Tuesday, June 4, 2013

Medical Treatment of Insulinomas


Dietary or medical management of insulinoma is recommended for animals that are showing signs of hypoglycemia and have previously undergone surgery and in those whose owners have declined surgery (1-6).

Specific chemotherapy can also be considered in animals in which all of the tumor cannot be resected and in those that have undergone previous surgery and again are showing signs of hypoglycemia. Just over half of dogs with insulinoma have metastases at the time of diagnosis (1-4), so it is reasonable to discuss the possibility of follow-up chemotherapy after surgery. Chemotherapy should be given only to patients with a confirmed histologic diagnosis of insulinoma.

Dietary management of hypoglycemia
Animals with insulinoma should be fed a diet that is high in protein, fat, and complex carbohydrates. Simple sugars, often contained in semimoist pet foods, should be avoided. Dogs should be fed small meals three to four times daily. Cats and ferrets may be fed free choice if they do not become obese. Exercise should be controlled and owners should attempt to limit excitement in these pets.

Glucocorticoids
Glucocorticoids are recommended when frequent feedings are no longer successful in controlling clinical signs of hypoglycemia. These drugs raise blood glucose by inhibiting glucose uptake in the peripheral tissues (creating insulin resistance) and stimulating hepatic glucose production (7-9).

Oral prednisone (or prednisolone) is started at the dosage of 0.25 mg/kg, twice daily (1-6). This dosage may be increased gradually as needed to control clinical signs or may be decreased if the disease is well controlled at the initial dosage. We should remember, however, that dosages of 1.1 mg/kg or higher given twice daily are considered immunosuppressive.

Diazoxide
Diazoxide (Proglycem, Teva Pharmaceuticals) is a nondiuretic benzothiadiazide that decreases insulin secretion, promotes gluconeogenesis and glycogenolysis, and inhibits the cellular uptake of glucose (10-12). Diazoxide can be difficult to obtain in the United States; however, reputable compounding pharmacies can often supply this drug.

The recommended starting dosage of diazoxide is 5 mg/kg, given orally twice daily (1-6,13). As with prednisone, the dosage may be increased as needed to control clinical signs. The maximal recommended dosage is 30 mg/kg twice daily.

The most common side effects of diazoxide are anorexia, vomiting, and diarrhea (1-6,13). These signs may be avoided or lessened by giving the medication with food. Ferrets find the diazoxide suspension distasteful, but because only small volumes are required, owners usually are able to administer it. Other potential side effects of diazoxide are hyperglycemia, bone marrow suppression, and sodium retention.

Octreotide acetate
Somatostatin is a polypeptide hormone that inhibits the secretion of insulin, glucagon, gastrin, secretin, and motilin. Octreotide acetate (Sandostatin, Novartis) is a long-acting somatostatin analogue that can be used in the management of patients with insulinoma (14).

Reports on the use of octreotide acetate in veterinary patients are limited and the response is mixed (4,12,15). About half of dogs with refractory hypoglycemia will show a response to octreotide acetate.  Ferrets refractory to other forms of treatment may show improvement in clinical signs in some, but certainly not all, cases.

The recommended dosage is 1 to 2 μg/kg given subcutaneously two to three times daily. This drug is relatively expensive, but may be practical for use in small dogs, cats, or ferrets due to their small size.

Currently, there is no way of predicting which patients will respond to octreotide acetate. Metastatic lesions may express fewer somatostatin receptors than the primary mass, so octreotide may be less effective in patients with advanced disease. This agent does appear to be safe and can be administered by owners at home. Thus, it should be considered for the treatment of animals with insulinoma that are refractory to or unable to tolerate traditional medical or surgical therapy (4,12).

Streptozotocin
Streptozotocin (Zanosar, Teva Pharmaceuticals) is a chemotherapeutic drug that selectively destroys pancreatic beta cells (16-19). When given alone, this drug may cause severe, acute renal failure in dogs. However, the drug can be administered safely if given with aggressive saline diuresis (17-19). Treatment is discontinued if there is clear tumor progression, resistant or recurrent hypoglycemia, or drug toxicity.

Streptozotocin may induce diabetes in some dogs, but the chemotherapy drug may be given along with appropriate insulin therapy if gross disease is still present.  No reports have described the use of streptozotocin in cats or ferrets with insulinoma. Further study of this agent is needed in all species.

Prognosis
The short-term prognosis for dogs with insulinoma is good, although most will eventually die of this disease. While survival time depends on the stage of the disease and the success of surgery, it also depends on the owners’ willingness to treat aggressively and follow up with symptomatic therapy once signs of hypoglycemia return.

Approximately two-thirds to three-quarters of dogs survive 6 months or longer after surgery (often over a year) before intractable hypoglycemia recurs. Reported median survival time is much longer in dogs initially treated with surgery than in those treated with medical management alone (1-5,20,21). Individualizing therapy with the use of combinations of medical and surgical therapy based on the stage and extent of disease may improve prognosis and survival time in any given patient.  

