State of the Art Lecture - Treatment Options for Canine Hyperadrenocorticism
1. Surgical management
a. Bilateral adrenalectomy
i. Technically difficult
ii. Poor surgical/anesthetic risk
iii. Permanently hypoadrenal and require lifelong replacement therapy
i. See discussion at the end of this section
ii. Lifelong therapy with thyroid hormone and prednisone necessary
2. Medical therapy
Most dogs with PDH live normal lives (average 2.2 years)
a. Recurrence of disease
b. CNS signs
c. Pulmonary thromboembolism
f. Congestive heart failure
2. Adrenal tumors
a. Adenomas: Good if no evidence of local invasion
b. Carcinomas: Guarded to grave with metastases
Trilostane Therapy of Canine Hyperadrenocorticism
The efficacy and safety of trilostane in the treatment of canine PDH were evaluated in a multicentre study at the Royal Veterinary College in London, the Veterinary Teaching Hospital in Dublin and Small Animal Hospital in Glasgow. Seventy-eight dogs with confirmed PDH were treated with trilostane for up to 3 years. The starting dose varied from 1.8 to 20 mg/kg (mean = 5.9 mg/kg).
Trilostane appeared to be well tolerated by almost all dogs with only 2 dogs developing signs and biochemical evidence of hypoadrenocorticism. One of these dogs recovered with appropriate therapy. The other died despite withdrawal of trilostane and administration of appropriate therapy. A further two dogs died within one week of starting trilostane but in neither case could a direct link with the trilostane therapy be established. The low prevalence of side effects compared favourably to those reported with mitotane.
Trilostane was found to be nearly as effective as mitotane in resolving the signs of hyperadrenocorticism. Polyuria, polydipsia and polyphagia had dissipated in 40 dogs within 3 weeks after starting trilostane. Within 2 months, a further 20 dogs showed decreases in their water and food consumption. These improvements were maintained as long as the dogs remained on adequate doses of trilostane. Skin changes resolved in 24 out of 39 (62%) dogs that initially presented with dermatological signs. All of these improvements were maintained as long as the dogs remained on adequate doses of trilostane. Only 8 dogs that were treated with trilostane for more than 2 months showed poor control of clinical signs. In contrast, mitotane is effective in about 80% of cases of pituitary-dependent hyperadrenocorticism (PDH).
Trilostane caused a significant (p < 0.001) reduction in both the mean basal and post-ACTH stimulation cortisol concentrations after 10 days of treatment. The post ACTH cortisol concentration decreased to less than 250 nmol/l (9 µg/dl) in 81% of dogs within one month and in another 15% at some time whilst on treatment. These improvements were also maintained in the study population for the duration of the trial.
Thirty-five dogs had at least one dose adjustment over the treatment period. The dose was increased in 23 dogs up to four times the starting dose. In one dog the dose was increased nine-fold over a period of six months. The dose was decreased in nine dogs to as low as a quarter of the starting dose.
The mean survival of all trilostane-treated dogs was 661 days. Direct comparison with mitotane was difficult, as 65% of the dogs were still alive at the time of censor and therefore the mean survival may still increase. By comparison, the mean survival of mitotane-treated dogs has been reported to be 810 to 900 days.
Dosage and Administration
The current suggested initial starting dose range for dogs with PDH is 1–2 mg/kg once daily. This needs to be adjusted according to clinical signs and serum cortisol values (see below). Doses up to 40–50 mg/kg (divided twice daily) have been given with no unwanted side effects. In some dogs, twice-daily dosing may be necessary. The drug is given with food.
A variety of treatments are available for PDH. Medical treatment options include drugs that chemically destroy the adrenals (Lysodren; op-DDD), inhibit enzymes in the adrenal leading to the synthesis of cortisol (ketoconazole, trilostane) or inhibit the release of ACTH from the pituitary gland (Anipryl or selegiline). While these treatments can improve the clinical signs in 40–80% of patients, they need to be chronically administered, necessitate frequent monitoring and do not cure or address the primary cause of the disease (the pituitary tumor). In humans, surgery to remove the tumor is the most successful long-term therapy. The most common approach used is the transsphenoidal method, in which a passageway is made in the sphenoid sinus, an air space behind the back of the nose, which is just below the pituitary gland. Surgical cure rates for PDH are reported to be in the range of 65–85%, although more recent long-term follow-up data suggest that the recurrence rate is as high as 25% within 5 years. When no discrete adenoma can be identified, remission of hypercortisolism is observed in only about 40%. Surgery has also been used to treat PDH in dogs. Several groups, most notably in the Netherlands, have performed these surgeries with success rates paralleling those reported for humans. However, these surgeries have generally not been performed in the US. Veterinarians at VCA WLAAH have developed the methods to perform these surgeries in the US and are conducting a research study to determine how effectively these surgeries can be performed.
Given the survival times and the ability to cure the disease by removing the pituitary tumor, we are conducting ongoing studies to evaluate the role of transsphenoidal hypophysectomy in the treatment of canine PDH. We will also be looking at the tumor tissue to investigate the pathogenesis of Cushing's disease and evaluate novel medical therapies.