This protocol addresses patients with Cushing's disease whose cortisol remains persistently elevated despite prior treatment — cortisol has not normalized at 2–3 months on maximum tolerated doses of first-line therapy, and urinary free cortisol (UFC) has not reached target.
Initial management may have included repeat transsphenoidal surgery (when tumor was evident on MRI), single-agent adrenal steroidogenesis inhibitor therapy (ketoconazole, osilodrostat, or metyrapone), pituitary-directed agents such as cabergoline or pasireotide when residual tumor was present, or radiation therapy for aggressive or unresectable disease. Escalation is warranted when urinary free cortisol remains elevated and has not normalized on maximum tolerated doses at the 2–3 month mark.
If cortisol does not normalize but is reduced and/or there is some clinical improvement, combination therapy can be considered.
Many experts consider combining ketoconazole with metyrapone or potentially ketoconazole with osilodrostat to maximize adrenal blockade when monotherapy is not effective or to allow lower doses of both drugs.
Ketoconazole plus cabergoline or pasireotide, and pasireotide plus cabergoline may be rational combinations if there is visible tumor present.
Other combinations that may be used include triplets of cabergoline, pasireotide, plus ketoconazole, and ketoconazole, metyrapone, plus mitotane.
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