection including pancreaticoduodenectomy may be necessary. This should only rarely be required. When metastatic insulinoma is found on a patient's initial presentation, the organ spread is to liver and sometimes to bone.
    • Avoid total pancreatectomy because of its high morbidity and mortality rates.
    • Major resections, such as the Whipple procedure, may become necessary when the tumor is found in the pancreatic head and local excision is not possible.
    • Resect all gross disease when multiple tumors or metastases are present.
    • If insulinoma is associated with MEN 1, the management strategy is modified because tumors are often multiple, diffusely spread in the pancreas, and of small size. Definite cure by surgery is rare.
    • Subtotal pancreatectomy with enucleation of tumors from the pancreatic head and uncinate processus often is recommended over simple enucleation because of frequent multiple tumors in MEN 1.
    • Intraoperative serum insulin measurements recently have been employed to ensure complete tumor removal. This may be important, particularly in patients with MEN 1 who harbor multiple insulinomas.
  • Tumor is found to be metastatic at surgery in about 5-10% of patients. It would be extremely uncommon for metastases to develop in a case in which only a solitary lesion was found on initial presentation.
    • If the patient is responsive to diazoxide, continue it, while more invasive imaging studies are performed before repetitive surgery is considered.
    • If the patient is not responsive (5-10%) or if drug intolerance is present and ectopic disease is excluded, a blind distal two-thirds pancreatectomy may be performed. (This procedure has only a 25% success rate.)
    • Most authorities recommend serial sectioning during resection.
    • Tumors that are not found at surgery normally are located in the pancreatic head (54%), body (20%), and tail (14%).
  • Metastatic disease found
    • Even when metastases are found, surgical excision is often feasible before any medical, chemotherapeutic, or other interventional therapy is considered.
    • Resect all gross disease, including wedge resections of hepatic metastases.
    • Avoid ligation of the hepatic artery in case further regional infusion therapy becomes necessary.

Consultations

Consult with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring. The approach should be multidisciplinary, with an endocrinologist, surgeon, and anesthesiologist.

Diet

  • Because most tumors are not responsive to glucose, carbohydrate feedings every 2-3 hours can help maintain euglycemia, although obesity may develop.
  • Glucagon should be available for emergency use.

Activity

Exercise may aggravate hypoglycemia in patients with insulinoma.

Medication

Diazoxide is the drug of choice because it inhibits insulin release from the tumor. Adverse effects must be treated with hydrochlorothiazide. In patients not responsive to or intolerant of diazoxide (10%), somatostatin may be indicated to prevent hypoglycemia.

Hyperglycemic agents

Inhibit insulin release from the tumor.


Diazoxide (Proglycem, Hyperstat)

Produces an increase in blood glucose within 1 h by inhibition of insulin release from the insulinoma.

Adult

3-8 mg/kg/d PO divided q8h

Pediatric

Administer as in adults

May displace other substances (coumarin, bilirubin) because it highly binds to proteins; diphenylhydantoin may lose control on seizures

Documented hypersensitivity; functional hypoglycemia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Initiate only under close clinical supervision; prolonged treatment requires regular monitoring of the urine for sugar and ketones; monitor blood sugar levels for dose adjustments
The plasma half-life is prolonged in impaired renal function; the antihypertensive effect of other drugs may be enhanced; dose reduction of coumarin or its derivatives may be necessary

Diuretics

Used to counteract edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.


Hydrochlorothiazide (Microzide, HydroDIURIL, Esidrix)

Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Adult

25-50 mg/d PO

Pediatric

1 mg/lb/d PO divided bid

Potentiation of orthostatic hypotension may occur with alcohol, barbiturates, or narcotics; dosage adjustments of the antidiabetic drug may be required; other antihypertensive drugs may cause additive effect or potentiation; discontinue thiazides before testing parathyroid function

Documented hypersensitivity; anuria

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Closely observe all patients for fluid or electrolyte imbalance; hypokalemia and hypomagnesemia may develop; thiazides may decrease urinary calcium excretion

Somatostatin analogs

May control symptoms by suppressing secretion of gastroenteropancreatic peptides including insulin. High-dose treatment also may lead to additional antiproliferative effects. However, long-term application of somatostatin may down-regulate receptor expression levels, resulting in decreased efficiency despite increasing doses. Both short- and long-acting depot preparations are available.


Octreotide acetate (Sandostatin)

Acts similarly to the natural hormone somatostatin and can suppress secretion of gastroenteropancreatic peptides including insulin.

Adult

200-300 mcg/d IV/SC divided bid/qid (range 150-750 mcg) during initial 2 wk; adjust dose to individual; LAR long-acting preparation can be used once/mo

Pediatric

Not established; 3-40 mcg/kg/d IV/SC has been used

Imbalances in fluid and electrolytes or glycemic states may occur, requiring adjustment of doses; has been associated with alterations in nutrient absorption; consider its effect on any orally administered drug

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dose adjustments may be required to control symptoms; cholelithiasis may develop; may alter insulin requirements in diabetes mellitus; absorption of dietary fats may be altered
In severe renal failure, the half-life may be increased

Antineoplastic Agents

These agents inhibit cell growth and proliferation.


