Nonselective adrenocorticolysis with mitotane

In 1988, an alternative protocol for the medical management of PDH in dogs with mitotane was proposed.¹⁹ This protocol is popular in Europe because of the reduced long-term cost of mitotane and an increase in the disease-free interval.^19-22 But the expense associated with proper monitoring and administration of mineralocorticoids may obviate any price differences.

Mechanism of action

Safety

This protocol preemptively treats for rapid decreases in serum cortisol concentrations and hypoaldosteronism, so dogs should experience few adverse effects if the medications are administered properly. When this protocol was first attempted in 49 dogs, transient adverse effects occurred in about 20% of dogs.¹⁹ Similar to dogs treated with selective adrenocortical lysis, only 4% to 6% of dogs developed severe signs of mineralocorticoid deficiency despite prescribed mineralocorticoid supplementation.^6,19 In a separate study of 129 dogs, 30% developed clinical signs of hypoadrenocorticism requiring alteration in mitotane administration, but the clinical signs dissipated after withholding mitotane with no long-term complications.²⁰

Whereas failure to administer maintenance mitotane poses no immediate life-threatening consequences, failure to administer glucocorticoids or mineralocorticoids to dogs treated with the nonselective adrenocortical lysis protocol may result in an addisonian crisis.^4,5 For this reason, this protocol should be offered to only the most compliant owners. Strict adherence to medication administration and careful monitoring are necessary to prevent the potentially deadly complications of hypoadrenocorticism.

Efficacy

Nonselective adrenocortical lysis results in complete remission in more than 86% of dogs with PDH, with a median disease-free interval of 402 days.^19,22 One study found that 26% of dogs required a second course of treatment within one year, but 29% of dogs were in remission for two years or longer.¹⁹ In another study, 77% of dogs were estimated to be free of disease based on owner observation of clinical signs after one year, 53% after two years, and 44% after three years.²² In contrast, about half of dogs treated with the selective adrenocortical lysis protocol will relapse within one year.⁶ Although it appears the nonselective protocol may have a longer disease-free interval, whether this benefit justifies the increased risks associated with hypoadrenocorticism is unknown. Noncompliance in the treatment of PDH is rarely life-threatening; noncompliance in the treatment of hypoadrenocorticism is life-threatening.

Administration and monitoring

Mitotane is administered orally with food at 50 to 75 mg/kg/day divided into three or four doses for 20 to 25 days.^19-22 Lifelong replacement therapy with glucocorticoids and mineralocorticoids is begun on the third day. Described protocols involve the use of cortisone acetate at a temporarily high dosage of 2 mg/kg daily and fludrocortisone at 0.0125 mg/kg/day.²¹ After induction is complete, physical examination findings and serum electrolyte concentrations should be evaluated. If a dog is doing well clinically, the glucocorticoid dosage can be reduced to physiologic dosages (1 mg/kg/day of cortisone acetate).²¹ This protocol also advocates the oral administration of sodium chloride, but salt supplementation is often omitted from the treatment of hypoadrenocorticism without detriment.^5,21 As an alternative to cortisone, prednisone or prednisolone may be used at an equipotent dosage of 0.4 mg/kg/day initially or 0.2 mg/kg/day after induction. Desoxycorticosterone (about 2.2 mg/kg every 25 days) could be used as a mineralocorticoid replacement alternative to fludrocortisone.^19,22 Routine reevaluation should occur every four to six months.^4,5,17,21,22