Will cabergoline be effective as therapy for a patient with recurrent ACTH‑dependent Cushing disease after two pituitary surgeries, negative postoperative MRI, and persistent abnormal dexamethasone‑suppression test?

Cabergoline for Recurrent ACTH-Dependent Cushing Disease After Failed Surgeries

Cabergoline has limited efficacy in Cushing disease and should not be relied upon as primary therapy in this case, though it may be considered as adjunctive treatment if the patient has mild residual hypercortisolism while awaiting definitive therapy. 1

Evidence for Cabergoline Efficacy in Cushing Disease

Limited Biochemical Response

• Preoperative cabergoline showed a significant cortisol decrease in only 25% of patients treated prospectively for 6 weeks, indicating poor overall efficacy. 1
• In a large retrospective multicenter study of 62 patients, only 40% achieved normal urinary free cortisol (UFC) within 12 months on cabergoline monotherapy, and 28% of these initial responders eventually experienced treatment escape or intolerance during long-term follow-up. 2
• Sustained long-term control of hypercortisolism was achieved in only 23% of patients overall, with a median duration of 32.5 months. 2

Role in Mild Disease Only

• Current guidelines recommend cabergoline only for patients with mild Cushing disease, as it is less effective than steroidogenesis inhibitors and has a slower onset of action. 1
• For patients with mild-to-moderate disease and visible residual tumor, cabergoline may be preferred over other agents due to potential for tumor shrinkage, though this benefit must be weighed against its limited efficacy. 1

Preferred Medical Therapy Options for This Patient

First-Line Steroidogenesis Inhibitors

• Osilodrostat or metyrapone should be prioritized as they work within hours to normalize cortisol, whereas ketoconazole works within days—all are more reliable than cabergoline for recurrent disease. 1, 3
• For patients with no visible tumor on MRI (as in this case), ketoconazole, osilodrostat, or metyrapone are the recommended first-line medical therapies. 1

Monitoring Requirements

• UFC should be measured every 2-4 weeks during dose titration to ensure biochemical control. 3
• ACTH levels require concurrent monitoring, with sustained elevations prompting repeat MRI at 6-12 months after initiating therapy and then every few years. 3
• Baseline and periodic ECGs are mandatory to monitor for QTc prolongation with steroidogenesis inhibitors. 3

Clinical Considerations for Cabergoline Use

When Cabergoline Might Be Considered

• Cabergoline may be added to steroidogenesis inhibitors if hypercortisolism is not adequately controlled, particularly if there is visible tumor that might benefit from potential shrinkage effects. 1
• In the retrospective study, 56% of patients on steroidogenesis inhibitors who received cabergoline add-on therapy achieved control during the first year at doses of 1.0 mg/week (range 0.5-3.5 mg). 2

Dosing and Response Patterns

• Complete responders to cabergoline received lower doses (median 1.5 mg/week) compared to non-responders (3.5 mg/week), suggesting that higher doses do not overcome resistance. 2
• No baseline parameter, including UFC or prolactin levels, predicted response to cabergoline, making it difficult to identify which patients will benefit. 2

Critical Pitfalls to Avoid

• Do not use cabergoline as monotherapy in patients with persistent disease after two surgeries and negative MRI, as the likelihood of achieving durable control is only 20-25% at best. 2
• Avoid cabergoline in patients with history of bipolar disorder or impulse control disorders due to dopaminergic side effects. 1
• Do not delay definitive therapy (repeat surgery at an experienced center or radiation therapy) while attempting prolonged trials of cabergoline, as this exposes the patient to ongoing morbidity from hypercortisolism. 1, 3

Alternative Definitive Approaches

Repeat Surgery Consideration

• Repeat transsphenoidal surgery may be considered if an experienced pituitary surgeon at a high-volume center deems it feasible, with remission rates of 37-88% depending on center expertise. 3, 4

Radiation Therapy

• Conventional pituitary radiation achieves biochemical remission in approximately two-thirds of patients over several years and is a viable option when medical therapy fails. 3
• Stereotactic radiosurgery achieves biochemical control in approximately 80% of patients, though hypopituitarism occurs in 25-50% and increases over time. 1, 4

Bilateral Adrenalectomy

• Bilateral adrenalectomy should be reserved only for severe refractory disease or life-threatening emergencies when medical therapy fails to control hypercortisolism. 1, 3