Hot Literature: Trilostane or mitotane for canine adrenal-dependent hyperadrenocorticism: What factors influence survival?

Adrenal-dependent hyperadrenocorticism (ADH) accounts for about 15% of all cases of canine hyperadrenocorticism and may result from an adrenal adenoma or carcinoma. Traditionally, the drug of choice for the medical management of dogs with ADH has been mitotane, an adrenolytic derivative of DDT. Previous studies have found that dogs with ADH have a median survival time of 320 days when treated with mitotane.

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Trilostane, which acts by inhibiting cortisol synthesis, has recently been introduced for treating canine pituitary-dependent and adrenal-dependent hyperadrenocorticism (Vetoryl—Dechra Veterinary Products). Treatment with trilostane in dogs with ADH has resulted in survival times between 117 and 506 days, but these values are based on a small series and two case reports.

A recent retrospective study looked at factors that may influence survival in dogs with ADH medically managed with either trilostane or mitotane.

STUDY DESIGN

Clinical data were analyzed for all dogs with ADH diagnosed at four participating referral institutions between January 1996 and December 2008. Only dogs that were treated medically with either trilostane or mitotane were included. Hyperadrenocorticism was diagnosed by either an ACTH stimulation test or a low-dose dexamethasone suppression test. ADH was confirmed based on a combination of low endogenous ACTH concentrations and abdominal ultrasonographic findings of unilateral adrenal enlargement.

Variables that were assessed as possible predictors of survival were method of diagnosis, breed, drug treatment, reproductive status, sex, age, weight, presence or absence of blood vessel invasion at time of diagnosis, presence or absence of concurrent disease, and presence or absence of metastatic disease. The referral center where the patient received its diagnosis and was treated was also assessed since a variable such as geographic location and clinician preferences may have affected treatment decisions.

Treatment with mitotane consisted of an induction phase (50 mg/kg/day up to 1,000 mg/dog) and a maintenance phase (50 mg/kg/week) to achieve post-ACTH stimulation cortisol concentrations of < 4.32 µg/dl. Dogs treated with trilostane were dosed according to the manufacturer's United Kingdom label based on weight and available capsule sizes (< 5 kg: 30 mg; 5.1 to 20 kg: 60 mg; 21 to 40 kg: 120 mg; > 40 kg: 120 to 240 mg) and were treated once daily. Response to treatment was based on the results of a four-hour post-treatment ACTH stimulation test with a post-ACTH cortisol concentration goal of < 4.32 µg/dl. In either group, dogs that showed clinical signs of hypocortisolemia or electrolyte abnormalities consistent with hypoadrenocorticism had their treatment temporarily discontinued and restarted at a lower dose once their signs resolved.

Ultimately, 37 cases were included in the study, and there were no significant differences among age, sex, or breed. Of the 37 dogs, 13 were treated with mitotane, 22 were treated with trilostane, and two were treated with mitotane and then trilostane. None were treated with both drugs concurrently.

STUDY RESULTS AND SIGNIFICANCE

When looking at using an adrenolytic drug (mitotane) to treat ADH vs. an adrenostatic one (trilostane), it would seem intuitive that a drug that destroys the adrenal cortex would result in longer survival times. Researchers found, however, that survival times between the two groups were similar across all variables. The median survival for all dogs was 277 days.

The only variable that had a statistically significant impact on survival was the presence of metastatic disease. Eight dogs were found to have metastatic disease, and, of these, four were treated with mitotane, three with trilostane, and one with both. The median survival in both groups was 61 days.

While these findings are intriguing, some study limitations need to be considered. Because of the retrospective nature of the study, it is unknown why medical management was chosen in these cases, but it was presumed that factors such as gross metastases at diagnosis, local invasiveness of the tumor, or financial restrictions prevented surgery from being a possible option in these dogs. It is also unclear why clinicians chose one drug over the other. Drug availability may have played a role in drug selection since the use of trilostane in general became more popular over the course of the study period. In addition, changes in trilostane dosing recommendations and monitoring changed over the course of the study period and may have influenced the outcomes.

Previous studies have shown that about 50% of dogs with ADH have a malignant adrenal tumor. There was no histopathologic confirmation of tumor type for most of these cases, however, and it is possible that the presence of malignancy would have affected survival times. The researchers also noted that about one-third of dogs in the study had concurrent illness, but, given the median age of the dogs was 11 years, some form of concurrent disease may be expected.

Ultimately, 22 dogs with ADH were enrolled in this study and treated with trilostane. While this is the largest case series evaluating dogs with ADH, it is still a small population size, so it is possible that small differences between the groups may have gone unrecognized. Despite this, researchers concluded that medical management of dogs with ADH is a viable option and that either trilostane or mitotane may be used.

Helm JR, McLauchlan G, Bode LA, et al. A comparison of factors that influence survival in dogs with adrenal-dependent hyperadrenocorticism treated with mitotane or trilostane. J Vet Intern Med 2011;25(2):251-260.

This "Hot Literature" update was provided by Jennifer L. Garcia, DVM, DACVIM, a veterinary internal medicine consultant in Houston, Texas.