What is the optimal medical therapy for a patient with recurrent ACTH‑dependent Cushing disease after two pituitary surgeries, a negative postoperative MRI, and a persistently positive dexamethasone suppression test?

Medical Management for Recurrent Cushing Disease After Two Failed Surgeries with Negative MRI

For this patient with biochemically confirmed recurrent Cushing disease (positive DST) after two pituitary surgeries and a negative MRI, initiate medical therapy with osilodrostat as first-line treatment, given its superior efficacy in normalizing urinary free cortisol compared to other agents. 1, 2, 3

Initial Treatment Approach

First-Line Medical Therapy: Osilodrostat

• Osilodrostat is FDA-approved specifically for Cushing disease patients who are not surgical candidates or have persistent/recurrent disease after surgery 3
• Start at 2 mg twice daily and titrate up to 7 mg twice daily (maximum 30 mg twice daily) based on urinary free cortisol normalization 4
• Osilodrostat demonstrates the highest efficacy among steroidogenesis inhibitors for achieving UFC normalization in prospective trials 1
• This agent works within hours by blocking 11β-hydroxylase, the final step in cortisol synthesis 2

Alternative First-Line Options

If osilodrostat is unavailable or not tolerated:

• Ketoconazole 400-1200 mg/day achieves UFC normalization in approximately 65% of patients initially, though 15-25% experience escape phenomenon 4
• Metyrapone 500 mg/day to 6 g/day shows approximately 70% UFC normalization in retrospective studies 1, 4
• Both ketoconazole and metyrapone work within days to hours respectively 2

When to Consider Repeat Surgery Despite Negative MRI

Reoperation may still be appropriate in highly selected cases even without visible tumor on MRI 1:

• If an experienced surgeon at a high-volume pituitary center considers it feasible AND positive ACTH-staining adenoma pathology or central ACTH gradient on IPSS was documented at initial operation 1
• Remission rates after reoperation range from 37-88%, with better outcomes at specialized centers 1, 2
• However, given this patient has already undergone two surgeries, medical therapy is more appropriate unless new tumor becomes visible 1

Monitoring During Medical Therapy

Biochemical Monitoring

• Measure 24-hour urinary free cortisol every 2-4 weeks during dose titration 1
• Monitor morning ACTH levels, as significant elevations may indicate tumor growth requiring MRI evaluation 1
• Important caveat: ACTH has a short half-life and fluctuates, so elevations do not necessarily reflect tumor growth 1

Imaging Surveillance

• Perform MRI 6-12 months after initiating medical therapy, then repeat every few years 1
• More frequent imaging if ACTH levels progressively increase 1

Safety Monitoring for Osilodrostat

• Monitor for adrenal insufficiency from overtreatment—dose-titrate to achieve cortisol normalization rather than complete blockade 1
• Check QTc interval at baseline and during treatment 1
• Monitor electrolytes for hypokalemia and hypertension from mineralocorticoid precursor accumulation 1

When to Escalate or Modify Treatment

Combination Therapy Indications

Consider combination therapy if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated monotherapy doses 1:

• Ketoconazole plus metyrapone maximizes adrenal blockade when monotherapy is ineffective 2, 4
• Monitor for overlapping toxicities, particularly QTc prolongation 1
• If visible tumor eventually appears on MRI, consider adding cabergoline (tumor-directed agent) to a steroidogenesis inhibitor 2, 4

When to Switch Agents

• Switch to a different medication class if there is clear treatment resistance (not just under-dosing) 1
• If cortisol reduces but does not normalize and there is some clinical improvement, add combination therapy rather than switching 1

Radiation Therapy Consideration

Radiation therapy achieves biochemical remission in approximately two-thirds of patients over several years 1:

• Consider as adjuvant therapy for persistent disease, particularly if medical therapy fails 1, 2
• Medical therapy serves as bridge treatment while awaiting radiation effects, which take months to years 4
• Critical pitfall: Hypopituitarism occurs in 25-50% of patients after radiation and increases over time 2

Bilateral Adrenalectomy as Last Resort

Reserve bilateral adrenalectomy for when medical therapy fails to control severe hypercortisolism 2:

• Provides immediate control of cortisol excess 2
• Results in long-term clinical improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients 2
• Major drawback: Requires lifelong glucocorticoid and mineralocorticoid replacement 2

Long-Term Surveillance Requirements

Lifetime follow-up is essential as recurrence can occur up to 15 years after apparent control 4, 5:

• Annual late-night salivary cortisol (LNSC) testing is the most sensitive test for detecting recurrence 1, 4, 5
• LNSC becomes abnormal before DST and UFC 1, 5
• Perform semi-annual clinical examination and 24-hour UFC for at least 2 years, then annual evaluation for life 4

Critical Pitfalls to Avoid

• Do not misinterpret insufficient disease control from under-dosing as treatment resistance—ensure maximum tolerated doses before declaring treatment failure 1
• If tumor size progressively increases on imaging, suspend medical therapy and reassess management, as this may indicate aggressive disease behavior 1
• Never perform surveillance testing while patient is on exogenous glucocorticoids, as these suppress ACTH and endogenous cortisol, rendering results uninterpretable 5
• Do not rely on single LNSC measurements due to wide intra-individual variability—serial testing is required 4, 5