References:
  1. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
  2. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
  3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
  4. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
  5. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
  6. Nelson RW, Foodman MS. Medical management of canine hyperinsulinism. J Am Vet Med Assoc 1985;187:78-82. 
  7. Olefsky JM, Kimmerling G. Effects of glucocorticoids oncarbohydrate metabolism. Am J Med Sci 1976;271:202-210. 
  8. Chap Z, Jones RH, Chou J, et al. Effect of dexamethasone onhepatic glucose and insulin metabolism after oral glucose in conscious dogs. J Clin Invest 1986;78:1355-1361. 
  9. Moore GE, Hoenig M. Effects of orally administeredprednisone on glucose tolerance and insulin secretion in clinically normal dogs. Am J Vet Res 1993;54:126-129.
  10. Tabachnick, II, Gulbenkian A. Mechanism of diazoxide hyperglycemia in animals. Ann N Y Acad Sci 1968;150:204-218. Koch-Weser J. Diazoxide. N Engl J Med 1976;294:1271-1273. 
  11. Paulissian R. Diazoxide. Int Anesthesiol Clin 1978;16:201-237. 
  12. Meleo K. Management of insulinoma patients with refractory hypoglycemia. Prob Vet Med 1990;2:602-609. 
  13. Parker AJ, Musselman EM, O'Brien D. Diazoxide treatment of canine insulinoma. Vet Rec 1981;109:178-179. 
  14. Maton PN. The use of the long-acting somatostatin analogue,octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am 1989;18:897-922. 
  15. Simpson KW, Stepien RL, Elwood CM, et al. Evaluation of the long-acting somatostatin analogue octreotide in the management of insulinoma in three dogs. J Small Anim Pract 1995;36:161-165. 
  16. Meyer DJ. Temporary remission of hypoglycemia in a dog with an insulinoma after treatment with streptozotocin. Am J Vet Res 1977;38:1201-1204. 
  17. Moore AS, Nelson RW, Henry CJ, et al. Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989-1999). J Am Vet Med Assoc 2002;221:811-818. 
  18. Bell R, Mooney CT, Mansfield CS, et al. Treatment of insulinoma in a springer spaniel with streptozotocin. J Small Anim Pract 2005;46:247-250. 
  19. Northrup NC, Rassnick KM, Gieger TL, et al. Prospective evaluation of biweekly streptozotocin in 19 dogs with insulinoma. J Vet Intern Med 2013;27:483-490. 
  20. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230. 
  21. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156. 

7 comments:

Angelplusa said...

My 11 year old mixed breed dog has just been diagnosed with insulinoma discovered during adrenal gland removal for cushings disease. They removed part of the pancreas but said it had spread to the lymph node and liver. He is on predisone 1 and a half pill every morning and phenobarbitol to avoid the seizures he had prior to surgery. Dr.Ettinger, the oncologist at Yonkers where his surgery was done recommended chemo but could give no idea of how it would improve life expectancy. It is very expensive and I am curious as to what other options we have at this point as it sounds like it is most effective with a single tumor. Any thoughts?

Dr. Mark E. Peterson said...

Surgery offers the best chance for long-term control of this malignant tumor. However, use of prednisone alone after the surgery can help control the low blood glucose concentrations for prolonged periods in some of these dogs (1,2).

As far as chemotherapy is concerned, the best would be use of streptozotocin (3-5). In one study (3) of 19 dogs, side effects were common (renal failure, diabetes mellitus). None of the dogs were cured. The overall survival time in those dogs was only about a year, so more work definitely needs to be done.

If this was my dog, I'd probably just stick to medical control of the hypoglycemia with prednisone and other drugs, and not do the chemotherapy - at least with the streptozotocin.

1. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156.
2. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230.
3. Moore AS, Nelson RW, Henry CJ, et al. Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989-1999). J Am Vet Med Assoc 2002;221:811-818.
4. Northrup NC, Rassnick KM, Gieger TL, et al. Prospective evaluation of biweekly streptozotocin in 19 dogs with insulinoma. J Vet Intern Med 2013;27:483-490.

Allie Stone said...

My dog was also recently diagnosed with an insulinoma and had surgery to remove the tumor so I'm now trying to figure out what the best next steps are. Is chemo still the treatment of choice for a single tumor? What's the most effective protocol these days? Has any more research been done on the streptozotocin? Also, do you know of any clinical studies that might be going on right now for dogs with insulinomas?

Dr. Mark E. Peterson said...

If surgery was successful and your dog is asymptomatic, I would simply monitor blood glucose and insulin levels every 3 months at this time.

TRoy said...

My 10 yr old dog was diagnosed 6 mo. ago (August) with an insulinoma. She started on Prednisone and we added diazoxide in December. The past week her glucose levels have dropped significantly, but suprisingly she acts o.k., a little slow, but no seizures. I am going to have to bring her in again for another followup with my vet. I'm not sure I just want to keep upping the doses of meds. and I know there will be a point when they just won't help any longer. I cannot find much info in my online searches, how will I know when we get to this point.

Dr. Mark E. Peterson said...

You will know when the seizures and weakness can no longer be controlled.

沈慶璇 said...

Dr. Mark, my 14yr old Beagle (13kg) was diagnosed with an insulinoma a month ago, we are using Sandostatin now, our vet says it's acute treatment with 20micrograms/kg SC q12hr, I wonder when will we know we get to the point to turn into chronic treatment with 2micrograms/kg SC q12hr?

Additionally, the daily cost of Sandostatin is extremely expensive, for human there is Sandostatin LAR Depot which is only injected once a month, would it be used on dog? And how much would be the dosage?

Please help me out, I'd be extremely grateful! Sebastian