Streptozocin (Zanosar)

Used in fasting hypoglycemia caused by tumor. Has high affinity for neuroendocrine cells, inhibits cell proliferation, and is cytolytic. Interferes with normal function of DNA by alkylation and protein modification.

Adult

500 mg/m2 IV for 5 d q6wk

Pediatric

Not established

Aminoglycosides, loop diuretics and doxorubicin may increase nephrotoxicity; phenytoin may decrease effects; use with caution with steroids as can cause hyperglycemia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Severe nausea and vomiting is common; liver dysfunction can occur; renal toxicity is dose-related and cumulative; closely monitor renal, hepatic, and hematologic function

More on Insulinoma

Overview: Insulinoma
Differential Diagnoses & Workup: Insulinoma
Treatment & Medication: Insulinoma
Follow-up: Insulinoma
Multimedia: Insulinoma
References
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References

  1. Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. Sep-Oct 1998;2(5):472-82. [Medline].

  2. Mathur A, Gorden P, Libutti SK. Insulinoma. Surg Clin North Am. Oct 2009;89(5):1105-21. [Medline].

  3. Dadan J, Wojskowicz P, Wojskowicz A. Neuroendocrine tumors of the pancreas. Wiad Lek. 2008;61(1-3):43-7. [Medline].

  4. Larijani B, Aghakhani S, Lor SS, Farzaneh Z, Pajouhi M, Bastanhagh MH. Insulinoma in Iran: a 20-year review. Ann Saudi Med. Nov-Dec 2005;25(6):477-80. [Medline].

  5. Fernandez-Cruz L, Blanco L, Cosa R, Rendon H. Is laparoscopic resection adequate in patients with neuroendocrine pancreatic tumors?. World J Surg. May 2008;32(5):904-17. [Medline].

  6. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med. Mar 1999;106(3):307-10. [Medline].

  7. Schmitt J, Boullu-Sanchis S, Moreau F, Drui S, Louis B, Chabrier G, et al. Association of malignant insulinoma and type 2 diabetes mellitus: a case report. Ann Endocrinol (Paris). Feb 2008;69(1):69-72. [Medline].

  8. Hrascan R, Pecina-Slaus N, Martic TN, Colic JF, Gall-Troselj K, Pavelic K. Analysis of selected genes in neuroendocrine tumours: insulinomas and phaeochromocytomas. J Neuroendocrinol. Aug 2008;20(8):1015-22. [Medline].

  9. Waickus CM, de Bustros A, Shakil A. Recognizing factitious hypoglycemia in the family practice setting. J Am Board Fam Pract. Mar-Apr 1999;12(2):133-6. [Medline].

  10. Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am. Sep 1999;28(3):603-18, vii. [Medline].

  11. Eriguchi N, Aoyagi S, Hara M, et al. Nesidioblastosis with hyperinsulinemic hypoglycemia in adults: report of two cases. Surg Today. 1999;29(4):361-3. [Medline].

  12. Starke A, Saddig C, Kirch B, Tschahargane C, Goretzki P. Islet hyperplasia in adults: challenge to preoperatively diagnose non-insulinoma pancreatogenic hypoglycemia syndrome. World J Surg. May 2006;30(5):670-9. [Medline].

  13. van Bon AC, Benhadi N, Endert E, Fliers E, Wiersinga WM. Evaluation of endocrine tests. D: the prolonged fasting test for insulinoma. Neth J Med. Jul-Aug 2009;67(7):274-8. [Medline].

  14. Boukhman MP, Karam JM, Shaver J, et al. Localization of insulinomas. Arch Surg. Aug 1999;134(8):818-22; discussion 822-3. [Medline].

  15. Hashimoto LA, Walsh RM. Preoperative localization of insulinomas is not necessary. J Am Coll Surg. Oct 1999;189(4):368-73. [Medline].

  16. Liu Y, Song Q, Jin HT, Lin XZ, Chen KM. The value of multidetector-row CT in the preoperative detection of pancreatic insulinomas. Radiol Med. Sep 30 2009;[Medline].

  17. Anaye A, Mathieu A, Closset J, Bali MA, Metens T, Matos C. Successful preoperative localization of a small pancreatic insulinoma by diffusion-weighted MRI. JOP. Sep 4 2009;10(5):528-31. [Medline].

  18. Kirkeby H, Vilmann P, Burcharth F. Insulinoma diagnosed by endoscopic ultrasonography-guided biopsy. J Laparoendosc Adv Surg Tech A. Jun 1999;9(3):295-8. [Medline].

  19. Proye C, Malvaux P, Pattou F, et al. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery. Dec 1998;124(6):1134-43; discussion 1143-4. [Medline].

  20. McLean A. Endoscopic ultrasound in the detection of pancreatic islet cell tumours. Cancer Imaging. Mar 29 2004;4(2):84-91. [Medline].

