What is the recommended medical treatment for hypercortisolism caused by adrenocortical carcinoma?

Medical Treatment for Hypercortisolism in Adrenocortical Carcinoma

Medical therapy to control hormonal excess is mandatory in patients with adrenocortical carcinoma and hypercortisolism, using a combination of mitotane plus fast-acting steroidogenesis inhibitors (metyrapone or ketoconazole) to prevent life-threatening complications including immunosuppression, diabetes, and muscle weakness. 1

Immediate Management Strategy

The urgency of controlling hypercortisolism in ACC cannot be overstated, as these patients suffer from severe immunosuppression, diabetes, and muscle weakness that significantly impact quality of life and mortality. 1

First-Line Combination Approach

• Start metyrapone immediately as the primary fast-acting agent because it provides rapid cortisol control within hours and its metabolism is not altered by concomitant mitotane therapy. 1

• Add mitotane concurrently as it is the cornerstone drug for ACC management, though recognize its efficacy is delayed by several weeks. 1, 2, 3

• Ketoconazole (400-1200 mg/day) is an alternative to metyrapone, achieving UFC normalization in approximately 64% of patients, though it requires regular liver function monitoring. 4, 5

Rationale for Combination Therapy

The ESMO-EURACAN guidelines explicitly state that mitotane alone is insufficient for acute control due to its delayed onset of action. 1 Metyrapone is specifically highlighted as well-tolerated and safe to administer with mitotane and cytotoxic chemotherapy because its pharmacokinetics remain stable. 1

Alternative and Emerging Agents

Osilodrostat

• Consider osilodrostat for severe hypercortisolism when first-line agents fail or are not tolerated, as it provides rapid cortisol control without hepatotoxicity or hypogonadism concerns. 4, 6

• Use a block-and-replace strategy if iatrogenic adrenal insufficiency develops during osilodrostat therapy, adding hydrocortisone replacement. 6

• Note that osilodrostat is currently FDA-approved only for pituitary Cushing's disease, making this off-label use in ACC. 6

Mifepristone (Glucocorticoid Receptor Antagonist)

• Mifepristone has rapid onset but its use is limited by challenges in monitoring efficacy and safety, as biochemical markers become unreliable. 2

Monitoring Challenges with Mitotane

Critical caveat: In patients on mitotane treatment, serum cortisol and ACTH levels may be falsely altered and thus unreliable for defining cortisol normalization. 2 This makes clinical parameters (improvement in weight, hypertension, glucose metabolism, muscle strength) and urinary free cortisol more valuable for monitoring. 4

Adjunctive Local Therapies

• Discuss liver embolization in patients with hepatic metastases contributing to severe hormone excess, as local therapies can reduce tumor burden and hormone production. 1

Severe/Life-Threatening Hypercortisolism

• Immediate endocrinology consultation is necessary for severe hypercortisolism with life-threatening complications such as severe opportunistic infections. 7

• Hypercortisolism must be controlled before cancer chemotherapy or surgery to reduce therapy-induced complications and mortality. 7

• In rare cases of severe symptomatic hormone excess refractory to medical management, cytoreductive surgery may be indicated after attempts to control symptoms with fast-acting anti-secretory agents and local therapies. 1

Treatment Algorithm

1. Initiate metyrapone immediately for rapid cortisol control
2. Add mitotane concurrently for long-term disease control
3. Monitor clinical response (weight, blood pressure, glucose, muscle strength) and urinary free cortisol
4. If inadequate control: Add ketoconazole or switch to osilodrostat
5. If severe/refractory: Consider local therapies (embolization) or cytoreductive surgery
6. Throughout treatment: Provide glucocorticoid replacement if adrenal insufficiency develops

Common Pitfalls to Avoid

• Do not rely on serum cortisol/ACTH levels for monitoring in patients on mitotane. 2
• Do not use mitotane monotherapy for acute control—always combine with fast-acting agents. 1, 3
• Do not forget glucocorticoid replacement if medical therapy induces adrenal insufficiency. 6
• Do not delay treatment in severe cases—hypercortisolism control is as important as cancer treatment for survival. 7, 2