What is the best management approach for Cushing's disease?

Management of Cushing's Disease

The best management approach for Cushing's disease is selective transsphenoidal adenomectomy as first-line treatment, performed by an experienced pituitary surgeon. 1

First-Line Treatment: Surgical Approach

• Selective adenomectomy via transsphenoidal approach is the treatment of choice, with the goal of removing the ACTH-secreting adenoma while preserving normal pituitary tissue 1
• Surgery should be performed by an experienced surgeon specializing in pituitary surgery, as surgeon experience is a significant predictor of success 1
• Early post-operative remission is associated with successful identification of the adenoma during surgery, while long-term remission correlates with younger age, smaller adenoma size, absence of cavernous sinus or dural invasion, and morning serum cortisol <1 μg/dl (<28 nmol/l) after surgery 1

Management Algorithm for Persistent or Recurrent Disease

Second-Line Options:

1. Repeat Transsphenoidal Surgery

   • Consider for patients with persistent or recurrent disease, especially when tumor is visible on MRI 1
   • Early biochemical remission rates of up to 93% have been reported in pediatric patients undergoing repeat surgery 1
   • Surgical failure is associated with lack of identifiable pituitary adenoma, clinical severity, and presence of major depression 2

2. Radiotherapy

   • Indicated for recurrent disease not amenable to curative surgery 1
   • Options include stereotactic radiotherapy, fractionated proton beam therapy, and gamma knife radiosurgery 1
   • For fractionated treatment, a total dose of 45 Gy in 25 fractions over 35 days is typically effective 1
   • Radiotherapy is more rapidly effective in children than adults, often initiated 2-4 weeks after unsuccessful surgery 1
   • Remission rates after radiation therapy reach approximately 85% after a considerable latency period 3

3. Medical Therapy

   • Used to reduce cortisol burden while awaiting definitive surgery or the effect of radiotherapy 1, 4
   • Key options include:
     • Metyrapone or ketoconazole as adrenal steroidogenesis inhibitors 1, 4
     • Ketoconazole shows biochemical control in approximately 63% of patients as second-line treatment 5
     • Pasireotide (SIGNIFOR LAR) is indicated for patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative 6
   • Medical therapy requires careful monitoring for adverse effects:
     • Ketoconazole: hepatotoxicity (10-20% of patients), gastrointestinal disturbances, adrenal insufficiency 1
     • Metyrapone: hirsutism, dizziness, arthralgia, hypokalemia, nausea 4
     • Pasireotide: requires baseline evaluations of fasting plasma glucose, HbA1c, liver tests, ECG, serum potassium and magnesium levels 6

4. Bilateral Adrenalectomy

   • Consider for patients with severe refractory disease or life-threatening emergencies 4
   • Provides definitive control of hypercortisolism but requires lifelong adrenal hormone replacement 3
   • Risk of developing Nelson syndrome (estimated 71.2% remain free of Nelson syndrome after 10 years) 2

Long-Term Monitoring and Follow-up

• Lifelong follow-up is essential as recurrence can occur up to 15 years after apparent surgical cure 1, 4
• The estimated cumulative percentage of patients remaining in remission after successful pituitary surgery is 93.7% after 2 years, 80.6% after 5 years, and 74.1% after 10 years 2
• Monitor for development of hypopituitarism following surgery or radiotherapy 1
• Evaluate for growth hormone deficiency 3-6 months postoperatively in patients who have not completed linear growth 1

Important Clinical Considerations

• Cushing's disease is associated with increased mortality, primarily due to cardiovascular complications, and numerous comorbidities including metabolic disorders, skeletal disorders, infections, and neuropsychiatric disturbances 7
• Bilateral inferior petrosal sinus sampling (BIPSS) may help lateralize pituitary ACTH secretion when no lesion is visible on MRI, with predictive value for lateralization of 75-80% 1
• Untreated hypercortisolemia leads to devastating effects, making prompt diagnosis and effective treatment critical 8
• Even after successful treatment, negative physical and psychosocial sequelae of chronic hypercortisolism may persist 7