  21. Christ E, Wild D, Forrer F, Brändle M, Sahli R, Clerici T, et al. Glucagon-Like Peptide-1 Receptor Imaging for Localization of Insulinomas. J Clin Endocrinol Metab. Oct 9 2009;[Medline].

  22. Arnold R, Simon B, Wied M. Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review. Digestion. 2000;62 Suppl 1:84-91. [Medline].

  23. Limmer S, Huppert PE, Juette V, Lenhart A, Welte M, Wietholtz H. Radiofrequency ablation of solitary pancreatic insulinoma in a patient with episodes of severe hypoglycemia. Eur J Gastroenterol Hepatol. Sep 2009;21(9):1097-101. [Medline].

  24. Lo CY, Lam KY, Fan ST. Surgical strategy for insulinomas in multiple endocrine neoplasia type I. Am J Surg. Apr 1998;175(4):305-7. [Medline].

  25. Dexter SP, Martin IG, Leindler L, et al. Laparoscopic enucleation of a solitary pancreatic insulinoma. Surg Endosc. Apr 1999;13(4):406-8. [Medline].

  26. Moscetti L, Saltarelli R, Giuliani R, et al. Intra-arterial liver chemotherapy and hormone therapy in malignant insulinoma: case report and review of the literature. Tumori. Nov-Dec 2000;86(6):475-9. [Medline].

  27. Smith MC, Liu J, Chen T, et al. OctreoTher: ongoing early clinical development of a somatostatin- receptor-targeted radionuclide antineoplastic therapy. Digestion. 2000;62 Suppl 1:69-72. [Medline].

  28. Bourcier ME, Sherrod A, DiGuardo M, Vinik AI. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab. Sep 2009;94(9):3157-62. [Medline].

  29. Gonzalez-Gonzalez A, Recio-Cordova JM. Liver metastases 9 years after removal of a malignant insulinoma which was initially considered benign. JOP. 2006;7(2):226-9. [Full Text].

  30. Abboud B, Boujaoude J. Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol. Feb 7 2008;14(5):657-65. [Medline].

  31. Ahlman H, Wangberg B, Jansson S, et al. Interventional treatment of gastrointestinal neuroendocrine tumours. Digestion. 2000;62 Suppl 1:59-68. [Medline].

  32. Begu-Le Corroller A, Valero R, Moutardier V, Henry JF, Le Treut YP, Gueydan M. Aggressive multimodal therapy of sporadic malignant insulinoma can improve survival: A retrospective 35-year study of 12 patients. Diabetes Metab. Jun 13 2008;[Medline].

  33. Diagnosis and management of pancreatic endocrine tumors. In: De Vita V, Lawrence T, Rosenberg S. Cancer. Principles and Practice of Oncology. 8th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins; 2008:1706-15.

  34. Faggiano A, Mansueto G, Ferolla P, Milone F, del Basso de Caro ML, Lombardi G, et al. Diagnostic and prognostic implications of the World Health Organization classification of neuroendocrine tumors. J Endocrinol Invest. Mar 2008;31(3):216-23. [Medline].

  35. Grant CS. Surgical aspects of hyperinsulinemic hypoglycemia. Endocrinol Metab Clin North Am. Sep 1999;28(3):533-54. [Medline].

  36. Jensen RT. Pancreatic endocrine tumors: recent advances. Ann Oncol. 1999;10 Suppl 4:170-6. [Medline].

  37. Keymeulen B, Bossuyt A, Peeters TL, Somers G. 111In-octreotide scintigraphy: a tool to select patients with endocrine pancreatic tumors for octreotide treatment?. Ann Nucl Med. Aug 1995;9(3):149-52. [Medline].

  38. Kuzin NM, Egorov AV, Kondrashin SA, et al. Preoperative and intraoperative topographic diagnosis of insulinomas. World J Surg. Jun 1998;22(6):593-7; discussion 597-8. [Medline].

  39. Le Roith D. Tumor-induced hypoglycemia. N Engl J Med. Sep 2 1999;341(10):757-8. [Medline].

  40. Molven A, Matre GE, Duran M, Wanders RJ, Rishaug U, Njolstad PR. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes. Jan 2004;53(1):221-7. [Medline].

  41. Rougier P, Mitry E. Chemotherapy in the treatment of neuroendocrine malignant tumors. Digestion. 2000;62 Suppl 1:73-8. [Medline].

  42. Ruszniewski P, Malka D. Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumors. Digestion. 2000;62 Suppl 1:79-83. [Medline].

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Further Reading

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Keywords

insulinoma, hyperinsulinism, endogenous hyperinsulinism, islet cell adenoma, pancreatic islet cell, neuroendocrine tumor, hypoglycemia, B-cell tumor of the pancreas, adenoma of the islets of Langerhans

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Contributor Information and Disclosures

Author

Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Zonera Ashraf Ali, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Pradyumna D Phatak, MBBS, MD,, Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute
Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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