Medical Treatment for Adrenal Tumors in Dogs with Cushing's Syndrome: Mitotane or Trilostane

My patient is a 13-year old, FS, Dachshund who has been morbidly obese for most of her life. She presented for a routine annual exam with PU/PD and many classic signs of Cushing's disease (e.g., pot bellied appearance, thin skin with bilateral truncal alopecia, and muscular atrophy).

Results of a CBC and serum biochemical testing revealed a high WBC count with mature neutrophilia, and a high serum alkaline phosphatase concentration (>2400 IU/L). A complete urinalysis was normal (specific gravity low at 1.009) but a urine culture was positive for E.coli. Based on the sensitivity, I started the dog on Baytril.

Because the clinical signs and screening tests indicated Cushing's syndrome, I next did a low-dose dexamethasone suppression test, with the following cortisol results.

• Cortisol basal sample: 12.1 μg/dl (reference range, 1-5 μg/dl)
• Cortisol 4 hr: 12.4 μg/dl (reference range, 0.0-1.4 μg/dl)
• Cortisol 8 hr: 8.6 μg/dl (reference range, 0.0-1.4 μg/dl)

Because the results of that test were positive, I next did a high-dose dexamethasone suppression test to help determine the cause of the Cushing's, with the following cortisol results.

• Cortisol basal sample: 8.6 μg/dl (reference range, 1-5 μg/dl)
• Cortisol 4 hr: 5.7 μg/dl (reference range, 0.0-1.4 μg/dl)
• Cortisol 8 hr: 4.6 μg/dl (reference range, 0.0-1.4 μg/dl)

Because of the inadequate cortisol suppression, I recommended an abdominal ultrasound to see if an adrenal mass is present and if there is any metastasis. However, the owner declined any further workup. The owner will not do surgery, even if an adrenal tumor is present, and wants to treat medically.

So my question to you is this. I think the dog has an adrenal tumor. Which is the best medical therapy to use — mitotane (Lysodren) or trilostane (Vetoryl)?

My Response:

Why I recommend further diagnostics to determine the cause
Based on the results of your pituitary-adrenal function testing (i.e., lack of serum cortisol suppression on both the low- and high-dose dexamethasone suppression tests), we still don't know the cause of this dog's Cushing's syndrome (1,2). Based on the fact that pituitary-dependent Cushing's disease (PDH) is more common than functional adrenal tumors, the dog has about a 50:50 chance of having an cortisol-secreting adrenal tumor versus non-suppressible PDH. If the dog does have PDH, however, she has an increased risk of having a larger pituitary macroadenoma at this time (2,3).

So the main reason to do further testing, as you probably know, is both to determine prognosis and help determine treatment (1,2). Other than abdominal ultrasonography, you could measure a plasma ACTH level to determine the cause of the dog's Cushing's syndrome. If the plasma ACTH is low, that would be diagnostic for an adrenal tumor (combined with the lack of suppression on the dexamethasone suppression test). If, on the other hand, the plasma ACTH value is high-normal to high, that would be diagnostic for non-suppressible PDH (1,2).

Treatment and monitoring for Cushing's syndrome is expensive!
If your owner will not do any further testing, this may be a good time to remind them that—no matter what the cause of this dog's disease—Cushing's syndrome is an expensive disease to treat. Use of mitotane, trilostane, adrenalectomy, or radiation therapy are all very expensive. So I always worry when dog owners tell me that it's getting too expensive to proceed with the workup!

Pros and cons of Lysodren vs Vetoryl
So which drug to use—mitotane or trilostane? If the dog has PDH, she should respond clinically to either drug (1,4-6), but if an expanding pituitary tumor is present, that might lead to neurological signs within a few months (3,7). If the dog has an adrenal tumor, the standard doses of mitotane would be unlikely to help, but this failure to control the cortisol levels would help "suggest" that an adrenal tumor is the underlying cause (1,8,9).

Use of standard doses of trilostane, on the other hand, is more effective in lowering cortisol values in dogs with adrenal tumors so this may be the way to go if the client refuses any additional workup (6,10). However, if adrenal carcinoma is present, this drug would do nothing to stop tumor invasion or metastasis. And again, if the dog has non-suppressible PDH with a pituitary macrotumor, this might lead to neurological signs within a few months.

References:

1. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clinical Techiques in Small Animal Practice 2007;22:2-11.
2. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010; pp. 1816-1840.
3. Sarfaty D, Carrillo JM, Peterson ME. Neurologic, endocrinologic, and pathologic findings associated with large pituitary tumors in dogs: eight cases (1976-1984). 1988;193:854-856.
4. Kintzer PP, Peterson ME. Mitotane (o,p'-DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. Journal of Veterinary Internal Medicine 1991;5:182-90.
5. Clemente M, De Andrés PJ, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Veterinary Record 2007;161:805-809.
6. Ramsey IK. Trilostane in dogs. The Veterinary Clinics of North America Small Animal Practice 2010;40:269-283.
7. Ihle SL. Pituitary corticotroph macrotumors. Diagnosis and treatment. The Veterinary Clinics of North America Small Animal Practice 1997;27:287-297.
8. Kintzer PP, Peterson ME. Mitotane treatment of 32 dogs with cortisol-secreting adrenocortical neoplasms. Journal of the American Veterinary Medical Association 1994;205:54-61.
9. Kintzer PP, Peterson ME. Diagnosis and management of canine cortisol-secreting adrenal tumors. The Veterinary Clinics of North America Small Animal Practice  1997;27:299-307.
10. Helm JR, McLauchlan G, Boden LA, et al. A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. Journal of Veterinary Internal Medicine 2011; 25:251-260.